Synthesis and evaluation of azalamellarin N and its A-ring-modified analogues as non-covalent inhibitors of the EGFR T790M/L858R mutant

Azalamellarin N, a synthetic lactam congener of the marine natural product lamellarin N, and its A-ring-modified analogues were synthesized and evaluated as potent and non-covalent inhibitors of the drug-resistant epidermal growth factor receptor T790M/L858R mutant. An in vitro tyrosine kinase assay indicated that the inhibitory activities of the synthetic azalamellarin analogues were higher than those of the corresponding lamellarins.The azalamellarin analogue bearing two 3-(dimethylamino)propoxy groups at C20- and C21-positions exhibited the highest activity and selectivity against the mutant kinase [IC50 (T790M/L858R) = 1.7 nM; IC50 (WT) = 4.6 nM]. The inhibitory activity was attributed to the hydrogen bonding interaction between the lactam NH group of the B-ring and carbonyl group of a methionine residue

Linfuranones B and C, Furanone-Containing Polyketides from a Plant-Associated <i>Sphaerimonospora mesophila</i>

Two new furanone-containing polyketides, linfuranones B and C, were isolated from a plant-associated actinomycete of the genus <i>Sphaerimonospora</i>. Their structures were determined by NMR and MS spectroscopic analyses, and the absolute configurations were established by anisotropic methods and chemical degradation approaches. <i>In silico</i> analysis of biosynthetic genes suggested that linfuranone B is generated from linfuranone C by oxidative cleavage of the polyketide chain. Linfuranones B and C induced preadipocyte differentiation into matured adipocytes at 20–40 μM without showing cytotoxicity