291536-12-4Relevant articles and documents
BICYCLIC INHIBITORS OF CBX CHROMODOMAINS
-
Paragraph 00152-00153, (2021/04/02)
A genus of bicyclic inhibitors of CBX chromodomains is disclosed. The compounds are of the following genus: The compounds inhibit CBX proteins and, as a consequence, they are useful for treating prostate cancer, ovarian cancer, and B-cell lymphoma.
Discovery to solve multidrug resistance: Design, synthesis, and biological evaluation of novel agents
Qiu, Qianqian,Shi, Wei,Zhao, Shiyuan,Zhu, Yan,Ding, Zhengquan,Zhou, Shaoyang,Kairuki, Mutta,Huang, Wenlong,Qian, Hai
, (2019/08/26)
Chemotherapy remains a pillar in the treatment and management of various cancers. However, multidrug resistance (MDR) becomes a severe problem after long-term administration of chemotherapy drugs. Overexpression of P-glycoprotein (P-gp) is a significant cause for tumor MDR. Therefore, P-gp inhibition is considered as an effective strategy to reverse MDR. A third-generation P-gp inhibitor tariquidar was selected as a lead compound, and a new series of triazol-N-ethyl tetrahydroisoquinoline based compounds were designed as novel P-gp inhibitors and synthesized through click chemistry. These compounds presented higher reversal activities than the positive-control verapamil (VRP). Among 18 compounds, compound 11 without cytotoxicity reversed MDR in a dose-dependent manner, with a persistent longer chemosensitizing effect and reversibility compared to others. Mechanism studies discovered that compound 11 could escalate the intracellular accumulation of rhodamine-123 and doxorubicin in K562/A02 cells as well as inhibit their efflux from cells. The results obtained suggest that compound 11 is more potent than VRP administered under the same conditions; it may be a potent and safe candidate for P-gp modulation for further development.
Discovery of aromatic amides with triazole-core as potent reversal agents against P-glycoprotein-mediated multidrug resistance
Qiu, Qianqian,Zhu, Jilan,Chen, Qiutong,Jiang, Ziqian,Xu, Jiting,Jiang, Xueting,Huang, Wenlong,Liu, Zhongquan,Ye, Jing,Xu, Xiaojuan
, (2019/07/02)
P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a major impediment for clinical cancer therapy. 19 novel aromatic amides with triazole-core as MDR reversal agents were designed and synthesized via click chemistry to reverse MDR. Among them, compound 42 was identified as the most promising candidate with high potency (EC50 = 78.1 ± 5.4 nM), low cytotoxity (SI > 1282) and persistent duration in reversing doxorubicin (DOX) resistance in K562/A02 cells. 42 also enhanced the potency of other P-gp associated cytotoxic agents with different structures. In further study, remarkably increased intracellular accumulation of Rh123 and DOX in K562/A02 cells was achieved by compound 42, while CYP3A4 activity had no change by compound 42. These results indicate that compound 42 as a relatively safe modulator of P-gp-mediated MDR has good potential for further development.
