- The synthesis and characterization of tetramic acid derivatives as Mdm2-p53 inhibitors
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We present syntheses, prediction of tautomer forms and activities of the second generation of the Mdm2-p53 inhibitors that are based on the tetramic acid scaffold. The inhibitors do not contain 6-chloroindole. Binding of these compounds to Mdm2 was checked by two orthogonal methods: the fluorescence polarization and the 1H-15N HSQC NMR titration experiments. We discovered that the 3-phenylthio-substituted tetramic acid derivatives exist in solution solely in their enol forms which is in contrast to the similar 3-aliphatic substituted derivatives. The inhibitory (Ki) and dissociation (KD) constants are in low micromolar ranges with the best binding compound 9a having KD = 2.9 μM. Furthermore, our data show that the compounds indeed bind to the p53-binding pocket of Mdm2 and do not cause dimerization of Mdm2. The current work provides solid base for further rational design of the Mdm2/p53 inhibitors.
- Muszak, Damian,?abuzek, Beata,Brela, Mateusz Z.,Twarda-Clapa, Aleksandra,Czub, Miroslawa,Musielak, Bogdan,Surmiak, Ewa,Holak, Tad A.
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- HEXANE-SOLUBLE COMPLEXES OF ALKYL- AND ALKENYL-SODIUM COMPOUNDS WITH MAGNESIUM ALKOXIDES
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Unsolvated alkylsodium compounds are solubilized in hexane or methylcyclohexane by complexation with magnesium 2-ethoxyethoxide.The soluble species appear to have well defined stoichiometries, characterized by the Na/Mg ratio.Thus butylsodium forms 2/1 complex which is of moderate thermal stability, but if sufficient magnesium alkoxide is added to the 2/1 complex to make the Na/Mg ratio 1/1, than the complex becomes thermally very stable.Both of the BuNa complexes exhibit normal organometallic reactivity toward CO2, but with benzophenone the main product is the reduction rather than the addition product.The pronounced reducing ability is also manifested by the reduction of transition metal salts to either the matallic state (e.g.AgNO3, CoCl2) or to a lower valency state (e.g.TiCl4).The BuNa complexes react very rapidly with potassium metal and undergo sodium metal displacement. Alkenylsodiums derived by metalation of olefins may also form soluble complexes with magnesium 2-ethoxyethoxide.
- Screttas, Constantinos G.,Micha-Screttas, Maria
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- Leishmanicidal activities of novel synthetic furoxan and benzofuroxan derivatives
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A novel series of furoxan (1,2,5-oxadiazole 2-oxide) (compounds 3, 4a and -b, 13a and -b, and 14a to -f) and benzofuroxan (benzo[c][1,2,5]oxadiazole 1-oxide) (compounds 7 and 8a to -c) derivatives were synthesized, characterized, and evaluated for in vitro activity against promastigote and intracellular amastigote forms of Leishmania amazonensis. The furoxan derivatives exhibited the ability to generate nitric oxide at different levels (7.8% to 27.4%). The benzofuroxan derivative 8a was able to increase nitrite production in medium supernatant from murine macrophages infected with L. amazonensis at 0.75 mM after 48 h. Furoxan and benzofuroxan derivatives showed remarkable leishmanicidal activity against both promastigote and intracellular amastigote forms. Compounds 8a, 14a and -b, and 14d exerted selective leishmanicidal activities superior to those of amphotericin B and pentamidine. In vitro studies at pH 5.4 reveal that compound 8a is stable until 8 h and that compound 14a behaves as a prodrug, releasing the active aldehyde 13a. These compounds have emerged as promising novel drug candidates for the treatment of leishmaniasis. Copyright
- Dutra, Luiz Ant?nio,De Almeida, Letícia,Passalacqua, Thais G.,Reis, Juliana Santana,Torres, Fabio A. E.,Martinez, Isabel,Peccinini, Rosangela Gon?alves,Chin, Chung Man,Chegaev, Konstantin,Guglielmo, Stefano,Fruttero, Roberta,Graminha, Marcia A. S.,Dos Santos, Jean Leandro
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- Arenediazothioalkanoic (Arylazothioalkanoic) acids by coupling of arenediazonium compounds with 2-Mercaptoalkanoic acids
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The title compounds–arenediazothioethanoic acids and 2-arenediazothiopropanoic acids–have been synthesized by the coupling of arenediazonium phosphates with 2-mercaptoacetic or 2-mercaptopropanoic acid in aqueous media at pH ~ 4. Included are hitherto unreported benzenediazothioethanoic acid and 2-benzenediazothiopropanoic acid prepared in pure form, as well as a number of mostly para ring-substituted examples. Mass spectral fragmentation patterns of selected title compounds are discussed, along with a brief preliminary account of their Z/E-isomerization and thermal stabilities.
- Buglass, Alan J.,Datta, Mrityunjoy
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- 3-Thiolated 2-azetidinones: Synthesis and in vitro antibacterial and antifungal activities
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A series of 3-thiolated β-lactams were synthesized by [2+2] ketene-imine cycloaddition reaction from S-substituted mercaptoacetic acids and Schiff bases. Then, some of the 3-methylthio β-lactams were converted to 3-(methylsulfinyl) β-lactams and 3-(methylsulfonyl) β-lactams using m-CPBA under different reaction conditions. All the compounds were characterized by spectral data and elemental analyses and were evaluated for their in vitro antibacterial and antifungal activities against pathogenic strains including Staphylococcus aureus (Methicillin resistant strain). The preliminary screening results indicated that some of these compounds demonstrated moderate to very good antibacterial and antifungal activities.
- Zarei, Maaroof,Mohamadzadeh, Masoud
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- Design and synthesis of furoxan-based nitric oxide-releasing glucocorticoid derivatives with potent anti-inflammatory activity and improved safety
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A series of furoxan-based nitric oxide-releasing glucocorticoid derivatives was synthesized. The pharmacological assays indicated that three compounds, including I4, I5, and I6, had anti-inflammatory activity. Furthermore compared with the leading compound hydrocortisone the safety of I6 was greatly improved. Due to releasing NO in vivo the side effects of glucocorticoids, including hypertension and osteoporosis, were effectively avoided.
- Fang, Lei,Zhang, Yihua,Lehmann, Jochen,Wang, You,Ji, Hui,Ding, Dayong
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- Novel NO-releasing scopoletin derivatives induce cell death via mitochondrial apoptosis pathway and cell cycle arrest
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A series of phenylsulfonyfuroxan-based NO-releasing scopoletin derivatives were designed and synthesized in the study. All target compounds showed significantly improved antiproliferative activity against four cancer cell lines (MDA-MB-231, MCF-7, HepG2 and A459) and lower cytotoxicity toward normal liver LO2 cells. Derivative 47 concentration-dependently inhibited the colony formation of MDA-MB-231 cells. NO-releasing assessment indicated that the intracellular NO level was almost positively correlated with the antiproliferative ability. Compound 47, which released the highest amounts of NO, showed the best potency (IC50 = 1.23 μM) against MDA-MB-231 cells. Mechanism research revealed for the first time that 47 blocked the proliferation of MDA-MB-231 cells by activating mitochondrial apoptosis pathway and arresting cell cycle at G2/M phase. Taken together, as a novel scopoletin derivative, 47 exhibited excellent inhibitory effects against malignant cancer cells and lower toxicity on normal cells. Thus, an in-depth evaluation of 47 to explore its complete therapeutic potential for cancer treatment is warranted.
