title: 4-oxa-1-azabicyclo[3.2.0]heptan-7-one derivatives as anti-tumor agents.
abstract: A series of naturally occurring and synthetic novel oxapenam (4-oxa-1-azabicyclo[3.2.0] heptan-7-one) derivatives with their antitumor activity and the structure-activity relationship among this class of compounds is reported. Among the synthetic 4-oxa-1-azabicyclo[3.2.0]heptan-7-one having an ester, amide, ether derivatives of hydroxy group at C-3 position exhibited either no activity or reduced the antitumor activity in vitro. The 3-amino acid 4-oxa-1-azabicyclo[3.2.0]heptan-7-one derivatives showed better antitumor activity than naturally occurring 4-oxa-1-azabicyclo[3.2.0]heptan-7-one derivative G0069A. The trans isomers exhibited superior stability and activity over the cis isomers at the 3- and 5-position. Some of these compounds showed strong cytotoxicity against P388 and KB cells with IC(50) value ranging from 0.004 to 0.6 micro g/ml and they did not show any cross resistance against ADR, 5-FU and VCR resistant cell lines in vitro. Of these, 3-hydroxy methyl, 3-(2-amino-2-carboxy-1-benzyloxy ethyl) and 3-(2-amino-2-carboxy ethyl) 4-oxa-1-azabicyclo[3.2.0] heptan-7-one inhibited 71-84% in vivo tumor growth of colon 26 and S-180 cells subcutaneously implanted into mice at a varying dose between 0.625-15 mg/kg/day depending upon the compounds and the tumor cell lines.
authors.affiliation: Naeja Pharmaceutical Inc., 4290-91 A Street, Edmonton, Alberta, CANADA T6E 5V2. rsingh@naeja.com
authors.forename: R
authors.initials: R
authors.lastname: Singh
authors.forename: R G
authors.initials: RG
authors.lastname: Micetich
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001381:Azepines / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003508:Cycloheptanes / Q000138:chemical synthesis / Q000493:pharmacokinetics; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D003508:Cycloheptanes; C000363:cycloheptanone