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.
Highlights
Sorafenib, 4- 4- 4-chloro-3-(trifluoromethyl)phenyl carbamoylamino phenoxy -N-methylpyridine2-carboxamide, is an oral multikinase inhibitor that inhibits cell surface tyrosine kinase receptors and downstream intracellular serine/threonine kinases (e.g., Raf-1, wild-type B-Raf and mutant B-Raf); these kinases are involved in tumour cell proliferation and tumour angiogenesis 1–3
The selected amines were chosen on the basis of their lipophilicity and limited number of possible conformations, providing more lipohilic and rigid final compounds 4
The reactions of acid chloride 1 with the title amines gave the amides in good yields
Summary
4- 4- 4-chloro-3-(trifluoromethyl)phenyl carbamoylamino phenoxy -N-methylpyridine2-carboxamide, is an oral multikinase inhibitor that inhibits cell surface tyrosine kinase receptors (e.g., vascular endothelial growth factor receptors and platelet-derived growth factor receptor-beta) and downstream intracellular serine/threonine kinases (e.g., Raf-1, wild-type B-Raf and mutant B-Raf); these kinases are involved in tumour cell proliferation and tumour angiogenesis 1–3. Clinical trials to use sorafenib for non-responsive thyroid cancer and glioblastoma are in progress as well. Both median survival and time to progression in sorafenib therapy showed only a. 3-month improvement in patients who received sorafenib compared to placebo 6,7 These facts point to sorafenib as an interesting lead compound for further derivatization in order to find a more effective drug. The newly prepared compounds are more lipophilic in an attempt to increase uptake and/or accumulation of the drug in tissues 8. We report their synthesis and in vitro evaluation of their cytostatic activity against several carcinoma cell lines
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