title: Structure-anti-leukemic activity relationship study of B- and D-ring modified and non-modified steroidal esters of chlorambucil's active metabolite.
abstract: We have studied the effect of modification of the B-steroidal ring to lactamic on the anti-leukemic potency of D-modified and D-non-modified steroidal esters of chlorambucil's active metabolite. The compounds synthesized were studied against leukemias P388 and L1210 after the subsequent estimation of their toxicity in vivo, and for their ability to induce sister chromatid exchanges (SCEs) and to inhibit cell proliferation in normal human lymphocytes in vitro. The in vitro results correlated well, on a molar basis, with the results obtained from the study of the anti-leukemic potency. In a comparative study, the B-lactamic steroidal derivatives proved less active than the 7-oxidized ones against both leukemias. The presence of the -NHCO- group in the B-steroidal ring did not have the same positive effect on the biological action of chlorambucil's active metabolite esters as in the D-lactamic ring. However, this new modification of the B-ring rendered the final esteric derivatives much more toxic, compared with to the corresponding esters with a simple B-ring. This loss of the anti-leukemic specificity, which occurs from the modification of the B-ring, is additional evidence for the role of the steroidal part on the mechanism of action of these promising compounds. This provides support for the notion that the steroidal part of these molecules is not just a simple biological carrier, as has been speculated for many years.
authors.affiliation: Laboratory of Pharmaceutical Chemistry, Department of Pharmacy, University of Patras, Greece.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Papageorgiou
authors.forename: Anna I
authors.initials: AI
authors.lastname: Koutsourea
authors.forename: Evagelia S
authors.initials: ES
authors.lastname: Arsenou
authors.forename: Manolis A
authors.initials: MA
authors.lastname: Fousteris
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 / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D002699:Chlorambucil / Q000031:analogs & derivatives* / Q000737:chemistry; D004952:Esters / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D007938:Leukemia / Q000188:drug therapy*; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D012854:Sister Chromatid Exchange; D013256:Steroids / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004952:Esters; D013256:Steroids; D002699:Chlorambucil