- Selective AMPK activator leads to unfolded protein response downregulation and induces breast cancer cell death and autophagy
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Aims: AMPK plays a critical role regulating cell metabolism, growth and survival. Interfering with this enzyme activity has been extensively studied as putative mechanism for cancer therapy. The present work aims to identify a specific AMPK activator for cancer cells among a series of novel heterocyclic compounds. Materials and methods: A series of novel hybrid heterocyclic compounds, namely naphtoquinone-4-oxoquinoline and isoquinoline-5,8-quinone-4-oxoquinoline derivatives, were synthesized via Michael reaction and their structures confirmed by spectral data: infrared; 1H and 13C NMR spectroscopy (COSY, HSQC, HMBC); and high-resolution mass spectrometry (HRMS). The novel compounds were screened and tested for antitumoral activity and have part of their mechanism of action scrutinized. Key findings: Here, we identified a selective AMPK activator among the new hybrid heterocyclic compounds. This new compound presents selective cytotoxicity on breast cancer cells but not on non-cancer counterparts. We identified that by specifically activating AMPK in cancer cells, the drug downregulates unfolded protein response pathway, as well as inhibits mTOR signaling. Significance: These effects, that are selective for cancer cells, lead to activation of autophagy and, ultimately, to cancer cells death. Taken together, our data support the promising anticancer activity of this novel compound which is a strong modulator of metabolism.
- Nascimento Mello, Angélica Lauria,Sagrillo, Fernanda Savacini,de Souza, Alan Gon?alves,Costa, Amanda Rodrigues Pinto,Campos, Vinícius Rangel,Cunha, Anna Claudia,Imbroisi Filho, Ricardo,da Costa Santos Boechat, Fernanda,Sola-Penna, Mauro,de Souza, Maria Cecília Bastos Vieira,Zancan, Patricia
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- Synthesis of 6-ethyl-1,2,9-trioxopyrrolo[3,2-f ]quinoline-8-carboxylic acid
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Interaction of 6-amino-1-ethyl-4-oxoquinoline-3-carboxylic ester (7) with chloral hydrate and hydroxylamine hydrochloride gave the corresponding isonitroso-acetamido derivative 8 which, upon treatment with concentrated sulfuric acid, was converted regioselectively into 1,2,9-trioxopyrrolo[3,2-f] quinoline-8-carboxylic acid (3). This novel tricyclic system was isolated in good yield as a stable hydrate 3H. Structural assignments of the new compounds are based on microanalytical and spectral (MS and NMR) data.
- Al-As'ad, Randa M.,El-Abadelah, Mustafa M.,Sabri, Salim S.,Zahra, Jalal A.,Voelter, Wolfgang
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- 6-Nitro-1-benzylquinolones exhibiting specific antitubercular activity
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In this study, we synthesized novel nitro quinolone-based compounds and tested them in vitro against a panel of Gram-positive and Gram-negative pathogens including Mycobacterium tuberculosis (MTB), Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumonia, Staphylococcus aureus, and Escherichia coli for antibacterial activities and also against HeLa cells for overt cytotoxicity. Compound 8e was identified as a non-toxic, potent hit with selective activity (MIC90???0.24?μm) against MTB. 8e, however, showed no activity against DprE1 mutant, suggesting DprE1 as the likely target for this compound class.
- Beteck, Richard M.,Jordaan, Audrey,Swart, Tarryn,Van Der Kooy, Frank,Warner, Digby F.,Hoppe, Heinrich C.,Legoabe, Lesetja J.
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- Synthesis of Novel Ethyl (substituted)phenyl-4-oxothiazolidin-3-yl)-1-ethyl-4-oxo-1,4-dihydroquinoline-3-Carboxylates as Potential Anticancer Agents
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A series of ethyl (substituted)phenyl-4-oxothiazolidin-3-yl)-1-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylates (7a, 7b, 7c, 7d, 7e, 7f, 7g) has been prepared from reactions between aminoquinolones 6 with arenealdehydes and mercaptoacetic acid. The critical intermediates, 6a and 6b, were obtained from appropriate amines by a sequence of steps involving (i) reaction with diethylethoxymethylenemalonate, (ii) thermal cyclization in diphenyl ether, (iii) ethylation and (iv) Pd/C catalyzed reduction. New compounds 7a, 7b, 7c, 7d, 7e, 7f, 7g were fully identified and characterized by NMR (1H and 13C) and specifically for 7d by X-ray crystallography. Compounds 7b, 7c, 7d, 7e, 7f were found not to exhibit activity at 10 uM concentrations against gastric ascitis (AGP-01), gastric adenocarcinoma kind intestinal (ACP-02), colon (HCT-116) and murine melanome (B16F10) cancer cells. However, none exhibited cytotoxicity against normal cells human fibroblast (MRC-5), murine fibroblast (NIH3T3) and normal human melanocyte (Melan-A).
