title: Structure-activity relationships of cadeguomycin analogs.
abstract: The relationship between the activity and the chemical structure of cadeguomycin (CDM, 7-carboxy-7-deazaguanosine) was studied with six analogs of CDM. Both activities of CDM, enhancing the incorporation of [3H]thymidine in K562 cells and potentiating the cytotoxicity of cytosine arabinoside for K562 cells, were significantly augmented by the replacement of the 7-carboxyl group with cyano (CDM-CN) or formyl (CDM-CHO), but they were not changed by the replacement with methyl. The activities were almost completely diminished by the replacement of ribose with arabinose, but the simultaneous replacement of carboxyl and ribose with formyl and arabinose showed higher activities than those of CDM. The replacement of 7-carboxy-7-deazaguanine with 7-carboxy-7-deazainosine markedly weakened the activity. CDM-CN and CDM-CHO at 0.2 micrograms/ml significantly potentiated the activity of cytosine arabinoside against MOLT-3 cells but CDM at 1 micrograms/ml did not. These results indicate that the ribose and guanine moieties in the CDM molecule are very important for its activity. Also replacing the carboxyl group at the C-7 position with cyano or formyl group is a useful way to strengthen the CDM activity. These compounds would effectively potentiate cytosine arabinoside against various kinds of tumor cells which CDM could not do.
authors.affiliation: Institute of Applied Microbiology, University of Tokyo, Japan.
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.forename: K
authors.initials: K
authors.lastname: Okazaki
authors.forename: T
authors.initials: T
authors.lastname: Okabe
authors.forename: T
authors.initials: T
authors.lastname: Nishimura
authors.forename: T
authors.initials: T
authors.lastname: Kondo
authors.forename: N
authors.initials: N
authors.lastname: Tanaka
authors.forename: H
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D003597:Cytosine Nucleotides / Q000494:pharmacology; D004357:Drug Synergism; D006151:Guanosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D015394:Molecular Structure; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000900:Anti-Bacterial Agents; D003597:Cytosine Nucleotides; D003561:Cytarabine; D006151:Guanosine; C034568:cadeguomycin