4,5,6,7-Tetrahydro-isoxazolo-[4,5-c]-pyridines as a new class of cytotoxic Hsp90 inhibitors

•A series based on a tetrahydroisoxazolopyridine scaffold has been prepared.•Some compounds bind to Hsp90 and have cytotoxic activity at micro/submicroM range.•A resorcinol portion, bound as amide at N-5 demonstrated crucial for activity.•C-3 carboxamide function is preferred to ester.•A hydroxamic acid bound to C-3 carboxamide allows selective inhibition of HDAC6.

Hsp90 is considered an interesting therapeutic target for anticancer drug development. Here we describe a new class of 4,5,6,7-tetrahydro-isoxazolo-[4,5-c]-pyridine compounds. A small library of derivatives has been synthesized and investigated. Some reported compounds show interesting properties combining both notable binding to Hsp90 and potent cell growth inhibitory activity. N-5 substitution with a 2,4 resorcinol carboxamide appears crucial for activity. Moreover, a derivative bearing a hydroxamic acid residue bound to C-3 amide portion was found to inhibit both Hsp90 and HDAC6.

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