- Targeting nuclear protein TDP-43 by cell division cycle kinase 7 inhibitors: A new therapeutic approach for amyotrophic lateral sclerosis
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no known cure. Aggregates of the nuclear protein TDP-43 have been recognized as a hallmark of proteinopathy in both familial and sporadic cases of ALS. Post-translational modifications of this protein, include hyperphosphorylation, cause disruption of TDP-43 homeostasis and as a consequence, promotion of its neurotoxicity. Among the kinases involved in these changes, cell division cycle kinase 7 (CDC7) plays an important role by directly phosphorylating TDP-43. In the present manuscript the discovery, synthesis, and optimization of a new family of selective and ATP-competitive CDC7 inhibitors based on 6-mercaptopurine scaffold are described. Moreover, we demonstrate the ability of these inhibitors to reduce TDP-43 phosphorylation in both cell cultures and transgenic animal models such as C. elegans and Prp-hTDP43 (A315T) mice. Altogether, the compounds described here may be useful as versatile tools to explore the role of CDC7 in TDP-43 phosphorylation and also as new drug candidates for the future development of ALS therapies.
- Rojas-Prats, Elisa,Martinez-Gonzalez, Loreto,Gonzalo-Consuegra, Claudia,Liachko, Nicole F.,Perez, Concepción,Ramírez, David,Kraemer, Brian C.,Martin-Requero, ángeles,Perez, Daniel I.,Gil, Carmen,de Lago, Eva,Martinez, Ana
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supporting information
(2020/11/12)
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- The discovery of purine-based agents targeting triple-negative breast cancer and the αB-crystallin/VEGF protein–protein interaction
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Oestrogen receptor-negative breast cancer, particularly subtypes such as triple-negative breast cancer (TNBC, around 10–15% of cases), are characterised by poor long-term survival, poor response to therapy and early progression to metastasis. Purine-based compounds represent a privileged scaffold in anticancer drug design, with several clinically approved and experimental agents in clinical development comprising a purine core structure. In this study, a series of new purine-based compounds were synthesised; seven of the new analogues were found to significantly reduce the in vitro viability of TNBC cell lines (MDA-MB-231 and MDA-MB-436) with IC50 values of ≤50 μM. In previous work, we have proposed a new concept for targeting angiogenesis driving TNBC progression, by disrupting the protein–protein interaction between the molecular chaperone αB-crystallin (CRYAB) and VEGF. Since previous clinical studies applying anti-VEGF therapy to TNBC patients have met with limited success, we were interested to test our most promising purine analogues against CRYAB/VEGF, using a custom-designed cell-based CRYAB/VEGF165 interaction assay platform. Analogues 4e and 4f significantly reduced the interaction between CRYAB/VEGF165, and compound 4e (100 μM) was also found to decrease the levels of soluble VEGF expressed by MDA-MB-231 cells by 40%. In conclusion, these promising early activity profiles warrant further investigation to validate this concept.
- Fosu-Mensah, Nelly A.,Jiang, Wen,Brancale, Andrea,Cai, Jun,Westwell, Andrew D.
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p. 182 - 202
(2019/01/04)
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- Synthesis, anti-cancer activity and mechanism study of 6-mercapto-purine derivatives
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6-mercaptopurine (6-MP) is the first active metabolite inhibitor shown to suppress cancer cells. The aim of this study is to investigate the bioactivity of 6-MP derivatives and discover new anti-cancer agents. Four 6-mercaptopurine (6-MP) derivatives were synthesized and their anti-cancer activities were analyzed. All of the compounds showed anti-proliferative effects against HepG2 and A2780 cancer cells. Among the synthesized derivatives, 6-((naphthalen-2-ylmethyl)thio)-9H-purine (NMSP) which possessing a β-naphthalene, showed better anti-cancer activity than other compounds, with an IC50 value 6.09μg/mL. NMSP could induce S phase cell cycle arrest and apoptosis in HepG2 cells. Western blot analysis indicated that NMSP induced apoptosis is mitochondria-dependent. The novel 6-MP derivative discovered in this study is a promising drug candidate to be used as an anti-cancer agent.
