title: New sorafenib derivatives: synthesis, antiproliferative activity against tumour cell lines and antimetabolic evaluation.
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 (IC(50) = 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.
authors.affiliation: University of Zagreb, Zagreb, Croatia. bzbz@pharma.hr
authors.forename: Zeljka
authors.initials: Z
authors.lastname: Babić
authors.forename: Maja
authors.initials: M
authors.lastname: Crkvenčić
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Rajić
authors.forename: Ana-Matea
authors.initials: AM
authors.lastname: Mikecin
authors.forename: Marijeta
authors.initials: M
authors.lastname: Kralj
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Mariya
authors.initials: M
authors.lastname: Petrova
authors.forename: Jos
authors.initials: J
authors.lastname: Vanderleyden
authors.forename: Branka
authors.initials: B
authors.lastname: Zorc
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001557:Benzenesulfonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000077157:Sorafenib
chemical_list: D000964:Antimetabolites, Antineoplastic; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib