Biological evaluation of 2,3-dioxoindolin-N-phenylacetamide derivatives as potent CDC25B and PTP1B phosphatase inhibitors

Abstract

A series of 2,3-dioxoindolin-N-phenylacetamide derivatives was evaluated for inhibitory activity against CDC25B and PTP1B enzymes. Most of the derivatives showed inhibitory activity against CDC25B (IC 50 = 3.2-23.2 µg/mL) and PTP1B (IC 50 = 2.9-21.4 µg/mL). Compound 2h showed the most inhibitory activity in vitro with IC 50 values of 3.2 and 2.9 µg/mL against CDC25B and PTP1B, respectively, compared with the reference drugs Na 3 VO 4 (IC 50 = 2.7 µg/mL) and oleanolic acid (IC 50 = 2.3 µg/mL). The results of selectivity experiments showed that the 2,3-dioxoindolin-N-phenylacetamide derivatives were selective inhibitors against CDC25B and PTP1B. Enzyme kinetic experiments demonstrated that compound 2h was a specific inhibitor with the typical characteristics of a mixed inhibitor. In cytotoxic activity assays compound 2h had potent activity against A549, HeLa, and HCT116 cell lines. In addition, compound 2h showed potent tumor inhibitory activity in a colo205 xenograft model in vivo.

A Comprehensive Overview of the Developments of Cdc25 Phosphatase Inhibitors

“…Moreover, a series of 2,3-dioxoindolin-N-phenylacetamide derivatives was synthesized and evaluated for their inhibitory activity against Cdc25B and PTP1B enzymes. 2-(4-Chloro-2,3-dioxoindolin-1-yl)-N-phenylacetamide (114) showed the most inhibitory activity with IC 50 values of 3.2 and 2.9 µg/mL against Cdc25B and PTP1B, respectively [113].…”

“…Recently, the two triterpenoids 3β-hydroxylanosta-8,24Z-dien-26-oic acid (112) and cyclooctenol (113) were isolated from the stem and leaves of Schisandra chinensis. They showed significant inhibition of Cdc25A phosphatase with inhibitory rates of 85.5% and 98.1%, respectively at 100 µM [112].…”