Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell-and caspase-based HTS assay. Part 5: Modifications of the 2-and 3-positions

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 2; pp. 603 - 607
• Main Authors: KEMNITZER, William, SONGCHUN JIANG, GOURDEAU, Henriette, TSENG, Ben, DREWE, John, SUI XIONG CAI, YAN WANG, KASIBHATLA, Shailaja, CROGAN-GRUNDY, Candace, BUBENIK, Monica, LABRECQUE, Denis, DENIS, Real, LAMOTHE, Serge, ATTARDO, Giorgio
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 15.01.2008
• Subjects: Antineoplastic agents; Apoptosis - drug effects; Benzopyrans - chemistry; Benzopyrans - pharmacology; Biological and medical sciences; Caspases - metabolism; Cell Division - drug effects; Cell Line, Tumor; General aspects; Humans; Medical sciences; Pharmacology. Drug treatments; Structure-Activity Relationship; Antineoplastic agent; High throughput screening; Solid tumor; Nitrile; SAR; Cysteine endopeptidases; Liver; Cytotoxicity; Oxygen heterocycle; HTS assay; Structure activity relation; Bicyclic compound; Bromine Organic compounds; Aromatic compound; Colon; Mammary gland; Chemical synthesis; Tumor cell; Oxygen nitrogen heterocycle; Human; Ether; Enzyme; Benzene derivatives; Caspase; Anticancer agents; Tricyclic compound; Peptidases; Cell line; Hydrolases; Apoptosis inducers; Apoptosis
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2007.11.078

As a continuation of our efforts to discover and develop apoptosis inducing 4-aryl-4H-chromenes as novel anticancer agents, we explored modifications at the 2- and 3-positions. It was found that replacement of the 3-cyano group by an ester, including methyl and ethyl ester, resulted in >200-fold reduction of activity. Conversion of the 2-amino group into an amide or urea resulted in 4- to 10-fold drop of activity. Similarly, converting the 2-amino group into a hydrogen resulted in 4- to 10-fold reduction of activity. Compound 3d was highly active with an EC(50) value of 29 nM and a GI(50) value of 6 nM in T47D cells. Importantly, the 2-H analog 3d was found to be much more stable under acidic conditions compared to the 2-NH(2) analog 3b, suggesting that 2-H analogs might have better bioavailability than the 2-NH(2) analogs.