- Chen, Cheng,Chen, Li,Lei, Zhichao,Li, Na,Shi, Zhixian,Sun, Jianbo,Wang, Yujin
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- Antiproliferative chromone derivatives induce K562 cell death through endogenous and exogenous pathways
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A series of furoxan derivatives of chromone were prepared. The antiproliferative activities were tested against five cancer cell lines HepG2, MCF-7, HCT-116, B16, and K562, and two normal human cell lines L-02 and PBMCs. Among them, compound 15a exhibited the most potent antiproliferative activity. It was also found 15a produced more than 8 μM of NO at the peak time of 45 min by Griess assay. Generally, antiproliferative activity is positively related to NO release to some extent. Further in-depth studies on apoptosis-related mechanisms showed that 15a caused S-phase cell cycle arrest in a concentration-dependent manner and induced apoptosis significantly through mitochondria-related pathways. Human apoptosis protein array assay also demonstrated 15a increased the expression levels of pro-apoptotic Bax, Bad, HtrA2 and Trail R2/DR5. The expression of catalase and cell cycle blocker claspin were similarly up-regulated. In balance, 15a induced K562 cells death through both endogenous and exogenous pathways.
- Cao, Hao,Hua, Huiming,Huang, Xiaofang,Jiao, Runwei,Li, Dahong,Li, Haonan,Li, Zhanlin,Liu, Weiwei,Xu, Fanxing,Zang, Linghe
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- Oxidation of Organic Sulfides by Permanganate Ion
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The current literature on the oxidation of sulfides by permanganate contains a suggestion that the reaction mechanism involves an electrophilic oxygen transfer in an SN2-like mechanism.Contrary to this assumption, it is argued that the experimental facts obtained from a study of the oxidation of (arylthio)acetic acids can more reasonably be accommodated in a mechanism that is initiated by the formation of a coordinate covalent bond utilizing an unshared pair of sulfur electrons and empty manganese d-orbitals.Rearrangement of this intermediate then leads to the formation of sulfoxide and manganate(V) ion.
- Lee, Donald G.,Chen, Tao
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- Design, synthesis and apoptosis-related antiproliferative activities of chelidonine derivatives
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To get chelidonine derivatives with enhanced antiproliferative activity and selectivity, a series of nitric oxide donating derivatives (10a-f and 11a-j) were designed, synthesized and biologically evaluated. Compared with chelidonine, these compounds exhibited lower IC50 values against human hepatoma cells HepG2, breast cancer cells MCF-7, colon cancer cells HCT-116, as well as leukemia cells K562. Compound 11j displayed the strongest antiproliferative activity with IC50 values of 3.91, 6.90, 4.36 and 1.12 μM against the above four cells, respectively. Nevertheless, it showed an IC50 value >40 μM against human peripheral blood mononuclear cells (PBMCs), which demonstrated high selectivity between normal and cancer blood cells. In further mechanism studies, 11j showed the capability to induce K562 cells apoptosis, S phase cell cycle arrest and mitochondrial membrane potential disorder. Besides, 11j was found to be effective in promoting the expression of proapoptotic protein Bad and suppressing the expression of anti-apoptotic proteins Bcl-xL, catalase, survivin, claspin and clusterin.
- Cheng, Keguang,Gao, Xiang,Hu, Xu,Hua, Huiming,Huang, Xueyan,Li, Dahong,Li, Haonan,Li, Zhanlin,Liu, Lilin,Xu, Fanxing
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- Synthesis and biological activity of furoxan derivatives against Mycobacterium tuberculosis
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Tuberculosis (TB) remains a serious health problem responsible to cause millions of deaths annually. The scenario becomes alarming when it is evaluated that the number of new drugs does not increase proportionally to the emergence of resistance to the current therapy. Furoxan derivatives, known as nitric oxide (NO) donors, have been described to exhibit antitubercular activity. Herein, a novel series of hybrid furoxan derivatives (1,2,5-oxadiazole 2-N-oxide) (compounds 4a-c, 8a-c and 14a-c) were designed, synthesized and evaluated in?vitro against Mycobacterium tuberculosis (MTB) H37Rv (ATCC 27294) and a clinical isolate MDR-TB strain. The furoxan derivatives have exhibited MIC90values ranging from 1.03 to 62?μM (H37Rv) and 7.0–50.0?μM (MDR-TB). For the most active compounds (8c, 14a, 14b and 14c) the selectivity index ranged from 3.78 to 52.74 (MRC-5?cells) and 1.25–34.78 (J774A.1?cells). In addition, it was characterized for those compounds logPo/wvalues between 2.1 and 2.9. All compounds were able to release NO at levels ranging from 0.16 to 44.23%. Among the series, the phenylsulfonyl furoxan derivatives (compounds 14a-c) were the best NO-donor with the lowest MIC90values. The most active compound (14c) was also stable at different pHs (5.0 and 7.4). In conclusion, furoxan derivatives were identified as new promising compounds useful to treat tuberculosis.
- Fernandes, Guilherme Felipe dos Santos,de Souza, Paula Carolina,Marino, Leonardo Biancolino,Chegaev, Konstantin,Guglielmo, Stefano,Lazzarato, Loretta,Fruttero, Roberta,Chung, Man Chin,Pavan, Fernando Rogério,dos Santos, Jean Leandro
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- Nitric oxide-donating derivatives of hederacolchiside A1: Synthesis and biological evaluation in vitro and in vivo as potential anticancer agents
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A series of nitric oxide (NO) donating derivatives of hederacolchiside A1bearing triterpenoid saponin motif were designed, synthesized and evaluated for their anticancer activity. All of the tested furoxan-based NO releasing compounds showed significant proliferation inhibitory activities. Especially compound 6a exhibited strong cytotoxicity (IC50= 1.6–6.5 μM) against four human tumor cell lines (SMMC-7721, NCI-H460, U251, HCT-116) in vitro and the highest level of NO releasing. Furthermore, compound 6a was revealed low acute toxicity to mice and weak haemolytic activity with potent tumor growth inhibition against mice H22 hepatocellular cells in vivo (51.5%).
- Fang, Yuanying,Wang, Rikang,He, Mingzhen,Huang, Hesong,Wang, Qi,Yang, Zunhua,Li, Yan,Yang, Shilin,Jin, Yi
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- KINETICS AND MECHANISM OF OXIDATION OF (ARYLTHIO)ACETIC ACIDS BY PYRIDINIUM HYDROBROMIDE PERBROMIDE
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Oxidation of several monosubstituted (phenylthio)acetic acids (PTAA) by pyridinium hydrobromide perbromide (PHPB) was studied in aqueous acetic acid.The reaction is first order with respect to PHPB.Michaelis-Menten type kinetics are observed with respect to (arylthio)acetic acid.The effect of solvent composition indicates that the transition state is more polar than the reactants.The formation constants of the intermediate substrate-PHPB complexes and the rates of their decomposition were determined at different temperatures.The rates of oxidation of para and meta-substituted (phenylthio)acetic acids were correlated with Hammett's substituent constants.The ρ value is -1.60 at 35 deg c.The rates of oxidation of ortho substituted compounds are correlated with Charton's triparametric equation.A mechanism involving the decomposition of the intermediate complex in the slow rate-determining step affording a sulphonium ion which hydrolyses in a subsequent fast step to the sulphoxide is proposed.
- Karunakaran, K.,Elango, K. P.
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- Scutellarin derivatives as apoptosis inducers: Design, synthesis and biological evaluation
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To explore novel antitumor agents with high efficiency and low toxicity, a series of NO-donating scutellarin derivatives (14–17) were synthesized and the antiproliferative activities against MCF-7, HCT-116, PC-3 and HepG2 cancer cell lines were assessed. Among them, compound 14b was the strongest with IC50 values of 2.96?μM, 7.25?μM, 0.09?μM and 0.50?μM, respectively, and displayed low toxicity against normal human liver L-O2 cells with an IC50 of 47.96?μM, showing good selectivity between normal and malignant liver cells. Moreover, NO releasing ability of the derivatives has been studied. Mechanism studies of the most promising compounds 14b and 15a were carried out. The results indicated that 14b and 15a could induce apoptosis, cell cycle arrest at the S phase and led to mitochondrial dysfunction in the HepG2 and PC-3?cell lines, respectively. Furthermore, Human Apoptosis Protein Array kit assay demonstrated that 14b could induce apoptosis through down-regulating the levels of procaspase-3 and inhibiting the expression of survivin, c-IAP1, HSP27, HSP60, HSP70, HO-1/HMOX1/HSP32 and HO-2/HMOX2 in HepG2 cell line. These results guaranteed compound 14b to be a drug candidate against liver cancer for further investigation.
