Identification, semi-synthesis and evaluation of anti-ovarian cancer compounds from plants used in traditional medicines

Ovarian cancer is the second leading cause of death among women in the gynaecological category of cancers. The current post surgery treatment which involves the use of platinum-based therapy with its attendant adverse drug-resistance often results in the return of the cancer. This research work, explored the role of natural products as the major source of new drugs by the evaluation of the anti-ovarian cancer activities of three selected medicinal plants and the semi-synthesis of analogues of an anti-cancer agent; thymoquinone from Nigella sativa. Using a bioassay-guided approach, an investigation of the cell growth inhibition of the extracts/fractions of these plants on four human ovarian cancer cell lines, A2780, OVCAR 4, OVCAR 8, and CIS-A2780 showed that Acalypha wilkesiana, Margaritaria discoidea and Rutidea parviflora had promising anti-ovarian cancer activities. This is the first report of the anti-cancer activities of M. discoidea and R. parviflora. The bioactive compounds of the plants were isolated by HPLC, identified by mass spectrometry/NMR spectroscopy and investigated for cytotoxicity. Gallic acid, (IC50 range of 6.2±0.3 – 26.9±4.1 μM) was the active compound in A. wilkesiana. The significantly bioactive compounds of M. discoidea were securinine, (IC50 range of 2.7±0.7 – 8.7±0.1 μM), betulinic acid, (IC50 of 16.0±1.9 μM) and gallic acid. While palmatine, (IC50 range of 5.5±0.9 – 7.9±0.5 μM) was the major active compound in R. parviflora. Twenty-one thymoquinone analogues including eleven semi-synthetic ones were evaluated for cytotoxicity. A synthetic 2-dimethylamino-5-methyl-1,4-benzoquinone demonstrated optimum activity (IC50 range of 4.7±0.5 – 11.2±1.9 μM) and superior aqueous solubility. Palmatine, securinine and 2-dimethylamino-5-methyl-1,4-benzoquinone showed induction of apoptosis via increased caspase 3/7 activity. Palmatine demonstrated PAPR cleavage by western blot analysis. 2-dimethylamino-5-methyl-1,4-benzoquinone showed synergy with carboplatin and paclitaxel. These studies have provided scientific evidences for the potential treatment of ovarian cancer with these traditional medicinal plants and hit compounds for future optimization towards clinical trials.