Karstmycins A-H: Trichostatin Analogues with PTP1B Inhibitory Activities from Streptomyces sp. DX6D14

Eight pairs of undescribed trichostatin analogue enantiomers, (±)-karstmycins A-H (1a/1b-8a/8b), and three new enantiomers (9a-11a) together with five known analogues (9b-11b, 12, and 13) were isolated from karst cave-derived Streptomyces sp. DX6D14. The structures and absolute configurations of the new compounds were determined by extensive spectroscopic analysis, as well as nuclear magnetic resonance chemical shifts, optical rotation, and electronic circular dichroism calculations. Compounds 1 and 2 were rare trichostatins featuring a nitrile group, and compounds 3-5 were characterized by a unique piperidin-2-one moiety at the end of the branched C₇ side chain. Compounds 3a and 3b showed PTP1B inhibitory activity with IC₅₀ values of 27 ± 2 and 12 ± 2 μM, respectively, compared to the positive control, sodium orthovanadate (IC₅₀: 14 ± 1 μM). A kinetic study indicated that the most potent compound 3b was a mixed-type inhibitor for PTP1B. Molecular docking simulation revealed that 3b simultaneously interacted with the catalytic site and the peripheral site of PTP1B.