Tao Gan, Yang Cheng, Wenhao Tian, Zhiping Liu, Chunfang Gan, Yanmin Huang, Chunrui Cai, Jianguo Cui
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引用次数: 0
摘要
癌症是困扰人类的最主要疾病之一。追求高效低毒的抗癌药物一直是科学家们的首要研究目标。在本研究中,我们以雌二醇为基本框架,将两种硒氰类药物团以不同方式加入到类固醇核的 2 位点和 17 支链中。因此,我们合成了几种具有 2-硒氰-17-硒氰酯结构的雌二醇双硒氰酸酯化合物。与阳性对照类固醇抗肿瘤药物 2-甲氧基雌二醇相比,某些衍生物在体外对肿瘤细胞的抑制活性优于其单硒氰酸酯前体。在细胞凋亡和细胞周期实验中,代表性化合物 4b 以浓度依赖性方式诱导 HeLa 细胞发生程序性凋亡,同时主要导致细胞周期 G2 期停滞。此外,化合物 4b 还对细胞迁移有明显的抑制作用,并对斑马鱼模型中的 HeLa 异种移植肿瘤有显著的抑制活性。这些发现表明,这些化合物有望成为抗肿瘤药物,值得进一步研究。
Synthesis of novel estradiol bisselenocyanate with unique 2-selenocyano-17-selenocyanoesteryl structure and evaluation of antitumor activity.
Cancer is one of the most significant diseases that afflict human beings. The pursuit of high efficacy and low-toxicity anticancer drugs has always been a paramount research objective for scientists. In the present study, we incorporated two selenocyano pharmacophores into the 2-site and 17-branch chain of the steroid nucleus in various manners, utilizing estradiol as the fundamental framework. Consequently, several estradiol bisselenocyanate compounds with a 2-selenocyano-17-selenocyanoester structure were synthesized. When compared to the positive control steroidal anti-tumor drug 2-methoxyestradiol, certain derivatives exhibited superior inhibitory activity against tumor cells in vitro, surpassing their monoselenocyanate precursors. The representative compound 4b induced programmed apoptosis in HeLa cells in a concentration-dependent manner during apoptosis and cell cycle experiments, while causing G2 phase arrest predominantly in the cell cycle. Moreover, compound 4b exhibited significant inhibitory effects on cell migration and demonstrated remarkable inhibitory activity against HeLa xenograft tumors in zebrafish models. These findings suggest that these compounds hold potential as promising candidates for anti-tumor drugs and warrant further investigation.
期刊介绍:
Molecular Diversity is a new publication forum for the rapid publication of refereed papers dedicated to describing the development, application and theory of molecular diversity and combinatorial chemistry in basic and applied research and drug discovery. The journal publishes both short and full papers, perspectives, news and reviews dealing with all aspects of the generation of molecular diversity, application of diversity for screening against alternative targets of all types (biological, biophysical, technological), analysis of results obtained and their application in various scientific disciplines/approaches including:
combinatorial chemistry and parallel synthesis;
small molecule libraries;
microwave synthesis;
flow synthesis;
fluorous synthesis;
diversity oriented synthesis (DOS);
nanoreactors;
click chemistry;
multiplex technologies;
fragment- and ligand-based design;
structure/function/SAR;
computational chemistry and molecular design;
chemoinformatics;
screening techniques and screening interfaces;
analytical and purification methods;
robotics, automation and miniaturization;
targeted libraries;
display libraries;
peptides and peptoids;
proteins;
oligonucleotides;
carbohydrates;
natural diversity;
new methods of library formulation and deconvolution;
directed evolution, origin of life and recombination;
search techniques, landscapes, random chemistry and more;