Design, Synthesis and Characterisation of Potential Anticancer Agents Based on Natural Products and Studies on their biological effect

ABSTRACT

Natural products have played a key role in drug discovery and are still a prolific source of novel lead compounds or pharmacophores for medicinal chemistry. Pharmacological activity and druggability are two indispensable components advancing natural products from leads to drugs. Although naturally active substances are usually good lead compounds, most of them can hardly satisfy the demands for druggability. Hence, these structural phenotypes have to be modified and optimized to overcome existing deficiencies and shortcomings. Combretastatin A-4 (CA-4) 1 belongs to a class of natural stilbene derivatives isolated from the bark of the South African bush willow tree combretum caffrum that displays anticancer activity by binding to the tubulin colchicine-binding site. Polyunsaturated fatty acids (PUFA) are readily taken by cancer cells and have been used to improve cell targeting. CA-4-PUFA conjugates were synthesized by coupling combretastatin A-4 with several saturated and unsaturated fatty acids. The conjugates were characterized by NMR, FTIR and MS. The cytotoxicity of the compounds was evaluated against human breast cancer cells (MCF-7) using an MTS assay and the inhibition of tubulin polymerization was determined using a standard turbidity assay. Although all conjugates had an effect on tubulin polymerization, only the arachidonic acid conjugate 87 displayed cytotoxicity similar to the natural product. A CA-4 peptide conjugate (figure 25) targeted to prostrate cancer cells was also synthesized. This analogue will exploit the proteolytic activities of prostate specific antigen (PSA) to convert an inactive CA-4 pro drug into active cytotoxic agent within the tumour thus improving bioavailability and efficacy. Dihydroartemisinin 2 -an artermisinin derivative and 2-methoxyestradiol 4, an estrogen hormone metabolite have been known as potential cancer chemotherapeutic agents. These compounds have both in vitro and in vivo anticancer activity in different types of human cancer cells, such as gastric cancer, osteosarcoma, breast cancer, esophageal cancer, hepatocellular carcinoma, prostate cancer, pancreatic cancer, ovarian cancer and lung cancer. Polyunsaturated fatty acid conjugates of both compounds were synthesized and characterised and like the CA-4 PUFA conjugates, these analogues will readily be taken up by cancer cells thereby improving their efficacies. In addition, dimers of natural occurring plant metabolite, betulinic acid 3 which posseses anticancer activities were made and characterised with the view of testing their anticancer activity.