title: Discovery of substituted 4-anilino-2-(2-pyridyl)pyrimidines as a new series of apoptosis inducers using a cell- and caspase-based high throughput screening assay. Part 1: structure-activity relationships of the 4-anilino group.
abstract: A series of 4-anilino-2-(2-pyridyl)pyrimidines has been discovered as a new class of potent inducers of apoptosis using a cell-based HTS assay. Compound 5a was found to arrest T47D cells in G2/M and induced apoptosis. SAR studies showed that a small and electron-donating group at the meta-position of the anilino ring is important for activity. A 20-fold increase in potency, from hit compound 4-(3-methoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (5a) to lead compound 4-(2,5-dimethoxyanilino)-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (5l), was obtained through the SAR studies. Compound 5l is highly active with an EC50 value of 18 nM in the caspase activation assay in T47D breast cells. Interestingly, 5a and other meta-mono-substituted compounds were active against T47D cells but were not active against H1299 and HT29 cells, while 5l and other 2,5-disubstituted compounds were active against all the three cells. In a tubulin polymerization assay, compound 5l inhibited tubulin polymerization with an IC50 value of < 0.5 microM, while 5a was not active up to 50 microM.
authors.affiliation: EpiCept Corporation, San Diego, CA 92121, USA.
authors.forename: Nilantha
authors.initials: N
authors.lastname: Sirisoma
authors.forename: Shailaja
authors.initials: S
authors.lastname: Kasibhatla
authors.forename: Bao
authors.initials: B
authors.lastname: Nguyen
authors.forename: Azra
authors.initials: A
authors.lastname: Pervin
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Gisela
authors.initials: G
authors.lastname: Claassen
authors.forename: Ben
authors.initials: B
authors.lastname: Tseng
authors.forename: John
authors.initials: J
authors.lastname: Drewe
authors.forename: Sui Xiong
authors.initials: SX
authors.lastname: Cai
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy*; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D011743:Pyrimidines; D014404:Tubulin; D020169:Caspases