title: Structure-anti-leukemic activity relationship study of B- and D-ring modified and non-modified steroidal esters of chlorambucil.
abstract: In order to study the role of the steroidal moiety on the expression of anti-leukemic activity, we synthesized six derivatives of chlorambucil (CHL), and tested them on leukemias P388 and L1210 in vivo and in normal human lymphocytes in vitro. Five of the six tested compounds produced submultiple toxicity, while the measured anti-leukemic potency was significantly increased. The lactamization of the B-steroidal ring rendered the molecules more potent, but the corresponding 7-oxidized derivatives proved better in both leukemias tested. The lactamization of the D-steroidal ring afforded potent compounds, regardless of the configuration of the B-ring. The best among all derivatives contains both chemical modifications and is intended as a promising key molecule that must be further studied. We speculate that in leukemic cells a tumor-specific protein is overexpressed, the steroid has the ability to bind and block this protein from carrying out its normal function, and the drug-protein complex prevents the repair of the adducts. The synthesis, physicochemical and spectroscopic data of these compounds and a modified route for the synthesis of CHL are also reported.
authors.affiliation: Laboratory of Medicinal Chemistry, Department of Pharmacy, University of Patras, Greece. fusterism@mailbox.gr
authors.forename: Manolis A
authors.initials: MA
authors.lastname: Fousteris
authors.forename: Anna I
authors.initials: AI
authors.lastname: Koutsourea
authors.forename: Evaggelia S
authors.initials: ES
authors.lastname: Arsenou
authors.forename: Athanasios
authors.initials: A
authors.lastname: Papageorgiou
authors.forename: Dionysios
authors.initials: D
authors.lastname: Mourelatos
authors.forename: Sotiris S
authors.initials: SS
authors.lastname: Nikolaropoulos
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002699:Chlorambucil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D018906:Antineoplastic Agents, Alkylating; D002699:Chlorambucil