- Han, Tong,Li, Jia,Xue, Jingjing,Li, He,Xu, Fanxing,Cheng, Keguang,Li, Dahong,Li, Zhanlin,Gao, Ming,Hua, Huiming
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- Hybrids of phenylsulfonylfuroxan and coumarin as potent antitumor agents
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Sixteen furoxan-based nitric oxide (NO) releasing coumarin derivatives (6a-c, 8a-g, 10a, 13a,b, 15, and 17a,b) were designed, synthesized, and evaluated against the A549, HeLa, A2780, A2780/CDDP, and HUVEC cell lines. Most derivatives displayed potent antiproliferation activities. Among them, 8b exhibited the strongest antiproliferation activity on the four sensitive cell lines mentioned above and three drug resistant tumor cell lines A2780/CDDP, MDA-MB-231/Gem, and SKOV3/CDDP with IC50 values from 14 to 53 nM and from 62 to 140 nM, respectively. Furthermore, 8b inhibited the growth of A2780 in vivo and displayed lower toxicity on nontumorigenesis T29, showing good selectivity against malignant cells in vitro. Preliminary pharmacological studies showed that 8b induces apoptosis, arrests the cell cycle at the G2/M phase in the A2780 cell line, and disrupts the phosphorylation of MEK1 and ERK1. Overall, the NO-releasing capacity and the inhibition of ERK/MAPK pathway signaling may explain the potent antineoplastic activity of these compounds.
- Liu, Ming-Ming,Chen, Xiao-Yu,Huang, Yao-Qing,Feng, Pan,Guo, Ya-Lan,Yang, Gong,Chen, Ying
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- Synthesis and biological activities of 3-substituted analogues of tenuazonic acid
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A series of tenuazonic acid analogues in which the acetyl group was replaced with electron-withdrawing substituents have been synthesized with the aim of obtaining molecules with various bioactivities. Substituents such as cyano, sulfonyl, and amido were introduced at the 3-position of the pyrrolidine-2,4-dione nucleus of tenuazonic acid. 3-Cyano and sulfonyl pyrrolidine-2,4-dione compounds (2 and 6) were prepared via a Dieckmann cyclization as key step. 3-Amido pyrrolidine-2,4-dione compounds (9) were prepared by a microwave-assisted amidation reaction from corresponding 3-carboxylate derivative. The target compounds were evaluated; their herbicidal, fungicidal, and insecticidal activities, and the preliminary bioassay data showed that some 3-cyanopyrrolidine-2,4-diones 2 gave good insecticidal activity, whereas some 3-amido compounds 9 exhibited moderate to strong fungicidal activity against Pythium dissimile at 20 mg/L.
- Liu, Yu-Xiu,Cui, Zhi-Peng,Zhao, Hua-Ping,Li, Yong-Hong,Gu, Yu-Cheng,Wang, Qing-Min
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- Identification of New Nitric Oxide-Donating Peptides with Dual Biofilm Eradication and Antibacterial Activities for Intervention of Device-Related Infections
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Implantable medical device-related infections with biofilms have become a significant challenge in clinics. Based on the potential bacteria biofilm dispersing effect of nitric oxide (NO) and the unique antibacterial activity of antimicrobial peptides (AMP), we synthesized five peptides and selected the most potent one to conjugate its N-terminal with a furoxan moiety to offer a hitherto unknown NO-donating antimicrobial peptide (FOTyr-AMP), which exhibited Staphylococcus aureus and Escherichia coli biofilm dispersion and eradication, and potent antibacterial activities in vitro. In an implanted biofilm infection mice model, topical subcutaneous injection of FOTyr-AMP allowed synergetic eradication of bacterial biofilms and potent antibacterial activity, superior to the antibiotic cephalosporin C. Given the low hemolysis effect, little influence on the blood pressure, and potent in vivo efficacy of FOTyr-AMP, it is clear that subcutaneous administration of FOTyr-AMP could be a promising approach for the intervention of medical device-related biofilm infections with desirable safety.
- Fei, Yue,Wu, Jianbing,An, Hong-Wei,Zhu, Kai,Peng, Bo,Cai, Junquan,Zhang, Yihua,Li, Li-Li,Wang, Hao,Huang, Zhangjian
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- Novel NO-releasing plumbagin derivatives: Design, synthesis and evaluation of antiproliferative activity
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A series of plumbagin/NO donor hybrids were designed, synthesized and evaluated in vitro against triple negative breast cancer (MDA-MB-231), hepatocellular (HepG2) and lung (A549) carcinoma cells. Most furoxan-based plumbagin derivatives exhibited significantly superior potency compared to their parent compound. Noticeably, MDA-MB-231 cells are the most sensitive to these furoxan-based plumbagin derivatives as evidenced by IC50 values ranging from 1.24 to 5.20 μM. Besides, NO released amounts detection of all hybrids suggested that in most cases, the antiproliferative activities were positively correlated with the levels of intracellular NO release in MDA-MB-231 cells. The most active compound (11a) also possessed higher chemical stability at different pHs (6.0, 7.4 and 8.0) than plumbagin. Together, the above promising results warrant the future potential of plumbagin/NO hybrids as the lead compounds against triple negative breast cancer deserving further research.
- Bao, Na,Ou, Jinfeng,Xu, Manyi,Guan, Fuqin,Shi, Wei,Sun, Jianbo,Chen, Li
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- Evaluation of novel paclitaxel-loaded NO-donating polymeric micelles for an improved therapy for gastroenteric tumor
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This study reports the design and synthesis of NO-donating polymer to generate biodegradable polymeric micelle containing paclitaxel (NO/PTX) as a nanomedicine delivery system aimed to enhance the solubility and anti-cancer activity of paclitaxel (PTX). NO/PTX showed greater NO-releasing performance than nitroglycerin, displaying excellent tolerance in KM mice, and exhibited a two-fold stronger antiproliferative activity than PTXin vitroagainst HCT116, SW480, and SGC-7901 cell lines.In vivotumor growth inhibition assay results indicated that NO/PTX displayed lightly stronger activities against tumor growth than PTX at a dose of 10 mg kg?1, while the anti-tumor effect of NO/PTX was significantly improved than that of PTX and Genexol-PM groups at a dose of 15 mg kg?1(the inhibition rate: 67%vs.53% and 41%). In addition, NO/PTX showed an improved area under the plasma concentration-time curve and drug deposition in tumors in comparison to PTX. Wound healing assay and western blot analysis of EMT-related markers suggested that NO/PTX could inhibit the potential of HCT116 migration. Western blot analysis also demonstrated that NO/PTX dampened efflux activity of P-gp and up-regulated apoptosis-related proteins. Overall, these promising results suggested that the synergism between PTX and NO-donating micelles could contribute to the potent anti-cancer activity of NO/PTX.
- Fang, Yuanying,Jin, Yi,Li, Huilan,Li, Xiang,Liu, Ronghua,Tu, Liangxing,Xu, Guoliang,Yang, Zunhua
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- PhSH - (catalytic) KF as an efficient protocol for chemoselective ester O-alkyl cleavage under non-hydrolytic neutral condition
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Methyl esters are chemoselectively deprotected by thiophenol in presence of catalytic amount of KF in dry NMP (1-Methyl-2-pyrrolidinone) under non-hydrolytic neutral condition.
- Nayak, Mrinal K.,Chakraborti, Asit K.
