化学
二氢吡喃
胞浆
赫拉
细胞培养
PI3K/AKT/mTOR通路
对接(动物)
立体化学
蛋白质亚单位
生物信息学
细胞色素c
生物化学
细胞凋亡
细胞
酶
生物
医学
遗传学
护理部
基因
催化作用
作者
Mallikharjuna Rao Lambu,Suresh Kumar,Syed Khalid Yousuf,Deepak Kumar Sharma,Altaf Hussain,Ajay Kumar,Fayaz Malik,Debaraj Mukherjee
摘要
A set of nine trans-disubstituted dihydropyran-based medium ring macrolides has been synthesized using d-glucal as chiral pool and evaluated against a panel of three human cancer cell lines and a normal cell line. The synthetic route to the targeted molecule is simple, concise, and high yielding compared to other reported methods. Bioevaluation studies have resulted in the identification of a potent cytotoxic molecule (10) exhibiting dose-dependent growth inhibition against HL-60 cell line with an IC50 value of 1.10 ± 0.075 μM, which is lower than that of naturally occurring molecules of this class and of comparable activity to the synthetic drug fludarubin. Compound 10 inhibits the PI3K/AKT signaling pathway by selectively targeting the p110α subunit of PI3Kα. This leads to mitochondrial stress that causes translocation of cytochrome c from mitochondria to cytosol, which in turn activates caspase-mediated apoptotic cell death. Further in silico docking simulations of four macrolides with p110α subunits have been carried out to visualize the orientation pattern.
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