Syntheses of alkyl-de-sanguinarine-N5-methyl derivatives and evaluation of in vitro growth inhibitory activities against cancer cell lines / 药学学报

ABSTRACT

2,37,8-Bis(methylenedioxy)benzo[c]phenanthridine was synthesized in a strategy of converging synthesis with 6-bromo-2,3-dihydroxybenzaldehyde, 5-nitronaphthalene-2,3-diol, and dibromomethane, respectively, as starting materials. The reaction process included dioxy-de-dibromo nucleophilic substitution under alkaline condition, reduction reaction, Schiff base-forming reaction, and an arene radical cyclization step under the presence of Bu3SnH and AIBN as radical initiator, among others. The 2,37,8-bis(methylenedioxy)benzo[c] phenanthridine as intermediate was reacted with NaBH4 and different aliphatic acids as alkylation agent to afford 2,37,8-bis(methylenedioxy)-5,6-dihydro-N5-alkylbenzo[c]phenanthridines. These dihydro-type products were aromatized using DDQ as oxidant under alkaline condition, and then, salinized using HCl as source of equilibrium anion to yield the series of target alkyl-de-sanguinarine-N5-methyl derivatives. All the synthesized alkyl-de-sanguinarine-N5-methyl derivatives exhibited significantly improved in vitro growth inhibitory activities against cancer cell lines as compared with sanguinarine and the positive control. In pharmacological experiments targeting five cancer cell lines, the target compounds showed activities five-fold active than that of sanguinarine. The findings of this study indicated that the structure modification strategy of substituting n-alkyls for the N5-methyl of natural sanguinarine can be used to improve the growth inhibitory activities against cancer cell lines through increasing liposolubility and steric hindrance to protect the active 5,6-imine structure.