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- Discovery of novel NO-releasing celastrol derivatives with Hsp90 inhibition and cytotoxic activities
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To develop multifunctional drugs, a series of celastrol/NO donor hybrids were designed, synthesized and evaluated. The detection of NO release amounts showed that the more NO of these hybrids released, the more tumor cells were inhibited. 11b, which released the highest level of NO in vitro, exhibited superior potency (IC50 = 0.48 ± 0.06 μM) compared to the other compounds. Further pharmacological studies showed that 11b induced dysregulations of the Hsp90 clients (Akt and Cdk4), apoptosis, and cell cycle arrested at G0/G1 phase against A549 cells. These results suggested that inhibition of Hsp90 and release of NO was synergistic in cancer cells. Overall, the NO-releasing capacity and the inhibition of Hsp90 pathway signaling might explain the potent anti-proliferative activities of these compounds.
- Li, Na,Xu, Manyi,Bao, Na,Shi, Wei,Li, Qixing,Zhang, Xiaowei,Sun, Jianbo,Chen, Li
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- Antiproliferative activity and apoptosis inducing effects of nitric oxide donating derivatives of evodiamine
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The first series of nitric oxide donating derivatives of evodiamine were designed and prepared. NO releasing ability of all target derivatives was evaluated in BGC-823, Bel-7402 and L-02 cells. The cytotoxicity was evaluated against three human tumor cell lines (Bel-7402, A549 and BGC-823) and normal human liver cells L-02. The nitrate derivatives 11a and 11b only exhibited moderate activity and furoxan-based derivatives 13a-c, 14a and 14b showed promising activity. 13c showed good cytotoxic selectivity between tumor and normal liver cells and was further investigated for its apoptotic properties on human hepatocarcinoma Bel-7402 cells. The molecular mode of action revealed that 13c caused cell-cycle arrest at S phase and induced apoptosis in Bel-7402 cells through mitochondria-related caspase-dependent pathways.
- Zhao, Nan,Tian, Kang-Tao,Cheng, Ke-Guang,Han, Tong,Hu, Xu,Li, Da-Hong,Li, Zhan-Lin,Hua, Hui-Ming
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- (Trifluoromethylselenyl)methylchalcogenyl as Emerging Fluorinated Groups: Synthesis under Photoredox Catalysis and Determination of the Lipophilicity
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The synthesis of molecules bearing (trifluoromethylselenyl)methylchalcogenyl groups is described via an efficient two-step strategy based on a metal-free photoredox catalyzed decarboxylative trifluoromethylselenolation with good yields up to 88 %, which raised to 98 % in flow chemistry conditions. The flow methods allowed also to scale up the reaction. The mechanism of this key reaction was studied. The physicochemical characterization of these emerging groups was performed by determining their Hansch–Leo lipophilicity parameters with high values up to 2.24. This reaction was also extended to perfluoroalkylselenolation with yields up to 95 %. Finally, this method was successfully applied to the functionalization of relevant bioactive molecules such as tocopherol or estrone derivatives.
- Grollier, Kevin,De Zordo-Banliat, Arnaud,Bourdreux, Flavien,Pegot, Bruce,Dagousset, Guillaume,Magnier, Emmanuel,Billard, Thierry
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supporting information
p. 6028 - 6033
(2021/03/15)
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- Chromone 3-position nitric oxide donor derivative as well as preparation method and application thereof
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The invention relates to the fields of natural medicines and medicinal chemistry, and relates to a preparation method of a series of chromone 3-position nitric oxide donor derivatives with antitumor activity and a new application of the chromone 3-position nitric oxide donor derivatives in preparation of antitumor medicines. The chromone 3-position nitric oxide donor derivative and the pharmaceutically acceptable salt thereof are shown as a general formula I in the specification. Wherein R and R1 are described in the claims and the specification.
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Paragraph 0017; 0024; 0027
(2021/05/05)
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- Chromone 3-piperazine linked furazan derivative as well as preparation method and application thereof
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The invention relates to the fields of natural medicines and medicinal chemistry, and relates to a preparation method of a series of chromone 3-piperazine linked furazan derivatives with antitumor activity and a new application of the chromone 3-piperazine linked furazan derivatives in preparation of antitumor medicines. The chromone 3-piperazine linked furazan derivative and the pharmaceutically acceptable salt thereof disclosed by the invention are as shown in a general formula I in the specification. Wherein R is described in the claims and the specification.
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Paragraph 0014; 0021; 0024
(2021/05/05)
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- Chromone 2-position nitric oxide donor derivative as well as preparation method and application thereof
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The invention relates to the fields of natural medicines and medicinal chemistry, and relates to a preparation method of a series of chromone 2-position nitric oxide donor derivatives with antitumor activity and a new application of the chromone 2-position nitric oxide donor derivatives in preparation of antitumor medicines. The chromone 2-position nitric oxide donor derivative and the pharmaceutically acceptable salt thereof are shown as a general formula I in the specification. Wherein R and R1 are described in the claims and the specification.
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Paragraph 0021; 0024
(2021/05/05)
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- Chromone 2-piperazine linked furazan derivative as well as preparation method and application thereof
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The invention relates to the fields of natural medicines and medicinal chemistry, and relates to a preparation method of a series of chromone 2-piperazine linked furazan derivatives with antitumor activity and a new application of the chromone 2-piperazine linked furazan derivatives in preparation of antitumor medicines. The chromone 2-piperazine linked furazan derivative and the pharmaceutically acceptable salt thereof disclosed by the invention are as shown in a general formula I in the specification. Wherein R is described in the claims and the specification.
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Paragraph 0014; 0021; 0024
(2021/05/05)
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- Synthesis of and characterization of some Heterocyclic Compounds derived from Thiophenol
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This research work involved preparation of heterogeneous pent lateral cyclic compounds (thiazolidine -4- one, benzothiazole, triazole, 4-oxothiazolidin) using thiophenol as raw materials: Thiophenol was reacted with mono chloroacetic acid in the presence of potassium hydroxide to prepare (sh1) followed by ortho amino aniline results the (sh2). The reaction of thiophenol with ethylchloroacetate afforded (sh3) and the reaction of (sh3) with thiosemicarbazide and 4% NaOH leads to ring closure giving 1,2,4- triazole (sh5). A treatment of thiophenol with hydrazine hydrate to obtain the intermediate (sh6) with aromatic aldehyde synthesized azomethines (sh7- sh9) then treated with mercaptoacetic acid to obtained (sh10-sh12). A treatment of thiophenol with chloroacetyl chloride produced (sh13) compound then treated with hydrazine hydrate to obtain (sh14) compound followed by bromobenzaldehyde synthesized azomethine (sh15) compound then treated with mercaptoacetic acid to obtained (sh16) compound. Characterization results for the prepared compounds using IR spectroscopy, NMR and melting points confirmed their chemical structures.
- AL-Khazraji, Shaima Ibraheem Chyad
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p. 5655 - 5662
(2021/09/11)
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- Discovery of β-carboline-(phenylsulfonyl)furoxan hybrids as potential anti-breast cancer agents
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The cytotoxicity properties of the β-carboline alkaloids have been broadly investigated. However, the potential application of β-carbolines was hindered due to the moderate activity in cancer. In the present study, thirty β-carboline-(phenylsulfonyl)furoxan hybrids (11a–j, 12a–j and 13a–j) were designed and synthesized through esterification and amidation reaction strategy, and their inhibitory activities against the human breast cancer cell lines MCF-7 and MDA-MB-231 were evaluated by CCK-8 assay. Biological evaluation presented that the most promising amide derivative 13h, substituted with p-methoxyphenyl group at position 1, generated high concentration of NO and evidently depressed the MCF-7 (IC50 = 0.89 μM) and MDA-MB-231 (IC50 = 0.62 μM) cells proliferation. Particularly, the wound healing and transwell assays demonstrated that 13h significantly inhibited the migration and invasion of MDA-MB-231cells. Furthermore, the preliminary mechanisms studies indicated that 13h induced G2/M phase arrest and apoptosis possibly causing by ROS accumulation and ROS-mediated DNA damage. Based on these considerations, 13h may be a promising antimetastatic agent for breast cancer, which is noteworthy for further exploration.
