title: Tetrahydropyrrolo[3,2-c]azepin-4-ones as a new class of cytotoxic compounds.
abstract: Pyrroloazepinones 8a-j and 9a-j were designed by structural modification of lead compound 3. These compounds were tested on five tumor cell lines to determine the role of the azeto ring and the 2-methyl substituent in the cytotoxicity of compound 3. Our results show that compounds 8a-j (R1=CH3) have dramatically reduced cytotoxicity, resulting from the loss of the azeto moiety of lead compound 3. By contrast, azepinones 9a-j (R1=4-nitrophenyl) inhibited the proliferation of almost all cancer cell lines tested even though they lack the azeto ring. Preliminary SAR studies with these compounds revealed the importance of halogens at the para- or meta-position of the 1-phenyl moiety. Additionally, derivatives 9a (R2=H), 9e (R2=4-F), and 9g (R2=4-OMe) were selectively cytotoxic to U-251 cells. However, none of the pyrroloazepinones inhibited the enzymatic activity of CDK1/cyclin B, CDK5/p25, and GSK-3.
authors.affiliation: Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, 04510 Coyoacán, México, DF, Mexico. robmar@servidor.unam.mx
authors.forename: Roberto
authors.initials: R
authors.lastname: Martínez
authors.forename: J Gustavo
authors.initials: JG
authors.lastname: Avila
authors.forename: Ma Teresa
authors.initials: MT
authors.lastname: Ramírez
authors.forename: Araceli
authors.initials: A
authors.lastname: Pérez
authors.forename: Angeles
authors.initials: A
authors.lastname: Martínez
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D066298:In Vitro Techniques; D015394:Molecular Structure; D011758:Pyrroles / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D011758:Pyrroles