title: The aromatic azido group in anti-cancer drug design: application in the development of novel lipophilic dihydrofolate reductase inhibitors.
abstract: Two properties of the aromatic azido group have been exploited in the design of a novel dihydrofolate reductase inhibitor--lipophilicity and biotransformability. 2,4-Diamino-5-(3-azido-4-chlorophenyl)-6-ethylpyrimidine (MZP, 4), which can be prepared in three high-yielding synthetic steps from the antimalarial drug pyrimethamine (1), has a pKa of 7.19, a log P of 2.81 and inhibitory activity against the P388, L1210, B16 and M5076 tumours in vivo. The ethanesulphonic acid salt of MZP (MZPES, 6) is a potent inhibitor of rat liver dihydrofolate reductase (Ki 1.60 nM) and L1210 cells in vitro. Injections of MZPES in water (10 mg ml-1) at pH 4.1 can be sterilised by filtration and are stable provided they are protected from light.
authors.affiliation: Department of Pharmaceutical Sciences, Aston University, Birmingham, UK.
authors.forename: M F
authors.initials: MF
authors.lastname: Stevens
authors.forename: R J
authors.initials: RJ
authors.lastname: Griffin
authors.forename: S K
authors.initials: SK
authors.lastname: Wong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D005493:Folic Acid Antagonists; D006801:Humans; D051381:Rats; D012995:Solubility
chemical_list: D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists