Bioactive sesquiterpenoids from dicoma anomala subsp. gerrardii

Abstract

Through South Africa’s first collaborative project between a large scientific organisation, the Council for Scientific and Indust rial Research (CSIR), and the Traditional Healer’s Committee, Dicoma anomala was identified as a plant containing potent anticancer and antimalarial compo unds. In the process of evaluation, extracted plant material with reported or anecdotal use for the treatment of respiratory problems was found to have significant anticancer activity in vitro in a 3-cell line preliminary screen . The extract was further shown to have potent anticancer activity against the 60-cell line panel at the National Cancer Institute (NCI) in the USA. Bioassay-guided fractio nation, initially utilising an in vitro anticancer assay, and structural elucidation resul ted in two potent compounds with sesquiterpenoid skeletons (C-15 and C-30). The crystal structure of the C-15 compound, not published previously, was obtained. B oth compounds were further screened in an antiplasmodial assay during the cour se of the National Drug Development Platform (RSA: CSIR, MRC and UCT) proje ct, and were found to have potent activity against Plasmodium falciparum (a malaria protozoon). Although the C-15 compound had a selectivity index (SI) of 10, suggesting that it was suitable for subsequent development, the dimer was highly toxic (SI index of 1), limiting opportunities for future development. A further study of the structure- activity relationship (SAR), which was initiated fo r the C-15 compound, showed that removal of each unsaturated structural compone nt decreased activity 10–fold in both bioassays. Additional investigations were c arried out into amino-acid Michael adducts with the exocyclic double bond of t he C-15 sesquiterpenoids, and the products were characterised by NMR spectroscopy and mass spectrometry. A similar investigation, involving the conjugate addi tion of simple amines, was undertaken in an attempt to enhance the bioavailabi lity of the parent sesquiterpenoid. Three diethylamine derivatives wer e prepared and characterised. A general 10-fold drop in the bioactivity of these “pro-drug” derivatives in both assays was observed. Finally, the C-15 compound was tested in vivo in the Plasmodium berghei murine malaria model and was found to have some eff ect on the survival rates of the laboratory animals when c ompared with the control. A possible mode of action is suggested based on the e xperimental and published bioactivity data. Further studies to improve the bi oactivity and alternative design of future in vivo studies are also proposed.