DOI: 10.1002/cmdc.201000346 Synthesis of Imidazothiazole–Chalcone Derivatives as Anticancer and Apoptosis Inducing Agents Ahmed Kamal,* D. Dastagiri, M. Janaki Ramaiah, J. Surendranadha Reddy, E. Vijaya Bharathi, Chatla Srinivas, S. N. C. V. L. Pushpavalli, Dhananjaya Pal, and Manika Pal-Bhadra* [a] Introduction Chalcones are naturally occurring compounds that belong to the flavonoid family and have been associated with a wide va- riety of anticancer effects. [1] These compounds have also been reported to possess various other biological activities, such as antimalarial, [2, 3] anti-HIV, [4] and tyrosinase inhibition. [5] The re- markable biological potential of these chalcones is due to their possible interactions with various proteins related to apoptosis and cell proliferation. Recent studies have shown that these chalcones induce apoptosis in a variety of cell types, including breast cancers. [6–9] Over the last few years, research into the an- titumor properties of chalcones has received significant atten- tion, and the majority of the naturally occurring chalcones con- tain either hydroxy or methoxy groups in both the A and B rings. The 3,4,5-trimethoxyphenyl ring is thought to be essen- tial for the anticancer activity of chalcones. Some of the recent advances in the development of anticancer agents involve structural modification of chalcones to improve their bioavaila- bility and to study the role of various substituents on aryl or heteroaryl rings. [10] Moreover, heterocyclic derivatives of chal- cones in which the B ring is replaced by a heterocyclic ring have been systematically investigated. Imidazothiazoles are also well-known compounds, and many derivatives of this fused ring system have been evaluated for potential biological activity, particularly antitumor activity. [11, 12] Some representative chalcones and imidazothiazole derivatives are illustrated in Figure 1. Considering the potent bioactivities of compounds that pos- sess an imidazothiazole core, we synthesized new chalcone de- rivatives that incorporate an imidazothiazole skeleton and eval- uated their anticancer activity. The promising activity observed prompted us to investigate the role of these new compounds in the proliferation and apoptosis of a human breast cancer cell line (MCF-7). We also investigated the effect of these com- pounds on proteins that regulate cell-cycle progression. Results and Discussion Chemistry The imidazothiazole–chalcone derivatives 3a–p were prepared by Claisen–Schmidt condensation [13] of the appropriately sub- stituted acetophenones upon treatment with imidazo[2,1- b]thiazole aldehydes 8a–i in the presence of 10 % sodium hy- droxide, as shown in Scheme 1. The imidazo[2,1-b]thiazole al- dehydes 8 [14] were obtained by Vilsmeier reaction with the cor- responding imidazo[2,1-b]thiazoles 7, which were prepared from the appropriate 2-aminothiazoles 5 and bromoketones 4. The intermediate compounds 6 were isolated and used in the subsequent step without further purification. A new class of imidazo[2,1-b]thiazole chalcone derivatives were synthesized and evaluated for their anticancer activity. These chalcone derivatives show promising activity, with log GI 50 values ranging from À7.51 to À4.00. The detailed biological as- pects of these derivatives toward the MCF-7 cell line were studied. Interestingly, these chalcone derivatives induced G 0 / G 1 -phase cell-cycle arrest, down-regulation of G 1 -phase cell- cycle regulatory proteins such as cyclin D1 and cyclin E1, and up-regulation of CDK4. Moreover, these compounds elicit the characteristic features of apoptosis such as enhancement in the levels of p53, p21, and p27, suppression of NF-kB, and up- regulation of caspase-9. One of these chalcone derivatives, 3d, is potentially well suited for detailed biological studies, either alone or in combination with existing therapies. Figure 1. Structures of chalcone 1, imidazothiazole guanylhydrazones 2, and imidazothiazole–chalcone derivatives 3a–p. [a] Dr. A. Kamal, D. Dastagiri, Dr. M. J. Ramaiah, J. S. Reddy, E. V. Bharathi, C. Srinivas, S. N. C. V. L. Pushpavalli, D. Pal, Dr. M. Pal-Bhadra Chemical Biology Laboratory Indian Institute of Chemical Technology, Hyderabad 500607 (India) Fax:(+91) 40-2719-3189 E-mail : ahmedkamal@iict.res.in ChemMedChem 2010, 5, 1937 – 1947  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1937