- Hu, Xu,Gao, Xiang,Gao, Gang,Wang, Yanbing,Cao, Hao,Li, Dahong,Hua, Huiming
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- A highly stereoselective oxidation and an easy one pot elimination methodology for 3-allyl-3-phenylthio-β-lactams
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A novel, facile, highly efficient and stereoselective protocol for the synthesis of cis-3-allyl-3-phenylsulfinyl-β-lactams and 3-allylidene-β-lactams from cis-3-allyl-3-phenylthio-β-lactams using Selectfluor both as an oxidizing agent and as an eliminating agent with temperature as a control parameter over the reaction outcome has been reported. The methodology is able to conquer the earlier reported shortcomings of long reaction time (24–90 hrs.) and lack of control over product ratio. The synthesized compounds will serve as important synthons for compounds of enhanced biological activity and potency.
- Bari, Shamsher S.,Nagpal, Reshma,Pandey, Suvidha,Thakur, Aarti,Thapar, Renu
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- Oxidation of Primary Alcohols and Aldehydes to Carboxylic Acids via Hydrogen Atom Transfer
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The oxidation of primary alcohols and aldehydes to the corresponding carboxylic acids is a fundamental reaction in organic synthesis. In this paper, we report a new chemoselective process for the oxidation of primary alcohols and aldehydes. This metal-free reaction features a new oxidant, an easy to handle procedure, high isolated yields, and good to excellent functional group tolerance even in the presence of vulnerable secondary alcohols and tert-butanesulfinamides.
- Tan, Wen-Yun,Lu, Yi,Zhao, Jing-Feng,Chen, Wen,Zhang, Hongbin
-
supporting information
p. 6648 - 6653
(2021/09/08)
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- Rhodium-catalyzed Sommelet-Hauser type rearrangement of α-diazoimines: Synthesis of functionalized enamides
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An efficient rhodium catalyzed Sommelet-Hauser type rearrangement of sulfur ylides derived from α-thioesters and N-sulfonyl-1,2,3-triazoles has been successfully accomplished for the synthesis of various functionalized enamides. The developed reaction involves the unprecedented [2,3]-sigmatropic rearrangement of sulfur ylides with the imine motif. Importantly, the method works well with various substituted α-thioesters/-amides/-ketones and substituted N-sulfonyl-1,2,3-triazoles and allows the synthesis of diverse enamide derivatives in good to excellent yields. The reaction was also successfully extended to the one-pot synthesis of enamides from terminal alkynes.
- Anbarasan, Pazhamalai,Ramachandran, Kuppan,Reddy, Angula Chandra Shekar,Reddy, Palagulla Maheswar
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supporting information
p. 5649 - 5652
(2020/06/09)
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- Scopoletin benzene sulfonyl furazan oxynitride derivatives as well as preparation method and application thereof
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The invention belongs to the field of biological medicines, and discloses scopoletin benzene sulfonyl furazan oxynitride derivatives as shown in a formula I, wherein R is selected from H, acetamido and amino, X is selected from -(CH2)n-, and n is an integer of 2-6. Compared with scopoletin, the derivatives have a stronger proliferation inhibition effect on MDA-MB-231, MCF-7, HepG2 and A549 cell strains, the proliferation inhibition effect on tumor cells is remarkably superior to that of scopoletin, and the derivatives are expected to become a new anti-tumor drug. The invention also discloses an application of the derivatives in the preparation of antitumor drugs.
- -
-
Paragraph 0033-0034; 0036
(2020/06/20)
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- Competitive behavior of nitrogen based axial ligands in the oxovanadium(IV)-salen catalyzed sulfoxidation of phenylmercaptoacetic acid
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The sulfoxidation of twelve phenylmercaptoacetic acids (PMAA) by H2O2 catalyzed by three oxovanadium(IV)-salen complexes, having varied substituents on PMAA and salen with regard to their position, size and inductive effect, has been performed spectrophotometrically in 100percent acetonitrile medium. Three nitrogen bases (NB), pyridine (Py), imidazole (ImH) and 1-methylimidazole (MeIm), were used as axial ligands. It has been found that the rate of sulfoxidation is not only tuned by the substituents on PMAA and salen, but it is also varied by the addition of nitrogen bases. The observed order of retardation found among the different nitrogen bases is ImH > MeIm > Py. The rate of reaction decreases with the increase in concentration of the NB axial ligands. The strongly binding ImH shows the least reactivity. Hydroperoxovanadium(V)-salen has been proposed as the sole active oxidizing species. A detailed mechanistic study reveals that the low rate constant values in the presence of the nitrogen base is due to the existence of competition of NB with H2O2 and PMAA during the formation of active species and the coordination of PMAA with active species, respectively. Both electron donating and electron withdrawing substituents on PMAA retard the sulfoxidation rate significantly. The Hammett correlation between the rate constants and substituent constants shows a non-linear concave downward curve which is explained by the existence of two different rate determining steps within the same mechanism; coordination of PMAA with the active species for electron withdrawing substituents and transfer of oxygen to PMAA for electron donating substituents. All the experimental observations are explained by proposing a suitable mechanism.
- Kavitha, C.,Subramaniam, P.
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- Electrophilic Chlorine from Chlorosulfonium Salts: A Highly Chemoselective Reduction of Sulfoxides
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Herein, we describe a selective late-stage deoxygenation of sulfoxides based on a novel application of chlorosulfonium salts and demonstrate a new process using these species generated in situ from sulfoxides as the source of electrophilic chlorine. The use of highly nucleophilic 1,3,5-trimethoxybenzene (TMB) as the reducing agent is described for the first time and applied in the deoxygenation of simple and functionalized sulfoxides. The method is easy to handle, economic, suitable for gram-scale operations, and readily applied for poly-functionalized molecules, as demonstrated with more than 45 examples, including commercial medicines and analogues. We also report the results of competition experiments that define the more reactive sulfoxide and we present a mechanistic proposal based on substrate and product observations.
- Acosta-Guzmán, Paola,Mahecha-Mahecha, Camilo,Gamba-Sánchez, Diego
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supporting information
p. 10348 - 10354
(2020/07/13)
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- NO donor-type large yellow acid derivatives, their preparation method and medical use (by machine translation)
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The present invention relates to the field of pharmaceutical chemistry and drug therapeutics, in particular to NO donor-type large yellow acid derivative and its preparation method and application in pharmacy. The compound has anti-tumor effect, can be used for preparing anti-tumor drug. The invention also relates to a method for preparing such compounds. (by machine translation)
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-
Paragraph 0073; 0076; 0077
(2019/05/04)
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- Furoxan azoxyNO donor type tadine derivative and preparation method thereof (by machine translation)
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The invention discloses a furoxan azoxyNO donor type tadine derivative and a preparation method, and belongs to the technical field of chemical synthesis of medicines: the invention has the following structural formula shown in the general formula. Wherein. In addition, coumaric acid is selected as a connecting base, so that the curative effect; in addition, the compound disclosed by the invention can effectively release NO, and beneficial attempts are made for development of NO donor anti-atherosclerotic drugs in an external mode, and the method has the advantages of effectively improving the curative effect of drugs. 4 - R1 R2 (by machine translation)
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Paragraph 0057; 0059; 0060
(2019/10/01)
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- Quinoline quinine derivative as well as preparation method and application
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The invention discloses a quinoline quinine derivative or pharmaceutically acceptable salt, which is of a structure shown in a general formula Ia or Ib shown in the specification. By combination of structural characteristics, structure-function relationships and pharmacophore characteristics of quinoline quinine and furazan nitric acid, on the basis of a quinoline quinine structure, a furazan nitric acid NO donor is introduced; alcohol amines with different lengths are used as connection chains, so that a novel quinoline quinine derivative with NQO1 inhibition activity is designed and synthesized. Research results show that the compound disclosed by the invention has a strong inhibition effect on proliferation of various cells, and can obviously induce ROS expression of tumor cells to synergistically promote apoptosis or necrosis of the tumors.
