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

Molecules

Željka Babić¹  Maja Crkvenčić¹  Zrinka Rajić¹  Ana-Matea Mikecin¹  Marijeta Kralj¹  Jan Balzarini¹  Mariya Petrova¹  Jos Vanderleyden¹ 

[1] ¹Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovačića 1, HR-10000 Zagreb, Croatia

关键词: sorafenib;    amides;    cytostatic activity;    antimetabolic activity;    Caco-2 cells permeability;   

DOI  :  10.3390/molecules17011124

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.