Yahya Shaymaa M M, Abdelhamid Abdou O, Abd-Elhalim Mervat M, Elsayed Ghada H, Eskander Emad F
Hormones Department, National Research Centre, Dokki, Giza, Egypt.
Chemistry Department, Faculty of Science, Cairo University, Cairo, Egypt.
Steroids. 2017 Oct;126:15-23. doi: 10.1016/j.steroids.2017.08.002. Epub 2017 Aug 8.
Due to its high potency and selectivity, anticancer agents consisting of combined molecules have gained great interests. The current study introduces newly synthesized progesterone derivatives of promising anticancer effect. Moreover, the pro-apoptotic and anti-angiogenic effects of these compounds were studied extensively. Several thiazole, pyridine, pyrazole, thiazolopyridine and pyrazolopyridine progesterone derivatives were synthesized. The structure of the novel progesterone derivatives was elucidated and confirmed using the analytical and spectral data. This novel derivatives were tested for their cytotoxic effect against human breast cancer cells (MCF-7) using neutral red uptake assay. Tested compounds showed anticancer activity against MCF-7 cancer cell line in the descending order of 7>2>3>8>6>9>4. The expression levels of Bcl-2, survivin, CCND1, CDC2, P53 and P21, VEGF, Hif-1α, MMP-2, MMP-9, Ang-1, Ang-2, and FGF-1 genes were investigated using QRT-PCR (Quantitative real time-polymerase chain reaction). The study clarified that compounds 2, 3, 4, 6, 7, 8 and 9 showed significant pro-apoptotic effect through the down regulation of Bcl-2., besides, survivin and CCND1 expression levels were down regulated by compounds 3, 4, 6, 7, 8, 9. However, Compound 4 may exert this pro-apoptotic effect through the up-regulation of P53 gene expression. On the other hand, the anti-angiogenic effect of these newly synthesized derivatives was due to their down regulation of VEGF, Ang-2, MMP-9 and FGF-1; and the up-regulation of HIF-1α and ang-1. This study recommended promising pro-apoptotic and anti-angiogenic anticancer agents acting through the regulation of key regulators of apoptosis, cell cycle genes, and pro-angiogenic genes.
由于其高效性和选择性，由组合分子构成的抗癌药物引起了极大关注。当前研究介绍了具有有望的抗癌效果的新合成孕酮衍生物。此外，还对这些化合物的促凋亡和抗血管生成作用进行了广泛研究。合成了几种噻唑、吡啶、吡唑、噻唑并吡啶和吡唑并吡啶孕酮衍生物。利用分析和光谱数据阐明并确认了新型孕酮衍生物的结构。使用中性红摄取试验测试了这些新型衍生物对人乳腺癌细胞（MCF-7）的细胞毒性作用。测试的化合物对MCF-7癌细胞系显示出抗癌活性，活性顺序为7>2>3>8>6>9>4。使用定量实时聚合酶链反应（QRT-PCR）研究了Bcl-2、survivin、CCND1、CDC2、P53和P21、VEGF、Hif-1α、MMP-2、MMP-9、Ang-1、Ang-2和FGF-1基因的表达水平。该研究表明，化合物2、3、4、6、7、8和9通过下调Bcl-2显示出显著的促凋亡作用。此外，化合物3、4、6、7、8、9下调了survivin和CCND1的表达水平。然而，化合物4可能通过上调P53基因表达发挥这种促凋亡作用。另一方面，这些新合成衍生物的抗血管生成作用是由于它们下调了VEGF、Ang-2、MMP-9和FGF-1；并上调了HIF-1α和Ang-1。本研究推荐了通过调节凋亡、细胞周期基因和促血管生成基因的关键调节因子发挥作用的有前景的促凋亡和抗血管生成抗癌药物。