- Facchinetti, Victor,Guimares, Felipe A.,De Souza, Marcus Vincius N.,Gomes, Claudia Regina B.,De Souza, Maria Ceclia B. V.,Wardell, James L.,Wardell, Solange M. S. V.,Vasconcelos, Thatyana R. A.
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- Easy-to-access quinolone derivatives exhibiting antibacterial and anti-parasitic activities
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The cell wall of Mycobacterium tuberculosis (Mtb) has a unique structural organisation, comprising a high lipid content mixed with polysaccharides. This makes cell wall a formidable barrier impermeable to hydrophilic agents. In addition, during host infection, Mtb resides in macrophages within avascular necrotic granulomas and cavities, which shield the bacterium from the action of most antibiotics. To overcome these protective barriers, a new class of anti-TB agents exhibiting lipophilic character have been recommended by various reports in literature. Herein, a series of lipophilic heterocyclic quinolone compounds was synthesised and evaluated in vitro against pMSp12::GFP strain of Mtb, two protozoan parasites (Plasmodium falciparum and Trypanosoma brucei brucei) and against ESKAPE pathogens. The resultant compounds exhibited varied anti-Mtb activity with MIC90 values in the range of 0.24-31 μM. Cross-screening against P. falciparum and T.b. brucei, identified several compounds with antiprotozoal activities in the range of 0.4-20 μM. Compounds were generally inactive against ESKAPE pathogens, with only compounds 8c, 8g and 13 exhibiting moderate to poor activity against S. aureus and A. baumannii.
- Beteck, Richard M.,Hoppe, Heinrich C.,Jordaan, Audrey,Khanye, Setshaba D.,Laming, Dustin,Seldon, Ronnett,Warner, Digby F.
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- Easily accessed nitroquinolones exhibiting potent and selective anti-tubercular activity
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Nitro based DprE1 inhibitors exemplified by benzothiazinones have been reported to elicit potent anti-tubercular activity. Poor PK properties associated with benzothiazinones have inspired the discovery of alternative nitro based DprE1 inhibitors. Quinolone based antibiotics on the other hand have good PK properties. The potent anti-tubercular activity of nitro compounds and the good PK properties of the quinolones have elicited an interest in us to construct a new class of nitro containing compounds around the quinolone scaffold with the aim of identifying novel DprE1 inhibitors with potent anti-tubercular activity. Thus, we report herein the anti-tubercular activity of novel 6-nitroquinolone-3-carboxamide derivatives achieved using less than five cheap synthetic transformations. Among the 23 target compounds evaluated for anti-tubercular activity, 12 were active against Mtb─ exhibiting activity in the range of a molecular weight of 399 Da and ClogP value of 2.7 is the most active (MIC90: 2) and C-3 (R3) of the quinolone ring. The activity data suggest that the nature of R3 has a stronger influence on the SAR compared to R2; with a fluorobenzyl and chlorobenzyl moiety at R2 being the most favoured when R3 is an aliphatic amine. Docking study confirms that compound 25 binds to the same hydrophobic pocket as does TCA1, and other nitro based DprE1 inhibitors, with its nitro group in close proximity with Cys387 residue.
- Dube, Phelelisiwe S.,Legoabe, Lesetja J.,Jordaan, Audrey,Jesumoroti, Omobolanle J.,Tshiwawa, Tendamudzimu,Warner, Digby F.,Beteck, Richard M.
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- TARGETING PTPN22 IN CANCER THERAPY
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Described are methods of treating solid cancers in a subject. The methods comprise the steps of administering to the subject having the solid cancer or prone of getting the solid cancer an antagonist of PTPN22, or the functional part of PTPN22, and treating the solid cancer. Methods comprising use of other anticancer agents and adjuvants in conjunction with PTPN22 inhibitors are also provided.
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Paragraph 0159; 0160; 0161
(2021/01/29)
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- Antiviral activity of 4-oxoquinoline-3-carboxamide derivatives against bovine herpesvirus type 5
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Background: Bovine herpesvirus type 5 is an important agent of meningoencephalitis in cattle and has been identified in outbreaks of bovine neurological disease in several Brazilian states. In recent years, oxoquinoline derivatives have become an important focus in antiviral drug research. Methods: The cytotoxicity and anti BoHV-5RJ42/01 activity of a set of synthetic 4-oxoquinoline derivatives 4a-k were assayed on Madin-Darby Bovine Kidney cell and antiviral activity by plaque reduction assay. Results: The most promising substance (4h) exhibited CC50 and EC50 values of 1,239 μM ±5.5 and 6.0 μM ±1.5, respectively, with an SI =206. Two other compounds 4j (CC50 = 35 μM ±2 and EC50 = 24 μM ±7.0) and 4k (CC50= 55 μM ±2 and EC50 = 24 μM ±5.1) presented similar inhibitory profile and selectivity indexes of 1.4 and 2.9, respectively. The results of the time-of-addition studies revealed expressive reduction of virus production (≥80%) in different stages of virus replication cycle except for compound 4h that slightly inhibited virus yield in the first 2 h post infection, but it showed expressive virus inhibition after this time. Conclusions: All three compounds slightly interact with the virus on the virucidal assay and they are not able to block virus attachment and penetration. Antiviral effect of oxoquinoline 4h was more prominent than acyclovir which leads us to suggest compound 4h as a promising molecule for further anti-BoHV-5 drug design.