- -
-
Paragraph 0046-0049
(2020/09/20)
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- Design and synthesis of novel senkyunolide analogues as neuroprotective agents
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A class of senkyunolide analogues bearing benzofuranone fragment were designed, synthesized and evaluated for their neuroprotective effect in models of oxygen glucose deprivation (OGD) and oxidative stress. All tested compounds showed neuroprotection profile based on the cell viability assay. In particular, derivatives 1f–1i possessing furoxan-based nitric oxide releasing functionality exhibited significant biological activities in OGD models. More importantly, compound 1g containing short linker with furoxan displayed the most potent neuroprotection at the concentration of 100 μM (cell survival up to 145.2%). Besides, 1g also showed the middle level neuroprotective effect in model of oxidative stress.
- Fang, Yuanying,Wang, Rikang,Wang, Qi,Sun, Yongbing,Xie, Saisai,Yang, Zunhua,Li, Min,Jin, Yi,Yang, Shilin
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p. 668 - 672
(2018/01/27)
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- Design, synthesis and biological evaluation of novel furoxan-based coumarin derivatives as antitumor agents
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In order to find new anticancer drugs, a series of novel furoxan-based coumarin derivatives (10a–k) were synthesized and evaluated for their antiproliferative activities in vitro. All compounds displayed more potent inhibition on human cervical cancer HeLa cell proliferation than coumarin-3-carboxylic acid, and compounds 10b, 10c, 10f, 10h, and 10i with IC50 values ranging from 0.88 to 5.95 μM were even stronger than doxorubicin (IC50 = 10.21 μM). The further study showed that compound 10i exerted the highest antiproliferative activity (IC50 = 0.60 μM) against human breast cancer MCF-7 cells, and compound 10f had broader spectrum antiproliferative activity against five cancer cells with IC50 values in the low micromolar range of 1.86–9.85 μM. More interestingly, compound 10f had little effect on normal intestinal epithelial CCD841 cells. Our findings suggest that these novel furoxan-based coumarin derivatives may provide a new framework for the discovery of novel antitumor agents for the intervention of human carcinoma cells.
- Zhang, Zhuo,Bai, Zhi-Wei,Ling, Yong,He, Li-Qin,Huang, Peng,Gu, Hong-Xia,Hu, Rong-Feng
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p. 1198 - 1205
(2018/03/26)
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- Discovery of novel antitumor nitric oxide-donating β-elemene hybrids through inhibiting the PI3K/Akt pathway
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A series of novel furoxan-based NO-donating β-elemene hybrids were designed and synthesized to improve the anticancer efficacy of natural β-elemene. The bioassay results indicated that all of the target compounds exhibited significantly improved antiproliferative activities against three cancer cell lines (SGC-7901, HeLa and U87) compared to parent compound β-elemene. Interestingly, these compounds displayed excellent sensitivity to U87?cells with IC50 values ranging from 173 to 2?nM. Moreover, most compounds produced high levels of NO in?vitro, and the antitumor activity of 11a in U87?cells was markedly attenuated by an NO scavenger (hemoglobin or carboxy-PTIO). Further mechanism studies revealed that 11a caused the G2 phase arrest of the cell cycle and induced apoptosis of U87?cells by preventing the activation of the PI3K/Akt pathway. Moreover, 11a significantly suppressed the tumor growth in H22 liver cancer xenograft mouse model with a tumor inhibitory ratio (TIR) of 64.8%, which was superior to that of β-elemene (TIR, 49.6%) at the same dose of 60?mg/kg. Together, the remarkable biological profiles of these novel NO-donating β-elemene derivatives may make them promising candidates for the intervention of human cancers.
- Chen, Jichao,Wang, Tianyu,Xu, Shengtao,Zhang, Pengfei,Lin, Aijun,Wu, Liang,Yao, Hequan,Xie, Weijia,Zhu, Zheying,Xu, Jinyi
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p. 414 - 423
(2017/05/04)
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- NO donor matrine derivatives, its preparation method and medical use
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The invention relates to the field of medical chemistry and pharmacotherapeutics, and particularly relates to an NO donor type matrine derivative and a preparation method thereof and application in pharmacy. The compounds have an anti-tumor effect and can be used for preparing anti-tumor medicines. The invention also relates to a preparation method of the compounds.
- -
-
Paragraph 0233
(2017/08/08)
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- Nitric oxide donor type coumarin derivatives, preparation methods therefor and medicinal use of nitric oxide donor type coumarin derivatives
-
The invention relates to the fields of pharmacochemistry and pharmacotherapeutics and particularly relates to nitric oxide donor type coumarin derivatives, preparation methods therefor and an application of the nitric oxide donor type coumarin derivatives. The compounds play a role in resisting tumors and can be applied to the preparation of antitumor drugs.
- -
-
Paragraph 0487; 0512; 0513
(2017/09/01)
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- Nitric oxide-releasing derivatives of brefeldin A as potent and highly selective anticancer agents
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A series of NO-donating mono- or diester derivatives of brefeldin A were designed, synthesized and biologically evaluated. Some derivatives exhibited potent antiproliferative activity with low IC50 values. The most potent NO-donating hybrid 13b exhibited stronger cytotoxicity against human prostate cancer PC-3?cells, human colon carcinoma HT-29?cells and human liver cancer HepG-2?cells than BFA with IC50 values of 25?nM, 160?nM and 180?nM, respectively. More importantly, compound 13b showed good selectivity between human normal and tumor liver cells with selectivity index of 33. Additionally, 13b released higher levels of NO in HepG-2?cells than L-02?cells. Further mechanism concerning cellular apoptosis showed that 13b induced apoptosis and S phase cell cycle arrest in HepG-2?cells. Incubation with 13b increased the number of HepG-2?cells with collapsed mitochondrial membrane at low concentrations in dose-dependent manner. In addition, by using the Human Apoptosis Protein Array kit, several apoptosis-related proteins, including HO-1, HO-2 and survivin, were found to be markedly downregulated by 13b in HepG-2?cells. Furthermore, in western blot assay, 13b increased the expression of Bax, Cyt c and caspase 3, and reduced the relative levels of Bcl-2, Bcl-xl and pro-caspase 3 in HepG-2?cells.
- Tian, Kangtao,Xu, Fanxing,Gao, Xiang,Han, Tong,Li, Jia,Pan, Huaqi,Zang, Linghe,Li, Dahong,Li, Zhanlin,Uchita, Takahiro,Gao, Ming,Hua, Huiming
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p. 131 - 143
(2017/05/10)
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- Phenylsulfonylfuroxan NO-donor phenols: Synthesis and multifunctional activities evaluation
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Phenylsulfonyfuroxan nitric oxide (NO)-donor phenols were designed, synthesized and evaluated. The compounds were designed through a symbiotic approach using selected phenols and phenylsulfonylfuroxan NO-donor. The antioxidant activities of the hybrid compounds T2–T6 showed to be good in vivo. Compounds T4 and T6 revealed excellent yeast α-glucosidase inhibitory activity and anti-glycosylation activity. All of the compounds exhibited strong NO releasing activity and significant anti-platelet aggregation activity. The inhibition of platelet aggregation was more than 50% at low concentration (1.5?μM) and 95% at higher concentration (15?μM and 150?μM). The vasodilatation experiment demonstrated that the six compounds under test exhibited definite vasodilation activity (pIC50 ranged from 5.698 to 6.383), especially compound T6 (pIC50 was 6.383) which was similar to sodium nitroprusside (pIC50 was 6.786). Both anticoagulant and vasodilatation effects were correlated with their NO releasing activities. These hybrid phenylsulfonyfuroxan-based NO-donor phenols offer a multifunctional prodrug design concept for the development of therapeutic or preventive agents for metabolic syndrome.
