Synthesis and cytotoxicity of a novel series of saframycin-ecteinascidin analogs containing tetrahydro-β-carboline moieties

Abstract

A novel bistetrahydrocarboline heptacyclic skeleton and its twenty derivatives were prepared from l-tryptophan through a 15-step stereospecific route. The cytotoxicities of these compounds were tested against six human cancer cell lines including HCT-116, HepG2, BGC-823, MCF-7, A2780, and HT-29. Most of the derivatives with amide side chain exhibited the IC₅₀ values at the level of 10^-7 M, and a preliminary structure-activity relationship (SAR) was discussed. Both compound 30 with 2-pyridine amide side chain and compound 14 with phthalamide side chain showed the most potent and broad cytotoxicity towards all six cell lines with the IC₅₀ values at the level of 10^-8 M. Molecular docking of compound 30 indicated it bound to minor groove of DNA duplex.

Keywords: Bistetrahydrocarboline; Bistetrahydroisoquinoline; Cytotoxicity; Synthesis; l-tryptophan.