DOI: 10.1002/cmdc.201100019 Synthesis and Antitumor Evaluation of Nitrovinyl Biphenyls: Anticancer Agents Based on Allocolchicines Nishant Jain, [b] Divya Yada, [a] Thokhir B. Shaik, [b] Galanki Vasantha, [b] P. Surendra Reddy, [a] Shasi V. Kalivendi,* [b] and B. Sreedhar* [a] Introduction Microtubules are ubiquitous, cytoskeletal components of eu- karyotic cells. They serve as the primary structural substrates for cellular processes such as mitosis, cytoplasmic transport, and flagellar and cilia-based motility. [1] The central role of mi- crotubules in the process of separating duplicated chromo- somes before cell division makes them an important target for anticancer drugs. [2] Thus, molecules [3] that target tubulin halt the characteristic rapid division of cancer cells. [4] This therapeu- tic strategy has been validated by the clinical success of anti- microtubule drugs such as paclitaxel, docetaxel, vincristine, and vinblastine. Nonetheless, neurotoxicity and P-glycoprotein- mediated drug resistance limit the clinical utility of these drugs. [5] New generation taxoids, vinca alkaloids, and other novel chemical scaffolds that modulate microtubule dynamics have been developed in an effort to overcome these limita- tions. [6] Colchicine interacts with tubulin and perturbs the assembly dynamics of microtubules. Though its use has been limited due to toxic side effects, colchicine remains a useful lead com- pound for the generation of potent anticancer drugs. [7] Colchi- cine is a three ring compound, with trimethoxyphenyl ring A and tropolone methyl ether ring C held in rigid spacial configu- ration by seven-membered ring B. Rearrangement of ring C into carbobenzoxyphenyl ring C 1 results in allocolchicine 2 and its analogues 3–5, which have the characteristics of a biphenyl ring sterically stabilized by ring B. All of these proved to be ef- fective antimitotic agents which affect the tubulin-microtubule equilibrium. [8, 9] Compared with parent alkaloid 1, the allocolchi- cines combine higher affinity for tubulin with greater stability. [9] Allocolchicine analogues with a five-membered [10] or eight- membered [11] ring B, as well as compounds with the C7 func- tionality moved to C5, [12] were recently prepared but found to be ineffective against the tubulin polymerization process, de- spite their structural similarity with the active allocolchicinoids. It was also shown that any alteration to the trioxygenated moiety of ring A, which serves as an anchor for tubulin bind- ing, [13] leads to compounds with decreased anti-tubulin activi- ty. [14] In contrast, the biological activity of ring C-substituted al- locolchicinoids varies with the size, position, and nature of the substituents. [15] It was found that only natural ()-(7S)-colchicine, which adopts an aR biaryl configuration, binds effectively to tubulin. The aS,7R enantiomer does not interfere with the tubulin poly- merization process. Although (7S)-allocolchicinoids prefer an aR biaryl configuration, they exist in solvent-dependent equi- librium between aR and aS forms, and several active (7R)-allo- colchicinoids are known. [16] It is not clear whether the aR,7S form or the small amount of the aS,7S form present in solution in equilibrium, is active in the tubulin-binding process. More- over, compounds with one or more chiral centers are not always ideal drug candidates, although several total synthesis studies have been reported. [17] Based on the above observations, we used the primary phar- macophore of allocolchicines consisting of the A and C 1 rings as the lead for the development of new compounds having more accessible structures. This biphenyl pharmacophore is also present in a wide range of cytotoxic natural products such as steganacin 6, steganone 7, eupomatilone 8, apogalantha- A new class of nitrovinyl biphenyl compounds based on the structures of colchicines and allocolchicines were designed, synthesized, and shown to inhibit tubulin polymerization and cause mitotic arrest. A majority of these compounds were found to possess potent anticancer properties, with IC 50 values in the range of 0.05–7 mm, and are equally potent with colchi- cine in HeLa and MCF-7 cells. Compounds 14 e and 14 f inhib- ited tubulin assembly by more than 60 %, and flow cytometry studies indicated growth arrest of cells in the G 2 /M phase of the cell cycle in a concentration-dependent manner. Treatment of cells with 14 f resulted in upregulation of cyclin B1 and aurora kinase B mRNA levels, corresponding to growth arrest in the G 2 /M phase of the cell cycle as the mode of action. [a] D. Yada, P.S. Reddy, Dr. B. Sreedhar Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology (Council of Scientific and Industrial Research) Hyderabad 500607 (India) Fax: (+ 91) 40-27160921 E-mail : sreedharb@iict.res.in [b] Dr. N. Jain, T.B. Shaik, G. Vasantha, Dr. S. V. Kalivendi Centre for Chemical Biology, Indian Institute of Chemical Technology (Council of Scientific and Industrial Research), Hyderabad 500607 (India) Fax: (+ 91) 040 27160387 E-mail : kalivendi@iict.res.in Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cmdc.201100019. ChemMedChem 2011, 6, 859 – 868  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 859