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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Synthesis and in vitro evaluation of novel spiroketopyrazoles as acetyl-CoA carboxylase inhibitors and potential antitumor agents
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Synthesis and in vitro evaluation of novel spiroketopyrazoles as acetyl-CoA carboxylase inhibitors and potential antitumor agents

机译：新型螺旋吡唑作为乙酰-CoA羧化酶抑制剂和潜在抗肿瘤剂的合成与体外评价

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摘要

Acetyl-CoA carboxylase (ACC) is a rate-limiting enzyme in de novo fatty acid synthesis, which plays a critical role in the growth and survival of cancer cells. In this study, a series of spiroketopyrazole derivatives bearing quinoline moieties were synthesized, and in vitro anticancer activities of these compounds as ACC inhibitors were evaluated. The biological evaluation showed that compound 7j exhibited the strongest enzyme inhibitory activity (IC50 = 1.29 nM), while compound 7m displayed the most potent anti-proliferative activity against A549, HepG2, and MDA-MB-231 cells with corresponding IC50 values of 0.55, 0.38, and 1.65 mu M, respectively. The preliminary pharmacological studies confirmed that compound 7m reduced the intracellular malonyl-CoA and TG levels in a dose-dependent manner. Moreover, it could down-regulate cyclin D1 and CDK4 to disturb the cell cycle and up-regulate Bax, caspase-3, and PARP along with the suppression of Bcl-2 to induce apoptosis. Notably, the combination of 7m with doxorubicin synergistically decreased the HepG2 cell viability. These results indicated that compound 7m as a single agent, or in combination with other antitumor drugs, might be a promising therapeutic agent for the treatment of hepatocellular carcinoma. (C) 2020 Elsevier Masson SAS. All rights reserved.
机译：乙酰辅酶a羧化酶（ACC）是一种从头合成脂肪酸的限速酶，对癌细胞的生长和存活起着关键作用。本研究合成了一系列含有喹啉部分的螺环吡唑衍生物，并对这些化合物作为ACC抑制剂的体外抗癌活性进行了评价。生物学评价表明，化合物7j具有最强的酶抑制活性（IC50=1.29 nM），而化合物7m对A549、HepG2和MDA-MB-231细胞具有最强的抗增殖活性，相应的IC50值分别为0.55、0.38和1.65μM。初步药理研究证实，化合物7m以剂量依赖性方式降低细胞内丙二酰辅酶a和TG水平。下调cyclind1和CDK4干扰细胞周期，上调Bax、caspase-3和PARP，抑制Bcl-2诱导细胞凋亡。值得注意的是，7m与阿霉素联合使用可协同降低HepG2细胞活力。这些结果表明，化合物7m作为单一药物或与其他抗肿瘤药物联合使用，可能是治疗肝细胞癌的一种有前途的治疗药物。（C） 2020年爱思唯尔马森SAS。版权所有。

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