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

Abstract

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.

• Authors: Mallikharjuna R Lambu, Suresh Kumar, Syed K Yousuf, Deepak K Sharma, Altaf Hussain, Ajay Kumar, Fayaz Malik, Debaraj Mukherjee
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 56 Issue 15 Pg. 6122-35 (Aug 08 2013) ISSN: 1520-4804 [Electronic] United States
• PMID: 23845251 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Macrolides
• Phosphoinositide-3 Kinase Inhibitors
• Pyrans
• Class Ia Phosphatidylinositol 3-Kinase
• Proto-Oncogene Proteins c-akt

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Class Ia Phosphatidylinositol 3-Kinase (metabolism)
• Drug Screening Assays, Antitumor
• Humans
• Macrolides (chemical synthesis, chemistry, pharmacology)
• Membrane Potential, Mitochondrial (drug effects)
• Molecular Docking Simulation
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrans (chemical synthesis, chemistry, pharmacology)
• Signal Transduction
• Stereoisomerism
• Structure-Activity Relationship