- Xie, Yundong,Yang, Yaping,Li, Sen,Xu, Yanhong,Lu, Wenfang,Chen, Zizhang,Yang, Guangde,Li, Yiping,Cao, Yongxiao,Bian, Xiaoli
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p. 4407 - 4413
(2017/07/22)
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- Furazan type NO (nitric oxide) donor scutellarin derivative with anti-tumor activity and preparation method and application thereof
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The invention relates to the field of natural medicines and medicine chemistry, in particular to a furazan type NO (nitric oxide) donor scutellarin derivative with anti-tumor activity and a pharmaceutically acceptable salt thereof, and in particular to a furazan type NO donor-substituted scutellarin derivative with a piperazine ringfatty chain link arm on saccharide carboxyl sites and a preparation method and application thereof in preparing anti-tumor medicines. The structures of the furazan type NO donor scutellarin derivative with anti-tumor activity and the pharmaceutically acceptable salt thereof are shown in the formula I, wherein R and n R1 are described in the right claim and instructiondescription. The formula I is shown in the descriptionattached figure.
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-
Page/Page column 3; 5; 7; 8
(2017/08/31)
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- Preparation method and uses of 4-site furazan NO-donating derivatives of brefeldin A
-
The invention relates to the field of medicinal chemistry, and relates to derivatives obtained by modification on 4-site of brefeldin A. Particularly, the invention relates to 4-site furazan NO donor substituted brefeldin A derivatives which have antineoplastic activity, and uses of the derivatives in preparing antineoplastic drugs. The brefeldin A derivatives are as shown by a general formula I or II, shown in the description, wherein m and n are respectively integers within the range of 1 to 8.
- -
-
Paragraph 0014; 0042
(2017/08/30)
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- Gebre Pfund cephalosporin A of 4, 7 - bit double-furazane NO donor substituted derivative and its preparation and use (by machine translation)
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The invention relates to the field of pharmaceutical chemistry, relates to the laying of mines Pfund cephalosporin A of 4, 7 - bit at the same time modified derivatives. In particular relates to 4, 7 - bit fufu our kind NO donor substituted BRET Pfund cephalosporin A derivative and its preparation method and in use in the preparation of antineoplastic. The minelaying Pfund cephalosporin A derivatives such as formula I or II is shown, wherein m, n are respectively 1 - 8 of the integer. (by machine translation)
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-
Paragraph 0015; 0034
(2017/08/30)
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- Brefeldin A derivatives, and preparation method and uses thereof
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The invention relates to the field of medicinal chemistry, and relates to derivatives obtained by modification on 7-site of brefeldin A. Particularly, the invention relates to 7-site furazan NO donor substituted brefeldin A derivatives, and a preparation method of the derivatives and uses of the derivatives in preparing antineoplastic drugs. The brefeldin A derivatives are as shown by a general formula I or II, shown in the description, wherein m and n are respectively integers within the range of 1 to 8.
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-
Paragraph 0038; 0040
(2017/08/30)
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- Furazan NO-donating scutellarin derivative with anti-tumor activity, and preparation method and application thereof
-
The invention relates to the field of natural medicine and medicinal chemistry, in particular to a furazan NO-donating scutellarin derivative with anti-tumor activity, and a pharmaceutically acceptable salt thereof. The invention specifically relates to the furazan NO-donating substituted scutellarin derivatives with an aliphatic chain connecting arm on uronic acid base loci, and application for preparing anti-tumor drugs. The structures of the furazan NO-donating scutellarin derivative and the pharmaceutically acceptable salt thereof are shown in the following general formula I, wherein R and R1 are disclosed in claims and specifications. The formula is shown in the specification.
- -
-
Paragraph 0035; 0036; 0037
(2017/07/19)
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- Electrophilic and nucleophilic pathways in ligand oxide mediated reactions of phenylsulfinylacetic acids with oxo(salen)chromium(V) complexes
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The mechanism of oxidative decarboxylation of phenylsulfinylacetic acids (PSAA) by oxo(salen)Cr(V)+ ion in the presence of ligand oxides has been studied spectrophotometrically in acetonitrile medium. Addition of ligand oxides (LO) causes a red shift in the λmax values of oxo(salen) complexes and an increase in absorbance with the concentration of LO along with a clear isobestic point. The reaction shows first-order dependence on oxo(salen)-chromium(V)+ ion and fractional-order dependence on PSAA and ligand oxide. Michaelis-Menten kinetics without kinetic saturation was observed for the reaction. The order of reactivity among the ligand oxides is picoline N-oxide > pyridine N-oxide > triphenylphosphine oxide. The low catalytic activity of TPPO was rationalized. Both electron-withdrawing and electron-donating substituents in the phenyl ring of PSAA facilitate the reaction rate. The Hammett plots are non-linear upward type with negative ρ value for electron-donating substituents, (ρ- = -0.740 to -4.10) and positive ρ value for electron-withdrawing substituents (ρ+ = +0.057 to +0.886). Non-linear Hammett plot is explained by two possible mechanistic scenarios, electrophilic and nucleophilic attack of oxo(salen)chromium(V)+-LO adduct on PSAA as the substituent in PSAA is changed from electron-donating to electron-withdrawing. The linearity in the log k vs. Eox plot confirms single-electron transfer (SET) mechanism for PSAAs with electron-donating substituents.
- Subramaniam,Sugirtha Devi,Anbarasan
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p. 164 - 173
(2016/06/06)
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- Synthesis, biological activity, and apoptotic properties of NO-donor/enmein-type ent-kauranoid hybrids
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Herein, we reported on a series of synthetic nitric oxide-releasing enmein-type diterpenoid hybrids (9a–i). All the target compounds showed potent antibacterial activity against selected Gram-positive bacteria S. aureus and B. subtilis. The antiproliferative activity against human tumor K562, MGC-803, CaEs-17 and Bel-7402 cells, and human normal liver cells L-02 was tested and the structure activity relationships (SARs) were also concluded. Compounds 9b and 9d showed the best activity against S. aureus and B. subtilis with the same minimal inhibitory concentrations (MICs) of 4 and 2 μg/mL, respectively. The derivative 9f displayed IC50 values of 1.68, 1.11, 3.60 and 0.72 μM against the four cancer cell lines above and 18.80 μM against normal liver cells L-02; meanwhile, 9f also released a high level of NO at the time point of 60 min of 22.24 μmol/L. Furthermore, it was also found that 9f induced apoptosis via the mitochondria-related pathway and arrested cell cycle of Bel-7402 cells at S phase. These findings might be important to explore new chemical entities for the main causes of in-hospital mortality of S. aureus infection, combined with a solid tumor.
- Li, Dahong,Hu, Xu,Han, Tong,Xu, Shengtao,Zhou, Tingting,Wang, Zhenzhong,Cheng, Keguang,Li, Zhanlin,Hua, Huiming,Xiao, Wei,Xu, Jinyi
-
-
- NO-releasing enmein-type diterpenoid derivatives with selective antiproliferative activity and effects on apoptosis-related proteins
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: A series of nine enmein-type ent-kaurane diterpenoid and furoxan-based nitric oxide (NO) donor hybrids (10a-i) were designed and synthesized from commercially available oridonin (1). These hybrids were evaluated for their antiproliferative activity against Bel-7402, K562, MGC-803, and CaEs-17 human cancer cell lines and L-02 normal liver cells. The antiproliferative activity against tumor cells was stronger than the lead compound 1 and parent molecule 9 in most cases. Especially, compound 10f showed the strongest activity against human hepatocarcinoma Bel-7402 cell line with an IC50 of 0.81 μM and could also release 33.7 μmol/L NO at the time point of 60 min. Compounds 10a-i also showed cytotoxic selectivity between tumor and normal liver cells with IC50 ranging from 22.1 to 33.9 μM. Furthermore, the apoptotic properties on Bel-7402 cells revealed that 10f could induce S phase cell cycle arrest and apoptosis at low micromolar concentrations. The effects of 10f on apoptosis-related proteins were also investigated. The potent antiproliferative activities and mechanistic studies warrant further preclinical investigations.
