- Discovery of Novel Apigenin-Piperazine Hybrids as Potent and Selective Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors for the Treatment of Cancer
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Poly (ADP-ribose) polymerase-1 (PARP-1) is a potential target for the discovery of chemosensitizers and anticancer drugs. Amentoflavone (AMF) is reported to be a selective PARP-1 inhibitor. Here, structural modifications and trimming of AMF have led to a series of AMF derivatives (9a-h) and apigenin-piperazine/piperidine hybrids (14a-p, 15a-p, 17a-h, and 19a-f), respectively. Among these compounds, 15l exhibited a potent PARP-1 inhibitory effect (IC50 = 14.7 nM) and possessed high selectivity to PARP-1 over PARP-2 (61.2-fold). Molecular dynamics simulation and the cellular thermal shift assay revealed that 15l directly bound to the PARP-1 structure. In in vitro and in vivo studies, 15l showed a potent chemotherapy sensitizing effect against A549 cells and a selective cytotoxic effect toward SK-OV-3 cells through PARP-1 inhibition. 15l·2HCl also displayed good ADME characteristics, pharmacokinetic parameters, and a desirable safety margin. These findings demonstrated that 15l·2HCl may serve as a lead compound for chemosensitizers and the (BRCA-1)-deficient cancer therapy.
- Long, Huan,Hu, Xiaolong,Wang, Baolin,Wang, Quan,Wang, Rong,Liu, Shumeng,Xiong, Fei,Jiang, Zhenzhou,Zhang, Xiao-Qi,Ye, Wen-Cai,Wang, Hao
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p. 12089 - 12108
(2021/09/06)
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- VICINAL PRIMARY DIAMINES ASSOCIATED WITH METAL AND/OR FREE RADICAL CHELATION MOTIFS, AND ACTIVE AGAINST CARBONYL AND OXIDATIVE STRESS, AND USE THEREOF
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The invention relates to compounds of Formula I: or the salts thereof, as well as the use thereof in the pharmaceutical, cosmetic or agrofood industry.
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- Discovery of 2-substituted 1H-benzo[d]immidazole-4-carboxamide derivatives as novel poly(ADP-ribose)polymerase-1 inhibitors with in?vivo anti-tumor activity
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Novel 1H-benzo[d]immidazole-4-carboxamide derivatives bearing five-membered or six-membered N-heterocyclic moieties at the 2-position were designed and synthesized as PARP-1 inhibitors. Structure-activity relationships were conducted and led to a number of potent PARP-1 inhibitors having IC50 values in the single or double digit nanomolar level. Some potent PARP-1 inhibitors also had similar inhibitory activities against PARP-2. Among all the synthesized compounds, compound 10a and 11e displayed strong potentiation effects on temozolomide (TMZ) in MX-1?cells (PF50?=?7.10, PF50?=?4.17). In?vivo tumor growth inhibition was investigated using compound 10a in combination with TMZ, and it was demonstrated that compound 10a could strongly potentiate the cytotoxicity of TMZ in MX-1 xenograft tumor model. Two co-crystal structures of compounds 11b and 15e complexed with PARP-1 were achieved and demonstrated a unique binding mode of these benzo-imidazole derivatives.
- Zhou, Jie,Ji, Ming,Zhu, Zhixiang,Cao, Ran,Chen, Xiaoguang,Xu, Bailing
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supporting information
p. 26 - 41
(2017/03/23)
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- Unsymmetrical tetrasubstituted ureas from tertiary carbamoylimidazole: Activation by AlMe3
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An efficient and general method for the synthesis of unsymmetrical tetrasubstituted ureas from carbamoylimidazole is described. The conversion is achieved by the concurrent quarternization of the imidazole nitrogen and activation of amines with AlMe3. The Royal Society of Chemistry 2012.
- Velavan,Sumathi,Balasubramanian
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supporting information; experimental part
p. 6420 - 6431
(2012/09/05)
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- Synthesis of Macrocyclic, Triazine-Based Receptor Molecules
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The synthesis of triazine-based macrocyclic scaffolds is presented. The strategy employed allows for the facile functionalization of the macrocyclic molecules and combinatorial construction of putative receptor molecules. It is shown that the functional groups on the macrocyclic molecules, the size of the rings and the nature of the diamines linking the triazines can all be varied. In addition to the description of the stepwise synthesis of these compounds, it is shown that macrocycles based on triazine and xylenediamine are able to bind pyranosides and cyanuric acid.
- Loewik, Dennis W. P. M.,Lowe, Christopher R.
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p. 2825 - 2840
(2007/10/03)
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- A stepwise synthesis of triazine-based macrocyclic scaffolds
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The synthesis of a non-peptidic triazine-based macrocyclic scaffold is presented. The strategy employed allows for the facile functionalisation of the macrocyclic molecules and combinatorial construction of putative receptor molecules. (C) 2000 Elsevier Science Ltd.
- L?wik, Dennis W. P. M.,Lowe, Christopher R.
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p. 1837 - 1840
(2007/10/03)
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- Piperazinyl derivatives of purines and isosteres thereof as hypoglycemic agents
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There are disclosed certain 6-piperazinopurines and heteroaromatic derivatives thereof which have oral hypoglycemic acitivity and with such ability to lower blood sugar are useful in the treatment of type II diabetes and/or obesity with associated insulin
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