Medicinal Chemistry of Dihydropyran-Based Medium Ring Macrolides Related to Aspergillides: Selective Inhibition of PI3K伪

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• 作者：Mallikharjuna R. Lambu ; Suresh Kumar ; Syed K. Yousuf ; Deepak K. Sharma ; Altaf Hussain ; Ajay Kumar ; Fayaz Malik ; Debaraj Mukherjee
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：August 8, 2013
• 年：2013
• 卷：56
• 期：15
• 页码：6122-6135
• 全文大小：751K
• 年卷期：v.56,no.15(August 8, 2013)
• ISSN：1520-4804

文摘

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 卤 0.075 渭M, 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 p110伪 subunit of PI3K伪. 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 p110伪 subunits have been carried out to visualize the orientation pattern.