Discovery of 3-aryl-5-aryl-1,2,4-oxadiazoles as a new series of apoptosis inducers. 2. Identification of more aqueous soluble analogs as potential anticancer agents

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 15; pp. 4410 - 4415
• Main Authors: Kemnitzer, William, Kuemmerle, Jared, Zhang, Han-Zhong, Kasibhatla, Shailaja, Tseng, Ben, Drewe, John, Cai, Sui Xiong
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01-08-2009; Elsevier
• Subjects: Animals; Anticancer agents; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis inducers; Biological and medical sciences; Cell Line, Tumor; Chemistry, Pharmaceutical - methods; Combinatorial Chemistry Techniques; Drug Design; Drug Evaluation, Preclinical; General aspects; HTS; Humans; Infusions, Intravenous; Medical sciences; Mice; Models, Chemical; Molecular Structure; Neoplasm Transplantation; Oxadiazoles - chemical synthesis; Oxadiazoles - pharmacology; Pharmacology. Drug treatments; SAR; Solubility; Structure-Activity Relationship; Water - chemistry; Anticancer agents; Apoptosis inducers; SAR; HTS; Antineoplastic agent; Five membered ring; Intravenous administration; Lung; Furan derivatives; Cytotoxicity; Oxygen heterocycle; Structure activity relation; Chlorine Organic compounds; Bromine Organic compounds; Colon; Mammary gland; Chemical synthesis; Tumor cell; Oxygen nitrogen heterocycle; Human; Rodentia; Benzene derivatives; Malignant tumor; In vitro; Primary alcohol; Water soluble compound; In vivo; Mammary gland diseases; Vertebrata; Chemotherapy; Mammalia; Treatment; Cell line; Mouse; Animal; Cancer; Apoptosis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.05.052

SAR studies of 3-aryl-5-aryl-1,2,4-oxadiazoles and the identification of 4g and 4h as lead compounds are reported.
As a continuation of our efforts to discover and develop the 3-aryl-5-aryl-1,2,4-oxadiazole series of apoptosis inducers as potential anticancer agents, we explored substitutions at the 2- and 3-positions of the 3-aryl group to improve the aqueous solubility properties and identify development candidates. A small substitution such as methyl or hydroxymethyl at the 2-position was well tolerated. This modification, in combination with a 3-substituted furan ring as the 5-aryl group, resulted in 4g and 4h, which have improved solubility properties. Compound 4g was found to have good in vivo efficacy in animal studies via intravenous administration.