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New Sorafenib Derivatives: Synthesis, Antiproliferative Activity Against Tumour Cell Lines and Antimetabolic Evaluation
Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovačića 1, HR-10000 Zagreb, Croatia
Division of Molecular Medicine, Rudjer Bošković Institute, Bijenička cesta 54, HR-10000 Zagreb, Croatia
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
Centre of Microbial and Plant Genetics, Katholieke Universiteit Leuven, Kasteelpark Arenberg 20, Bus 2300, B-3001 Heverlee, Belgium
* Author to whom correspondence should be addressed.
Received: 26 November 2011; in revised form: 1 January 2012 / Accepted: 5 January 2012 / Published: 23 January 2012
Abstract: Sorafenib is a relatively new cytostatic drug approved for the treatment of renal cell and hepatocellular carcinoma. In this report we describe the synthesis of sorafenib derivatives 4a–e which differ from sorafenib in their amide part. A 4-step synthetic pathway includes preparation of 4-chloropyridine-2-carbonyl chloride hydrochloride (1), 4-chloro-pyridine-2-carboxamides 2a–e, 4-(4-aminophenoxy)-pyridine-2-carboxamides 3a–e and the target compounds 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-phenoxy]-pyridine-2-carboxamides 4a–e. All compounds were fully chemically characterized and evaluated for their cytostatic activity against a panel of carcinoma, lymphoma and leukemia tumour cell lines. In addition, their antimetabolic potential was investigated as well. The most prominent antiproliferative activity was obtained for compounds 4a–e (IC50 = 1-4.3 μmol·L−1). Their potency was comparable to the potency of sorafenib, or even better. The compounds inhibited DNA, RNA and protein synthesis to a similar extent and did not discriminate between tumour cell lines and primary fibroblasts in terms of their anti-proliferative activity.
Keywords: sorafenib; amides; cytostatic activity; antimetabolic activity; Caco-2 cells permeability
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Babić, Ž.; Crkvenčić, M.; Rajić, Z.; Mikecin, A.-M.; Kralj, M.; Balzarini, J.; Petrova, M.; Vanderleyden, J.; Zorc, B. New Sorafenib Derivatives: Synthesis, Antiproliferative Activity Against Tumour Cell Lines and Antimetabolic Evaluation. Molecules 2012, 17, 1124-1137.
Babić Ž, Crkvenčić M, Rajić Z, Mikecin A-M, Kralj M, Balzarini J, Petrova M, Vanderleyden J, Zorc B. New Sorafenib Derivatives: Synthesis, Antiproliferative Activity Against Tumour Cell Lines and Antimetabolic Evaluation. Molecules. 2012; 17(1):1124-1137.
Babić, Željka; Crkvenčić, Maja; Rajić, Zrinka; Mikecin, Ana-Matea; Kralj, Marijeta; Balzarini, Jan; Petrova, Mariya; Vanderleyden, Jos; Zorc, Branka. 2012. "New Sorafenib Derivatives: Synthesis, Antiproliferative Activity Against Tumour Cell Lines and Antimetabolic Evaluation." Molecules 17, no. 1: 1124-1137.