Synthesis Of AKBA Derivatives And Their Mitochondria-targeted Antitumor Activities

Natural products and their derivatives are important sources of drug research and development.Acetyl-11-keto-β-boswellic acid(AKBA)is one of the pentacyclic triterpenoids derived from frankincense,which has significant anti-tumor activity.Here,we carried out a series of structural modifications based on AKBA for more potential anti-tumor compounds.The three structural modification strategies involved are:1)introducing α,β-unsaturated ketone structure on ring A of AKBA.2)ethylenediamine as link chain on 24-carboxyl group to connect benzene ring,carbon chain or ring structure(ternary ring,six-membered ring),and hydrolysis of 3-ethyl ester.3)based on mitochondrial targeting strategy,to prepare mitochondrial targeting triphenylphosphine(TPP)derivatives using ethylenediamine as link.A total of 30 compounds were designed and synthesized.Bioactivity screening tests revealed that P-5,a mitochondrial targeting potential derivative,showed significantly stronger antitumor activity than that of AKBA,and it could induce vacuolization of A549 cells,while electron microscope images showed mitochondrial damage and endoplasmic reticulum swelling in the treated group.Further studies demonstrated that P-5 could down-regulate the expression of histone deacetylase SIRT3(silent mating type information regulation 2 homolog-3)and stimulate the production of reactive oxygen species in a time-and concentration-dependent manner.Antioxidant NAC could inhibit the level of reactive oxygen species but could not suppress vacuolization and cell death.Mitochondrial MPTP pores showed abnormal opening,mitochondrial membrane potential decreased,cytoplasmic calcium level increased and Alix protein expression decreased;apoptosis was not obvious and cell arrest occurred in G0/G1 phase.This paper designed ethylenediamine-linked substituents and triphenylphosphine salts of AKBA for the first time and attempted to analyze their structure-activity relationship and explore the action mechanism,which may be instructive for the anti-tumor research and development of structural modification based on AKBA.