title: Doxorubicin analogues incorporating chemically reactive substituents.
abstract: Doxorubicin (1) analogues 2-5, incorporating the following alkylating or latent alkylating substituents, R, on the 3'-position of the daunosamine sugar have been synthesized as potential antitumor agents: 2, R = NHCOC6H4(p)SO2F; 3, R = NHCOCH2Br; 4, R = NHCOCH2Cl; 5, R = NHCON(NO)CH2CH2Cl. These compounds were designed on the premise that alkylating anthracyclines might bind covalently to critical intracellular target macromolecules and overcome resistance to the parent agent attributable to reduced cellular drug accumulation. Growth inhibitory studies of the analogues were conducted in vitro against mouse leukemia cells (L1210 and P388) and human uterine sarcoma cells that are sensitive (MES-SA) and resistant (MES-SA/DOX) to doxorubicin. The analogues were 5-100-fold less potent than doxorubicin against the sensitive cell lines. However, they were only marginally cross-resistant with doxorubicin against MES-SA/DOX. Compounds 3 and 5 were also evaluated against a human myelocytic cell line (KBM-3) and a subline (KBM-3/DOX) resistant to doxorubicin. They were equally potent against both cell lines, indicating a complete lack of cross-resistance with doxorubicin. Alkylating anthracyclines may have potential for the treatment of tumors resistant to the parent agents.
authors.affiliation: Division of Medicine, University of Texas M. D. Anderson Cancer Center, Houston 77030.
authors.forename: D
authors.initials: D
authors.lastname: Farquhar
authors.forename: R A
authors.initials: RA
authors.lastname: Newman
authors.forename: J E
authors.initials: JE
authors.lastname: Zuckerman
authors.forename: B S
authors.initials: BS
authors.lastname: Andersson
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000627:therapeutic use; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D004317:Doxorubicin / Q000031:analogs & derivatives*; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D012513:Sarcoma, Experimental / Q000188:drug therapy
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin