Synthetic Studies of Biologically Active Natural Products – Ascididemin and 6-Substituted 2-Pyranones

Abstract

Synthetic studies of two classes of natural products, ascididemin and 6-stryl-4-methoxy-2-pyranone, are described. Compounds produced in these studies were submitted to a number of biological assays. The marine alkaloid ascididemin has considerable activity against Mycobacterium tuberculosis but unfortunately possesses significant cytotoxity and poor solubility. Analogues of ascididemin were prepared with variations at the 6-position and, in many instances, with replacement of the nitrogen at the 8-position with a carbon. Substituents were introduced that explored steric bulk and also enhanced aqueous solubility. Two new general routes were developed for the preparation of amide analogues at the 6-position of ascididemin. A set of 6-amidostyryl-8-deaza-ascididemin analogues showed considerable activity (MIC MTb 0.2-0.7 M), good solubility and modest to good selectivity (SIs from 6 to 125). 2-Pyranone natural products 1.14 and 1.15 have been reported to exhibit modest in vitro activity against Mycobacterium tuberculosis and the related 2-pyranones pseudopyronines A (1.27) and B (1.28) and analogues are reported to have anti-parasitic activity. To explore the structure activity relationship of these compounds a library of 6-substituted-4-methoxy-2-pyranones was prepared. Significant in vitro activity against Plasmodium falciparum was observed for several members of the compound library (e.g. 3.55 and 3.61 with IC50 values of of 1.3 and 3.6 M, respectively). Biomimetic photo-dimerisation of several styryl pyrones was explored and isolated dimers submitted to assays. X-ray crystal structures of two of the monomers were used to rationalise the resulting dimer structures. These dimerised pyrones were found to be generally more active against P. falciparum and less toxic than their monomers and had the best selectivity of the pyrone library evaluated.