The microtubule system of the eukaryotic cell plays indispensable role in the process of separating duplicated chromosomes before the cell division. Due to this essential function, they have been an important target for the development of cancer therapeutics. Several natural products such as Taxol, Vinca alkaloids, colchicine and their synthetic analogues that target microtubules have been used to treat several malignancies. However, cancer cells develop resistance to several of these agents by altering drug transporters and signaling pathways. Recently, combretastatins (CA) a group of diarylstilbenes isolated originally from stem wood of the South African tree Combretum caffrum have received much attention due to their potent anticancer activity against wide variety of human cancers including those that are multidrug resistant. These molecules specifically bind to the colchicine-binding site of the tubulins and prevent their polymerization required for the mitotic tubule formation thus possesses anti-proliferative and antivascular activities. A water soluble disodium phosphate derivative of CA has shown promising results in clinical trials of several malignancies, thus stimulating significant interest in a variety of CA analogues. However, the cis configuration of CA favors to form thermodynamically more stable trans isomer during storage and administration, producing a dramatic reduction in both tubulin binding and antiproliferative activities. Considering these limitations, we designed and synthesized a series of 3′,4′,5′-trimethoxy-2-phenylbiphenyl derivatives as cis-restricted CA analogues and evaluated for their antiproliferative activity, inhibitory effects on tubulin polymerization, cell cycle effects and apoptosis induction. Moreover, we adopted a novel strategy to synthesize these low molecular weight unsymmetrical terphenyls by a new synthetic methodology using Suzuki coupling in a one pot operation without isolating the biaryls intermediate. A majority of these compounds demonstrated significant anti-proliferative activity against most of the cell lines tested including that are multi-drug resistant. Interestingly, some of these compounds elicited DNA damage response in a dose dependent manner. Specifically, the compounds with acetamido and acetyl functional groups exhibited significant inhibitory activities in tubulin polymerization and growth inhibition. Consistent with their FACS profiles, Immunocytochemistry and biochemical analysis revealed loss of intact microtubule structure, up regulation of cyclin B1 and aurora kinase B mRNA levels, corresponding to growth arrest in the G2/M. More importantly, our one pot synthesis strategy of unsymmetrical terphenyls of this structural class paves the way for design and development of novel anticancer agents.
Citation Format: Surendra Reddy Punganuru, Sadanandam Palle, Kaushlendra Tripathi, Komaraiah Palle. Design and development of combretastatin based unsymmetrical terphenyls as small molecule antimitotic agents. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2475. doi:10.1158/1538-7445.AM2013-2475