title: Steroidal esters of the aromatic nitrogen mustard 2-[4-N,N-bis(2-chloroethyl)amino-phenyl]butanoic acid (2-PHE-BU):  synthesis and in-vivo biological evaluation.
abstract: On the basis of the results of in-silico predictions and in an effort to extend our structure-activity relationship studies, the aromatic nitrogen mustard 2-[4-N,N-bis(2-chloroethyl) amino-phenyl]butanoic acid (2-PHE-BU) was synthesized and conjugated with various steroidal alcohols. The resulting steroidal esters were evaluated for their in-vivo toxicity and antileukemic activity in P388-leukemia-bearing mice. The new derivatives showed significantly reduced toxicity and marginally improved antileukemic activity compared with free 2-PHE-BU. Nevertheless, they did not prove to be superior either to the template steroidal ester used for in-silico predictions or to previously synthesized steroidal esters of aromatic nitrogen mustards. The results obtained indicate that in-silico design predictions may guide the design and synthesis of new bioactive steroidal esters, but further parameters should be considered aiming at the discovery of compounds with optimum activity.
authors.affiliation: Laboratory of Medicinal Chemistry, Department of Pharmacy, School of Health Sciences, University of Patras, Patras, Greece.
authors.forename: Ioanna C
authors.initials: IC
authors.lastname: Papaconstantinou
authors.forename: Manolis A
authors.initials: MA
authors.lastname: Fousteris
authors.forename: Anna I
authors.initials: AI
authors.lastname: Koutsourea
authors.forename: Georgios N
authors.initials: GN
authors.lastname: Pairas
authors.forename: Athanasios D
authors.initials: AD
authors.lastname: Papageorgiou
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*; D003198:Computer Simulation; D017076:Computer-Aided Design; D004952:Esters / Q000737:chemistry; D005260:Female; D007941:Leukemia P388 / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013256:Steroids / Q000737:chemistry; D013329:Structure-Activity Relationship; D018675:Toxicity Tests
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004952:Esters; D009588:Nitrogen Mustard Compounds; D013256:Steroids