Department of Medicinal Chemistry, School of Pharmacy, Najran University, Najran, P.O. 1988, Saudi Arabia.
Department of Chemistry and Biochemistry, South Dakota State University, Brookings, SD, 57006, USA.
Eur J Med Chem. 2019 Jul 1;173:294-304. doi: 10.1016/j.ejmech.2019.04.018. Epub 2019 Apr 16.
Natural products have been known as a fundamental source for drug discovery leading to the evolution of Biological Oriented Organic Synthesis (BIOS) approach to assemble natural product mimics. Herein, a series of Cucurbitacin inspired estrone analogs was assembled to generate 18 novel synthesized analogs via installation of double bond across C-16/C-17 positions of estrone scaffold and diastereomeric separation of (R) and (S) at C-20. This was followed by biological screening against HEPG-2 cell lines to exhibit anti-proliferative activity ranging from IC 0.70-32 μM. Two analogs (MMA-102 and MMA-132) were chosen for further biological elucidation to exhibit dual inhibitory mechanism against the phosphorylating pathways of EGFR and MAPK (RAS/RAF/MEK/ERK) pathways. Both of MMA-102 and MMA-132 showed cell cycle arrest with elevated levels of apoptotic parameters. Molecular modeling simulations suggested the potential of MMA-102 and MMA-132 to compete with ATP within the catalytic binding domains of EGFR and MAPK pathway.
天然产物一直是药物发现的重要来源，这导致了生物导向有机合成（BIOS）方法的发展，用于组装天然产物类似物。在此，我们合成了一系列受葫芦素启发的雌酮类似物，通过在雌酮骨架的 C-16/C-17 位置引入双键，并对 C-20 处的（R）和（S）进行非对映异构体分离，生成了 18 种新的合成类似物。随后对 HEPG-2 细胞系进行了生物筛选，以显示出 0.70-32 μM 的抗增殖活性。选择了两种类似物（MMA-102 和 MMA-132）进行进一步的生物学阐明，以显示出对 EGFR 和 MAPK（RAS/RAF/MEK/ERK）途径磷酸化途径的双重抑制机制。MMA-102 和 MMA-132 均显示出细胞周期停滞，并伴有凋亡参数水平升高。分子模拟模拟表明，MMA-102 和 MMA-132 有可能在 EGFR 和 MAPK 途径的催化结合域中与 ATP 竞争。