- Pinto, Ana Maria V.,Leite, José Paulo G.,Marinho, Robson S.S.,Forezi, Luana da S.M.,Batalha, Pedro N.,Boechat, Fernanda da C.S.,Cunha, Anna C.,Silva, David O.,Gama, Ivson L.,Faro, Letícia V.,de Souza, Maria C.B.V.,Paix?o, Izabel Christina P.
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- Further studies on bis-charged tetraazacyclophanes as potent inhibitors of small conductance Ca2+-activated K+ channels
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Previously, quinolinium-based tetraazacyclophanes, such as UCL 1684 and UCL 1848, have been shown to be extraordinarily sensitive to changes in chemical structure (especially to the size of the cyclophane system) with respect to activity as potent non-peptidic blockers of the small conductance Ca 2+-activated K+ ion channels (SKCa). The present work has sought to optimize the structure of the linking chains in UCL 1848. We report the synthesis and SKCa channel-blocking activity of 29 analogues of UCL 1848 in which the central CH2 of UCL 1848 is replaced by other groups X or Y = O, S, CF2, CO, CHOH, CC, CHCH, CHMe to explore whether subtle changes in bond length or flexibility can improve potency still further. The possibility of improving potency by introducing ring substituents has also been explored by synthesizing and testing 25 analogues of UCL 1684 and UCL 1848 with substituents (NO2, NH2, CF 3, F, Cl, CH3, OCH3, OCF3, OH) in the 5, 6 or 7 positions of the aminoquinolinium rings. As in our earlier work, each compound was assayed for inhibition of the afterhyperpolarization (AHP) in rat sympathetic neurons, an action mediated by the SK3 subtype of the SK Ca channel. One of the new compounds (39, R7 = Cl, UCL 2053) is twice as potent as UCL 1848 and UCL 1684: seven are comparable in activity.
- Yang, Donglai,Arifhodzic, Lejla,Ganellin, C. Robin,Jenkinson, Donald H.
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supporting information
p. 907 - 923
(2013/07/27)
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- Oxoquinoline acyclonucleoside phosphonate analogues as a new class of specific inhibitors of human immunodeficiency virus type 1
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The emergence of a multidrug-resistant HIV-1 strain and the toxicity of anti-HIV-1 compounds approved for clinical use are the most significant problems facing antiretroviral therapies. Therefore, it is crucial to find new agents to overcome these issues. In this study, we synthesized a series of new oxoquinoline acyclonucleoside phosphonate analogues (ethyl 1- [(diisopropoxyphosphoryl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylates 3a-3k), which contained different substituents at the C6 or C7 positions of the oxoquinoline nucleus and an N1-bonded phosphonate group. We subsequently investigated these compounds' in vitro inhibitory effects against HIV-1-infected peripheral blood mononuclear cells (PBMCs). The most active compounds were the fluoro-substituted derivatives 3f and 3g, which presented excellent EC 50 values of 0.4 ± 0.2 μM (3f) and 0.2 ± 0.005 μM (3g) and selectivity index values (SI) of 6240 and 14675, respectively.
- Faro, Leticia V.,De Almeida, Jessica M.,Cirne-Santos, Claudio C.,Giongo, Viveca A.,Castello-Branco, Luis R.,Oliveira, Ingrid De B.,Barbosa, Juliana E.F.,Cunha, Anna C.,Ferreira, Vitor F.,De Souza, Marcos C.,Paixao, Izabel C.N.P.,De Souza, Maria Cecilia B.V.
