Xiangfu PENG, Mingsha SHAO, Shuchao MA, Lei YAO

Synthesis and antitumor activities of 2-(piperidin-4-yl)-thiazole-4-carboxamides analogues of tubulysins

Tubulysins are a family of natural products that exhibit potent antitumor activities, which have attractedmuch attention from synthetic and medicinal chemists. Previous attempts to aromatize the Tuv part of tubulysinanalogues led to a loss in antitumor activity, which suggested that the Ile and Tuv fragments of these analogues wereadopting different conformations than the natural products. In this study, a series of 2-(piperidin-4-yl)-thiazole-4-carboxamides have been prepared to investigate whether an intramolecular H-bond between key NH and OH groupsis responsible for the conformational control. The antitumor activities of these analogues have been screened usingMDA-MB-231-breast, Siha-cervical, MCF7-breast, and PC3-prostate cell lines, with ureas 5m and 5k shown to exhibitmoderate antitumor activities (IC50 values of 0.2 and 0.6 µM against MCF7 cells, respectively).

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1. Sasse, F.; Steinmetz, H.; Heil, J.; Höfle, G.; Reichenbach, H. J Antibiot. 2000, 53, 879-885.
2. Peltier, H. M.; McMahon, J. P.; Patterson, A. W.; Ellman, J. A. J. Am. Chem. Soc. 2006, 128, 16018-16019.
3. Pando, O.; Dörner, S.; Preusentanz, R.; Denkert, A.; Porzel, A.; Richter, W.; Wessjohann, L. Org. Lett., 2009, 11, 5567-5569.
4. Dömling, A.; Beck, B.; Eichelberger, U.; Sakamuri, S.; Menon, S.; Chen, Q.; Lu, Y.; Wessjohann, L. A. Angew. Chem. Int. Ed. Engl. 2006, 46, 2347-2348.
5. Nicolaou, K. C.; Erande, R. D.; Yin, J.; Vourloumis, D.; Aujay, M.; Sandoval, J.; Munneke, S.; Gavrilyuk, J. J. Am. Chem. Soc., 2018, 140, 3690-3711.
6. Pando, O.; Stark, S.; Denkert, A.; Porzel, A.; Preusentanz, R.; Wessjohann, L. A. J. Am. Chem. Soc., 2011, 133, 7692-7695.
7. Burkhart, J. L.; Müller, R.; Kazmaier, U. Eur. J. Org. Chem., 2011, 16, 3050-3059.
8. Balasubramanian, R.; Raghavan, B.; Begaye, A.; Sackett, D. L.; Fecik, R. A. J. Med. Chem., 2009, 52, 238-240.
9. Reddy, J. A.; Dorton, R.; Dawson, A.; Vetzel, M.; Parker, N.; Nicoson, J. S.; Westrick, E.; Klein, P. J.; Wang, Y.; Vlahov, I. R. et al. Mol. Pharm. 2009, 6, 1518-1525.
10. Leamon, C. P.; Reddy, J. A.; Vlahov, I. R.; Dorton, R.; Bloomfield, A.; Vetzel, M.; Klein, P. J.; Westrick, E.; Xu, L.; Wang, Y. Cancer Chemoth. Pharm., 2017, 79, 1151-1160.
11. Cohen, R.; Vugts, D. J.; Visser, G. W.; Stigter-van Walsum M.; Bolijn, M.; Spiga, M.; Lazzari, P.; Shankar, S.; Sani, M. et al. Cancer Res. 2014, 74, 5700-5710.
12. Ritchie, T. J.; Macdonald, S. J. Drug Discov. Today, 2009, 14, 1011-1020.
13. Li, S.; Xu, Y.; Shen, Q.; Liu, X.; Lu, J.; Chen, Y.; Lu, T.; Luo, C.; Luo, X.; Zheng, M. et al. Curr. Pharm. Des. 2013, 19, 6522-6533.
14. Domling, A.; Beck, B.; Eichelberger, U.; Sakamuri, S.; Menon, S.; Chen, Q. Z. Angew. Chem., 2006, 45, 7235-7239.
15. Bai, X.; Ma, X.; Xie, X.; Shao, M.; Guo, N.; Yan, N.; Yao, L. Chem. J. Chin. Univ. 2017, 38, 47-55.
16. Murray, B. C.; Peterson, M. T.; Fecik, R. A. Nat. Prod. Rep. 2015, 32, 654-662.
17. Xu, X., Friestad, G. K.; Yao, L. Mini-Rev. Med. Chem., 2013, 13, 1572-1578.
18. Park, Y.; Lee, J. K.; Ryu, J. S. Synlett 2015, 26, 1063-1068.