Molecules 2012, 17(1), 1124-1137; doi:10.3390/molecules17011124
Article

New Sorafenib Derivatives: Synthesis, Antiproliferative Activity Against Tumour Cell Lines and Antimetabolic Evaluation

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Received: 26 November 2011; in revised form: 1 January 2012 / Accepted: 5 January 2012 / Published: 23 January 2012
(This article belongs to the Section Medicinal Chemistry)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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 4ae 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 2ae, 4-(4-aminophenoxy)-pyridine-2-carboxamides 3ae and the target compounds 4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]-phenoxy]-pyridine-2-carboxamides 4ae. 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 4ae (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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MDPI and ACS Style

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.

AMA Style

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.

Chicago/Turabian Style

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.


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