Cascade Mono- and Di-Functionalization of Anticancer Diastereomeric Benzoxazole-Ansamycins toward the Development of Highly Potent Hsp90 Inhibitors of Decreased Toxicity in Normal Cells

Abstract To reduce toxicity of geldanamycin (GDM), the domino transformation of its benzoquinone core into benzoxazole has been performed. Structural studies of ester-phenol and ester-ether benzoxazole-type ansamycins indicate that the former is present as (Sp)-diastereomer, whereas the latter is present as conformation-“locked” (Rp)-diastereomer, which is more favorable at binding to Hsp90. Several of the obtained benzoxazole ansamycins revealed high anticancer potency in SKBr-3, MCF-7, SKOV-3, and PC-3 lines with improved selectivity and lower affinity to glutathione, compared to GDM. The most potent derivative 6 reveals excellent anticancer activity (IC50 < 0.6 μM) with Hsp90 as the primary target [KD6-Hsp90 = 0.3 μM], limited off-target effects (kinases), and decreased toxicity (selectivity indices = 2.75−3.48) regarding GDM. Ester-ether type derivative 22 reveals good anticancer potency in SKOV-3 (IC50 = 0.62 μM) with reduced toxicity in human dermal fibroblast and human umbilical vein endothelial cells, improved selectivity (SISKOV-3 = 2.75), apoptotic index AISKOV-3 ∼8, and high chemical and in vivo stabilities.