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

• Published in: Bioorganic & medicinal chemistry Vol. 14; no. 23; pp. 7761 - 7773
• Main Authors: Sirisoma, Nilantha, Kasibhatla, Shailaja, Nguyen, Bao, Pervin, Azra, Wang, Yang, Claassen, Gisela, Tseng, Ben, Drewe, John, Cai, Sui Xiong
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.12.2006; Elsevier Science
• Subjects: 4-Anilino-2-(2-pyridyl)pyrimidines; Aniline Compounds - chemistry; Aniline Compounds - pharmacology; Anticancer agents; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Breast Neoplasms - drug therapy; Caspases - drug effects; Caspases - metabolism; Cell Line, Tumor; Drug Screening Assays, Antitumor - methods; Female; General aspects; HTS; Humans; Inducers of apoptosis; Inhibitory Concentration 50; Medical sciences; Pharmacology. Drug treatments; Pyrimidines - chemistry; Pyrimidines - pharmacology; SAR; Structure-Activity Relationship; Tubulin - drug effects; Tubulin - metabolism; Tubulin inhibitors; Anticancer agents; SAR; 4-Anilino-2-(2-pyridyl)pyrimidines; Tubulin inhibitors; Inducers of apoptosis; HTS; Antineoplastic agent; High throughput screening; Cysteine endopeptidases; Lung; Activation; Pyridine derivatives; Tubulin; Structure activity relation; Colon; Mammary gland; Inhibition; Chemical synthesis; Antimitotic; Tumor cell; Human; Enzyme; Antitubulin; Caspase; Aniline derivatives; Peptidases; Cell line; Hydrolases; Pyrimidine derivatives; Fluorine Organic compounds; Aromatic amine; Apoptosis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.08.002

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 18nM 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 <0.5μM, while 5a was not active up to 50μM.