- Ma, Yu-Qin,Yan, Xing,Du, Rong,Yang, Xiao-Guang,Li, Yu-Xin,Gao, Ying,Li, Wen-Liang
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p. 570 - 576
(2016/07/19)
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- Synthesis, Anti-cancer Activity and Mechanism Study of 6-Mercapto-purine Derivatives
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6-mercaptopurine (6-MP) is the first active metabolite inhibitor shown to suppress cancer cells. The aim of this study is to investigate the bioactivity of 6-MP derivatives and discover new anti-cancer agents. Four 6-mercaptopurine (6-MP) derivatives were synthesized and their anti-cancer activities were analyzed. All of the compounds showed anti-proliferative effects against HepG2 and A2780 cancer cells. Among the synthesized derivatives, 6-((naphthalen-2-ylmethyl)thio)-9H-purine (NMSP) which possessing a β-naphthalene, showed better anti-cancer activity than other compounds, with an IC50 value 6.09μg/mL. NMSP could induce S phase cell cycle arrest and apoptosis in HepG2 cells. Western blot analysis indicated that NMSP induced apoptosis is mitochondria-dependent. The novel 6-MP derivative discovered in this study is a promising drug candidate to be used as an anti-cancer agent.
- Ma, Yu-Qin,Yan, Xing,Du, Rong,Yang, Xiao-Guang,Li, Yu-Xin,Gao, Ying,Li, Wen-Liang
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p. 570 - 576
(2016/10/12)
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- Modification of thionucleobases in ionic liquids
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A simple method was established for the preparation of thio-substituted thionucleobases using room temperature ionic liquids (RTILs) such as 1-butyl-3-methylimidazolium trifluoroacetate [BMIM]+[CF3COO]- and 1-methoxyethyl-3-methylimidazolium trifluoroacetate [MeOEtMIM]+[CF3COO]- as solvents and catalysts without any other catalyst. These reactions proceeded efficiently in RTILs with excellent yield of products. RTILs can be recycled and reused effectively without further purification.
- Hu, Xiaomei,Zhang, Bixian,Dong, Shijia,Gao, Yunfei
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- Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors
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On the basis of ATP adenine, a series of adenine and purine derivatives was prepared and tested for their ability to inhibit a spectrum of disease-related kinases. There has been scant research investigating the potential of cosubstrate derived kinase inhibitors for other kinases than CDKs. Our inhibitor design combined the purine system from the original cosubstrate ATP and phenyl moieties in order to explore possible interactions with the different regions of the ATP binding site in several disease-related protein kinases. There have been a number of hits for the assayed substances, which led us to conclude that the spectrum of compounds may prove to be a valuable tool kit for the evaluation of bonding and selectivity patterns for a wide variety of kinases.
- Laufer, Stefan A.,Domeyer, David M.,Scior, Thomas R. F.,Albrecht, Wolfgang,Hauser, Dominik R. J.
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p. 710 - 722
(2007/10/03)
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- Antimycobacterial Agents. 1. Thio Analogues of Purine
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Thio analogues of purine, pyridine, and pyrimidine were prepared based on the initial activity screening of several analogues of these heterocycles against Mycobacterium tuberculosis (Mtb). Certain 6-thio-substituted purine analogues described herein showed moderate to good inhibitory activity. In particular, two purine analogues 9-(ethylcarboxymethyl)-6-(decylthio)-9H-purine (20) and 9-(ethylcarboxymethyl)-6-(dodecylthio)-9H-purine (21) exhibited MIC values of 1.56 and 0.78 μg/mL respectively against the Mtb H37Rv strain. N9-Substitution apparently enhances the antimycobacterial activity in the purine series described herein.
- Pathak, Ashish K.,Pathak, Vibha,Seitz, Lainne E.,Suling, William J.,Reynolds, Robert C.
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p. 273 - 276
(2007/10/03)
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- Preparation, structural characterization, and acid-catalyzed isomerization of 3-, 7-, and 9-benzyl-6-benzylthiopurines
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Benzylation of 6-benzylthiopurine was examined. Structural assignments of the products were determined by 1-D and 2-D nmr spectroscopy (HMQC, HMBC, and nOe). In the presence of base, the isomeric N3-, N7-, and N9-benzylated products 4, 3, and 2 were isolated; however, only 9-benzyl-6-benzylthiopurine (2) was obtained in the absence of base. In the latter case, the initially formed N3- and N7-isomers were, in the presence of acid, converted to 9-benzyl-6-benzylthiopurine (2) via a 6-benzylthiopurine intermediate as evidenced by analysis of the reaction over time using reversed-phase hplc.
- Huang,Ragouzeos,Rideout
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p. 1685 - 1688
(2007/10/02)
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