Discovery of berberine analogs as potent and highly selective p300/CBP HAT inhibitors.

[Display omitted] • A series of novel berberine analogs were synthesized, and evaluated for their p300 inhibitory activity. • Structure-activity relationship studies yielded a more potent compound 5d. • Compound 5d specifically decreases H3K18Ac and interferes with the function of histone acetyltransferase. • Compound 5d exhibited good antitumor effects in MDA-MB-231 cells in vitro and in vivo. The protein p300 is a positive regulator of cancer progression and is related to many human pathological conditions. To find effective p300/CBP HAT inhibitors, we screened an internal compound library and identified berberine as a lead compound. Next, we designed, synthesized, and screened a series of novel berberine analogs, and discovered that analog 5d was a potent and highly selective p300/CBP HAT inhibitor with IC 50 values of 0.070 μM and 1.755 μM for p300 and CBP, respectively. Western blotting further proved that 5d specifically decreased H3K18Ac and interfere with the function of histone acetyltransferase. Although 5d had only a moderate inhibitory effect on the MDA-MB-231 cell line, 5d suppressed the growth of 4T1 tumor growth in mice with a tumor weight inhibition ratio (TWI) of 39.7%. Further, liposomes-encapsulated 5d increased its inhibition of tumor growth to 57.8 % TWI. In addition, 5d has no obvious toxicity to the main organ of mice and the pharmacokinetic study confirmed that 5d has good absorption properties in vivo. [ABSTRACT FROM AUTHOR]