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J Med Chem. 2013 Aug 8;56(15):6122-35. doi: 10.1021/jm400515c. Epub 2013 Jul 29.

Medicinal chemistry of dihydropyran-based medium ring macrolides related to aspergillides: selective inhibition of PI3Kα.

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  • 1Academy of Scientific and Innovative Research, New Delhi, India.


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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