title: Synthesis, in vivo antileukemic evaluation and comparative study of novel 5alpha-7-keto steroidal esters of chlorambucil and its active metabolite.
abstract: Recent structure-antileukemic activity studies showed that the steroidal part of complex molecules containing DNA alkylators does not play only the role of the "biological carrier". New such compounds designed to possess an allylic 7-ketone showed enhanced antileukemic potency compared with derivatives with a simple steroidal skeleton. In order to investigate whether the enhancement of the antileukemic potency is attributed to the introduction of the 7-ketone or to the Delta5-7-keto conjugated steroidal system we decided to reduce the Delta5 double bond. The 5alpha-7-keto-steroidal skeletons synthesized were tethered to chlorambucil and phenyl acetic acid's nitrogen mustard and studied against leukemia P338 in vivo. The reduction of the double bond had a negative impact on the antileukemic potency since the comparative study of the novel derivatives showed that a series of very potent Delta 5-7-keto-steroidal esters were converted by this modification to compounds with marginally accepted activity.
authors.affiliation: Laboratory of Pharmaceutical Chemistry, Department of Pharmacy, University of Patras, Greece.
authors.forename: Anna I
authors.initials: AI
authors.lastname: Koutsourea
authors.forename: Manolis A
authors.initials: MA
authors.lastname: Fousteris
authors.forename: Evagelia S
authors.initials: ES
authors.lastname: Arsenou
authors.forename: Athanasios
authors.initials: A
authors.lastname: Papageorgiou
authors.forename: George N
authors.initials: GN
authors.lastname: Pairas
authors.forename: Sotiris S
authors.initials: SS
authors.lastname: Nikolaropoulos
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D002384:Catalysis; D045744:Cell Line, Tumor; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002699:Chlorambucil / Q000737:chemistry* / Q000378:metabolism; D004952:Esters / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D005260:Female; D006868:Hydrolysis; D007938:Leukemia / Q000188:drug therapy*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D013256:Steroids / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004952:Esters; D013256:Steroids; D002699:Chlorambucil