Since cancer is one of the major causes of death all over the world, discovery of effective anticancer agents has long been desired. Plant alkaloids are often considered to be potent candidates. Cryptolepsis sanguinolenta is a medicinal plant which habits in West Africa. In a traditional medicine, a decoction of the root of C. sanguinolenta is used to treat fevers. Neocryptolepine, one of the plant alkaloids extracted from the root of C. sanguinolenta, are reported to have several activities such as DNA intercalation, anti-malaria and Topoisomerase inhibition. Topoisomerase (Topo) is double helical DNA relaxation enzyme and responsible for DNA replication, transcription and recombination. Inhibition of Topoisomerase is one of the mechanisms of anti-cancer agent. In this research, we synthesized a number of neocryptolepine derivatives with several substituents added to the backbone and evaluated their inhibitory activities of cell growth and topoisomerase.

The derivatives were synthesized from indole carboxylic acid methyl ester and aniline derivatives through well-known procedure. DNA relaxation activity of the derivatives was assessed on plasmid pBR322 DNA in the presence of TopoI or TopoII. Cell growth inhibition was assessed on six cancer cell lines; K562, LNCaP, MDA-MB-453, SKOv3, A549, and WiDr. Those cell lines were exposed to the derivatives for 72 hours and their 50% survival rate IC50 was estimated by MTT colorimetric assay. Although no derivative inhibited TopoII activity, 12 derivatives inhibited TopoI activity. The inhibition of TopoI by neocryptolepine derivatives appears to be caused by their planar organic constitution, which enable derivatives to intercalate into double helix of DNA. Cell growth inhibitory effect has been improved in some derivatives that received modification at their substituent. Those derivatives also exhibited TopoI inhibition correlating with inhibition of cell growth.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3711.