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p. 5055 - 5058
(2012/08/28)
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- Synthesis and anticancer activities of some novel 2-(benzo[d]thiazol-2-yl)- 8-substituted-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones
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A series of 2-(benzo[d]thiazol-2-yl)-8-substituted-2H-pyrazolo[4,3-c] quinolin-3(5H)-ones (3a-g) have been synthesized and evaluated for their in vitro antiproliferative activities against four human cancer cell lines: MDA-MB-435 (breast), HL-60 (leukemia), HCT-8 (colon) and SF-295 (central nervous system). The results showed that the compounds 3b (2-(benzo[d]thiazol-2-yl)-8- methyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-one) and 3c (2-(benzo[d]thiazol-2-yl)-8- bromo-2H-pyrazolo[4,3-c]quinolin-3(5H)-one) exhibited good cytotoxicity for three cell lines with IC50 values lower than 5 μg/mL. Analysis of theoretical toxicity risks have shown medium tumorigenic and irritant risks related to 3b and 3c in contrast to doxorubicin, the positive control.
- Reis, Raísa Da R.,Azevedo, Elisa C.,De Souza, Maria Cecília B.V.,Ferreira, Vitor Francisco,Montenegro, Raquel C.,Araújo, Ana Jérsia,Pessoa, Cláudia,Costa-Lotufo, Letícia V.,De Moraes, Manoel O.,Filho, José D.B.M.,De Souza, Alessandra M.T.,De Carvalho, Natasha C.,Castro, Helena C.,Rodrigues, Carlos R.,Vasconcelos, Thatyana R.A.
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p. 1448 - 1452
(2011/04/24)
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- THERAPEUTIC PYRAZOLOQUINOLINE DERIVATIVES
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The invention provides a novel chemical series of formula I, as well as methods of use thereof for binding to the benzodiazepine site of the GABAA receptor and modulating GABAA, and use of the compound of formula I for the treatment of GABAA receptor associated disorders. The general structure of formula I is shown below and can exist in tautomeric forms: The invention further provides a method of modulation of one or more GABAA subtypes in an animal comprising administering to the animal an effective amount of a compound of formula (I).
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Page/Page column 36-37
(2009/01/20)
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- Synthesis and anti-HSV-1 activity of quinolonic acyclovir analogues
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Several 1-[(2-hydroxy-ethoxy)methyl]-3-carbethoxy-4(1H)quinolones (2a-l) and l-[(2-hydroxy-ethoxy)methyl]-4(1H)quinolone-3-carboxylic acids (3a-j and 3l) were synthesized and 2a-j, 2l and 3a-j, 3l were evaluated against herpes simplex virus type 1 (HSV-1), employing a one-pot reaction: silylation of the desired quinolone (BSTFA 1% TMCS) followed by equimolar amount addition of 1,3-dioxolane, chlorotrimethylsilane and KI, at room temperature. The acyclonucleosides 2a-l were obtained in 40-77% yields. The esters 2a-j and 2l were subsequently converted into the corresponding hydroxyacids 3 in 40-70% yields. Attempts of hydrolysis of 2k produced only a mixture of degradation products. Antiviral activity of 2 and 3 on HSV-1 virus infection was assessed by the virus yield assay. Except for compounds 2i and 3e, the acyclonucleosides were found to reduce the virus yield by 70-99% at the concentration of 50 μM, being the acids, in general, more effective inhibitors than their corresponding esters. Compounds 3j and 2d exhibited antiviral activity against HSV-1 virus with EC50 of 0.7 ± 0.04 and 0.8 ± 0.09 μM, respectively. Both compounds were not toxic towards the Vero cell line.
- Lucero, Bianca D'A.,Gomes, Claudia Regina B.,Frugulhetti, Izabel Christina De P.P.,Faro, Leticia V.,Alvarenga, Lise,De Souza, Maria Cecilia B.V.,De Souza, Thiago M.L.,Ferreira, Vitor F.
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p. 1010 - 1013
(2008/12/23)
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- Design, synthesis, and biological evaluation of novel 4-hydro-quinoline-3- carboxamide derivatives as an immunomodulator
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A series of novel quinoline-3-carboxamide derivatives were synthesized and evaluated for their immunomodulatory activity. The compounds were tested in vitro for effects on spleen lymphocyte proliferation and TNF-α production by macrophage. Three compounds showed immunomodulatory profiles similar to and more potent than those of linomide and FR137316 and were selected for further pharmacological studies in vivo.
- He, Jun-Feng,Yun, Liu-Hong,Yang, Ri-Fang,Xiao, Zhi-Yong,Cheng, Jun-Ping,Zhou, Wen-Xia,Zhang, Yong-Xiang
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p. 2980 - 2985
(2007/10/03)
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- Microwave assisted Gould-Jacob reaction: Synthesis of 4-quinolones under solvent free conditions
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A single step Gould-Jacob reaction between aromatic amines and diethyl ethoxymethylenemalonates (EMME) for the synthesis of 4-quinolones under solvent free microwave irradiation has been carried out and compared with classical heating.
- Dave, Chaitanya G.,Joshipura, Hardik M.
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p. 650 - 652
(2007/10/03)
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