Design, synthesis and anti-breast tumor activity of Berberine hydrogen sulfide donor derivatives

In order to improve the antitumor activity of berberine, different hydrogen sulfide donors were synthesized by alkyl chain splicing berberine isoquinoline. The total of 33 new compounds were synthesized. It showed that ber-a5, ber-a8 and ber-b5 had strong inhibitory activity against MCF-7 and 4 T1 cells, and IC₅₀ of ber-a8 was 0.75 ± 0.03 μmol/L in MCF-7. Ber-a5, ber-a8 and ber-b5 were found to have good interactions with serine/threonine kinase (AKT) proteins and acted on the depressed pocket on the surface below the AB chain junction. In the H₂S release experiment, ber-a3 ∼ ber-a5, ber-b2 ∼ ber-b5 were able to release more H₂S under the catalysis of L-cysteine using anethol trithione as a hydrogen sulfide donor. The longer the chain, the stronger the H₂S release ability, the lower the IC₅₀. The pharmacokinetic parameters of most compounds such as PPB, BBB, and GI were improved compared with berberine in the ADMET predict test.