The chemistry of African Croton species

Abstract

The genus Croton consists of an important group of trees, with several of its species being commercially exploited either as medicines, biofuels or for the cosmetics industry. Plaunotol, an anti-peptic ulcer drug marketed as Kelnac® is isolated from the leaves of Croton stellatopilosus, Sangre De Drago from Croton lechleri is commercially available for the treatment of wounds and diarrhoea, and Croton megalocarpus seed oil is commercially available as a biofuel and for cosmetic uses. Several species of the Croton genus have been reported as being used ethnomedicinally to treat hypertension, rheumatism, inflammation, bleeding gums, malaria, diarrhoea, syphilitic ulcers, asthma, pain and diabetes. The genus Croton is one of the largest genera of the Euphorbiaceae sensu stricto, and consists of over 1300 species of shrubs and trees that are distributed in the warm tropics and sub-tropics. In Africa, there are more than 292 Croton species where 124 are reported to occur in continental Africa, 156 in Madagascar and 12 in the Indian Ocean islands of Reunion, Comoros, Mauritius and Sao Tome and Principe. This study focussed on the chemistry and pharmacological activity of three Central and East African Croton species, Croton mubango Mull. Arg. and Croton haumanianus J. Leonard from the Democratic Republic of Congo and Croton dictyophlebodes Radcl.-Sm from Tanzania. These species are traditionally used in the treatment of a variety of diseases. A total of seventy-five compounds were isolated from these species, including sixty diterpenoids, three triterpenoids, three sesquiterpenoids, three phytosterols, two phenolic compounds, one ferulic acid derivative, linoleic acid and two chlorophyll derivatives. The chemical structures of the isolated compounds were determined using NMR spectroscopy, mass spectrometry, and infrared and specific rotation experiments. DP4+ calculations were used to determine the absolute configuration of compound CM-6 whereas TDDFT-ECD simulation experiments were used to determine absolute configurations for compounds CM-1, CM-2, CM-5, CM-17, CH-19 and CH-21. Thirty-eight diterpenoids are described in this study for the first time, including eleven ent-abietane and one ent-pimarane diterpenoids from C. mubango, nine ent-kauranes, three ent-clerodanes and five ent-isopimaranes from C. haumanianus, and eight ent-clerodanes and one ent-trachylobane from C. dictyophlebodes. Thirty diterpenoids were submitted to the Development Therapeutics Program (DTP) of the National Cancer Institute (NCI) in the United States of America for the NCI 60 anticancer cell line screening programme. Compounds CM-17, CH-11, CH-12, CH-13 and CH-15 showed selective antiproliferative effects against three of the NCI 60 cancer cell lines. Compounds CH-11, CH-12, CH-13 and CH-15 were found to show 100% lethality against colon (HCT-116), melanoma (M14) and renal (786-0) cancer cell lines whereas CM-17 gave 99%, 89% and 82% cell lethality against melanoma (MALME-3M), renal (UO-31) and ovarian cancer (IGROV1) cell lines respectively at a concentration of 10-5 M.