title: 2-cyanoaminopyrimidines as a class of antitumor agents that promote tubulin polymerization.
abstract: A series of 4-chloro-2-cyanoamino-6-fluoroalkylamino-5-phenylpyrimidines was prepared as a result of our efforts to modify a series of [1,2,4]triazolo[1,5-a]pyrimidines that proved to be potent anticancer agents with a unique mechanism of tubulin inhibition. On the cyanoamino nitrogen, a methyl group is optimal for activity among alkyl groups introduced. The structure-activity relationship for the rest of the molecule resembles that of [1,2,4]triazolo[1,5-a]pyrimidines. A lead compound (5) retained in vitro potency compared with TTI-237. In the mechanism of action studies, it behaved in the same manner as TTI-237. In addition, it is also capable of overcoming multidrug resistance due to P-gp. These findings strongly suggest that this series of 2-cyanoaminopyrimidines binds at the same site and in the same binding mode as TTI-237. Further modifications of the 2-cyanoamino group are underway.
authors.affiliation: Discovery Medicinal Chemistry, Chemical and Screening Sciences, Wyeth Research, Pearl River, NY 10965, USA. zhangn@wyeth.com
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.forename: Semiramis
authors.initials: S
authors.lastname: Ayral-Kaloustian
authors.forename: Thai
authors.initials: T
authors.lastname: Nguyen
authors.forename: Richard
authors.initials: R
authors.lastname: Hernandez
authors.forename: Carl
authors.initials: C
authors.lastname: Beyer
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014404:Tubulin / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D006846:Hydrocarbons, Halogenated; D011743:Pyrimidines; D014230:Triazoles; D014404:Tubulin; C521494:cevipabulin