Tantawy Mohamed A, Shalby Aziza B, Barnawi Ibrahim Omar, Kattan Shahad W, Abd-Rabou Ahmed A, Elmegeed Gamal A
Hormones Department, Medical Research and Clinical Studies Institute, National Research Centre, Dokki, Giza, Egypt; Stem Cells Lab, Center of Excellence for Advanced Sciences, National Research Centre, Dokki, Cairo, Egypt.
Hormones Department, Medical Research and Clinical Studies Institute, National Research Centre, Dokki, Giza, Egypt; Stem Cells Lab, Center of Excellence for Advanced Sciences, National Research Centre, Dokki, Cairo, Egypt.
Steroids. 2023 May;193:109187. doi: 10.1016/j.steroids.2023.109187. Epub 2023 Feb 2.
To identify new steroidal agents with potential biological activities, we synthesized hybrid steroids containing thiazole, pyrazole, isoxazole, thiophene or phthalazine moiety. Epi-androsterone 1 reacted with phenylthiosemicarbazide to afford the corresponding androstane-4-phenyl-3-thiosemicarbazone derivative 2. The latter product was used in the synthesis of a series of annulated steroid derivatives. Also, Epi-androsterone 1 reacted with the thienopyridazine derivative 16 to afford the thieno[3,4-d]pyridazino-N-ylidenoandrostane derivative 17. Compound 17 reacted readily with electron-poor olefins to yield the corresponding phthalazine steroid derivatives. Detailed experimental and spectroscopic evidences for the structures of the newly synthesized compounds are explained. Compounds 3, 7, 8a, 12a, 14, 17 and 21a, were investigated individually as anticancer agents on different panel of human malignant cell lines. Moreover, a computer modelling investigation was performed to speculate the macromolecular targets for the most promising candidate. The results revealed a concentration-dependent reduction in the number of viable cells in all cancer cell lines. Most notably, compound 7 was the most effective compound against all tested cancer cell lines, especially against HepG2 cell line; therefore, the mode of action of this compound against HCC was investigated. Compound 7 was able to induce cell cycle arrest, and DNA fragmentation in HepG2 cells. Moreover, compound 7 induced apoptosis via upregulating the expression of caspase-3, -8, -9, P53, Bax and inhibiting the expression of BCL2, and CDK2 genes. Our results highlighted compound 7 as a promising anti-hepatocellular carcinoma agent, with theoretical, and practical potential binding affinity with CDK2; therefore, more investigations are required to elucidate its chemotherapeutic value as anti-HCC agent.
为了鉴定具有潜在生物活性的新型甾体药物，我们合成了含有噻唑、吡唑、异恶唑、噻吩或酞嗪部分的杂合甾体。表雄酮1与苯硫代氨基脲反应，得到相应的雄甾烷-4-苯基-3-硫代氨基脲衍生物2。后者用于合成一系列稠合甾体衍生物。此外，表雄酮1与噻吩并哒嗪衍生物16反应，得到噻吩并[3,4-d]哒嗪并-N-亚基雄甾烷衍生物17。化合物17与缺电子烯烃容易反应，生成相应的酞嗪甾体衍生物。解释了新合成化合物结构的详细实验和光谱证据。化合物3、7、8a、12a、14、17和21a分别作为抗癌剂在不同的人类恶性细胞系中进行了研究。此外，还进行了计算机建模研究，以推测最有前景的候选物的大分子靶点。结果显示，所有癌细胞系中活细胞数量均呈浓度依赖性减少。最值得注意的是，化合物7是对所有测试癌细胞系最有效的化合物，尤其是对HepG2细胞系；因此，研究了该化合物对肝癌的作用方式。化合物7能够诱导HepG2细胞的细胞周期停滞和DNA片段化。此外，化合物7通过上调caspase-3、-8、-9、P53、Bax的表达并抑制BCL2和CDK2基因的表达来诱导细胞凋亡。我们的结果突出了化合物7作为一种有前景的抗肝细胞癌药物，与CDK2具有理论和实际的潜在结合亲和力；因此，需要更多的研究来阐明其作为抗肝癌药物的化疗价值。