- Li, Dahong,Hu, Xu,Han, Tong,Liao, Jie,Xiao, Wei,Xu, Shengtao,Li, Zhanlin,Wang, Zhenzhong,Hua, Huiming,Xu, Jinyi
-
-
- Novel nitric oxide-releasing spirolactone-type diterpenoid derivatives with in vitro synergistic anticancer activity as apoptosis inducer
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Herein, we reported the cytotoxicity, NO-releasing property, and apoptosis induced ability of two series of novel nitric oxide-releasing spirolactone-type diterpenoid derivatives (10a–f and 15a–f). All the title compounds were more potent than oridonin (7) and parent compound (9 or 14) against human tumor Bel-7402, K562, MGC-803 and CaEs-17 cells. SARs were concluded based on above data. Compound 15d exhibited the strongest antiproliferative activity with the IC50of 0.86, 1.74, 1.16 and 3.75?μM, respectively, and could produce high level (above 25?μM) of NO at the time point of 60?min. Further mechanism evaluation showed that 15d could induce S phase cell cycle arrest and apoptosis at low micromolar concentrations in Bel-7402 cells via mitochondria-related pathways. It was expected that the remarkable biological profile of the synthetic NO-releasing spirolactone-type diterpenoid analogs make them possible as promising candidates for the development of anticancer agents.
- Li, Dahong,Han, Tong,Tian, Kangtao,Tang, Shuang,Xu, Shengtao,Hu, Xu,Wang, Lei,Li, Zhanlin,Hua, Huiming,Xu, Jinyi
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p. 4191 - 4196
(2016/08/17)
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- Importance of ground state stabilization in the oxovanadium(IV)-salophen mediated reactions of phenylsulfinylacetic acids by hydrogen peroxide – Non-linear Hammett correlation
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A systematic study on the oxidative decarboxylation of a series of phenylsulfinylacetic acids (PSAA) by hydrogen peroxide with four oxovanadium(IV)-salophen catalysts in 100% acetonitrile medium is presented. The hydroperoxovanadium(V)-salophen generated from the reaction mixture is identified as the bonafide active oxidizing species. Introduction of electron donating groups (EDG) in the oxovanadium(IV)-salophen catalyst and electron withdrawing groups (EWG) in PSAA enhances the reactivity, whereas EWG in the catalyst and EDG in PSAA have a retarding effect on the reaction. A Hammett correlation displays a non-linear downward curvature, which consists of two intersecting straight lines and the ρ value shifts from small positive to moderately high as the substituents change from EWG to EDG. The importance of the ground state stabilization of PSAA is inferred from a linear Yukawa–Tsuno plot. Based on the observed substituent effects and the spectral changes, a mechanism involving electrophilic attack of PSAA on the nucleophilic peroxo oxygen atom of the vanadium complex in the rate determining step followed by oxygen atom transfer is proposed.
- Subramaniam,Jeevi Esther Rathnakumari,Janet Sylvia Jaba Rose
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p. 496 - 503
(2016/07/21)
-
- Modulation of catalytic activity by ligand oxides in the sulfoxidation of phenylmercaptoacetic acids by oxo(salen)chromium(V) complexes
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Mechanism of sulfoxidation of eleven para-substituted phenyl mercaptoacetic acids (PMAAs) by three oxo(salen)chromium(V)+PF6?complexes in the presence of different ligand oxides (LOs) such as triphenylphosphine oxide, pyridine N-oxide and 4-picoline N-oxide have been studied spectrophotometrically in 100% acetonitrile medium. Spectral and kinetic profiles establish the formation of adduct, O[dbnd]Cr(V)(salen)+-LO as the reactive intermediate in the catalytic cycle. The rate of sulfoxidation is found to be enhanced significantly by the addition of LOs and introduction of substituent in PMAA and salen complex. Both electron releasing and electron withdrawing substituents in the substrate and oxidant facilitate the rate of sulfoxidation. Correlation with Hammett constants yields a non-linear concave upward curve. Based on the experimental results and substituent effects two different mechanisms, a direct oxygen atom transfer (DOT) for PMAAs with electron withdrawing substituents and a single electron transfer for PMAAs with electron donating substituents have been postulated.
- Subramaniam,Anbarasan,Sugirtha Devi,Ramdass
-
-
- A paradigm shift in rate determining step from single electron transfer between phenylsulfinylacetic acids and iron(III) polypyridyl complexes to nucleophilic attack of water to the produced sulfoxide radical cation: a non-linear Hammett
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Mechanism of oxidative decarboxylation of phenylsulfinylacetic acids (PSAAs) by iron(III) polypyridyl complexes in aqueous acetonitrile medium has been investigated spectrophotometrically. An initial intermediate formation between PSAA and [Fe(NN)3]3+ is confirmed from the observed Michaelis–Menten kinetics and fractional order dependence on PSAA. Significant rate retardation with concentration of [Fe(NN)3]3+ is rationalized on the basis of coordination of a water molecule at the carbon atom adjacent to the ring nitrogen of the metal polypyridyl complexes by nucleophilic attack at higher concentrations. Electron-withdrawing and electron-releasing substituents in PSAA facilitate the reaction and Hammett correlation gives an upward ‘V’ shaped curve. The apparent upward curvature is rationalized based on the change in the rate determining step from electron transfer to nucleophilic attack, by changing the substituents from electron-releasing to electron-withdrawing groups. Electron-releasing substituents in PSAA accelerate the electron transfer from PSAA to the complex and also stabilize the intermediate through resonance interaction leading to negative reaction constants (ρ). Conversely, electron-withdrawing groups, while retarding the electron transfer exert an accelerating effect on the nucleophilic attack of H2O which leading to low magnitude of ρ+ compared to high ρ? values of electron-releasing groups. Marcus theory is applied, and a fair agreement is seen with the experimental values. Copyright
- Subramaniam, Perumal,Janet Sylvia Jaba Rose, Jebamoney,Jeevi Esther Rathinakumari, Rajasingh
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p. 496 - 504
(2016/09/21)
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- With anti-tumor activity for NO [...] integrated tetradium alkali derivatives (by machine translation)
-
The present invention relates to natural medicine and the field of pharmaceutical chemistry, in particular to tetradium alkali 13-N bit modified derivative. This invention refers to these 13-N bit [...] NO donor substituted tetradium alkali derivative preparation method and evaluation of anti-tumor activity. The compound of the following structure: wherein R 1, R 2 to (CH 2) n or (CH 2) n1 O (CH 2) n2, n, n1, n2 to 1-8 integer. . (by machine translation)
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-
Paragraph 0026; 0027; 0028
(2017/01/02)
-
- Twisted Hemithioindigo Photoswitches: Solvent Polarity Determines the Type of Light-Induced Rotations
-
Controlling the internal motions of molecules by outside stimuli is a decisive task for the generation of responsive and complex molecular behavior and functionality. Light-induced structural changes of photoswitches are of special high interest due to the ease of signal application and high repeatability. Typically photoswitches use one reaction coordinate in their switching process and change between two more or less-defined states. Here we report on new twisted hemithioindigo photoswitches enabling two different reaction coordinates to be used for the switching process. Depending on the polarity of the solvent, either complete single bond (in DMSO) or double bond (in cyclohexane) rotation can be induced by visible light. This mutually independent switching establishes an unprecedented two-dimensional control of intramolecular rotations in this class of photoswitches. The mechanistic explanation involves formation of highly polar twisted intramolecular charge-transfer species in the excited state and is based on a large body of experimental quantifications, most notably ultrafast spectroscopy and quantum yield measurements in solvents of different polarity. The concept of pre-twisting in the ground state to open new, independent reaction coordinates in the excited state should be transferable to other photoswitching systems.
- Wiedbrauk, Sandra,Maerz, Benjamin,Samoylova, Elena,Reiner, Anne,Trommer, Florian,Mayer, Peter,Zinth, Wolfgang,Dube, Henry
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supporting information
p. 12219 - 12227
(2016/10/03)
-