title: 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.affiliation: Academy of Scientific and Innovative Research, New Delhi, India.
authors.forename: Mallikharjuna R
authors.initials: MR
authors.lastname: Lambu
authors.forename: Suresh
authors.initials: S
authors.lastname: Kumar
authors.forename: Syed K
authors.initials: SK
authors.lastname: Yousuf
authors.forename: Deepak K
authors.initials: DK
authors.lastname: Sharma
authors.forename: Altaf
authors.initials: A
authors.lastname: Hussain
authors.forename: Ajay
authors.initials: A
authors.lastname: Kumar
authors.forename: Fayaz
authors.initials: F
authors.lastname: Malik
authors.forename: Debaraj
authors.initials: D
authors.lastname: Mukherjee
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D062105:Molecular Docking Simulation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D018942:Macrolides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011714:Pyrans; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt