title: Chemical synthesis of 2beta-amino-5alpha-androstane-3alpha,17beta-diol N-derivatives and their antiproliferative effect on HL-60 human leukemia cells.
abstract: Even though few steroids are used for the treatment of leukemia, 2beta-(4-methylpiperazinyl)-5alpha-androstane-3alpha,17beta-diol (1) was recently reported for its ability to inhibit the proliferation of human leukemia HL-60 cells. With an efficient procedure that we had developed for the aminolysis of hindered steroidal epoxides, we synthesized a series of 2beta-amino-5alpha-androstane-3alpha,17beta-diol N-derivatives structurally similar to 1. Hence, the opening of 2,3alpha-epoxy-5alpha-androstan-17beta-diol with primary and secondary amines allowed the synthesis of aminosteroids with diverse length, ramification, and functionalization of the 2beta-side chain. Sixty-four steroid derivatives were tested for their capacity to inhibit the proliferation of HL-60 cells; thus obtaining first structure-activity relationship results. Ten aminosteroids with long alkyl chains (7-16 carbons) or bulky groups (diphenyl or adamantyl) have shown antiproliferative activity over 78% at 10microM and superior to that of the lead compound. The 3,3-diphenylpropylamino, 4-nonylpiperazinyl and octylamino derivatives of 5alpha-androstane-3alpha,17beta-diol inhibited the HL-60 cell growth with IC(50) of 3.1, 4.2 and 6.4microM, respectively. They were also found to induce the HL-60 cell differentiation.
authors: Medicinal Chemistry Division, Oncology and Molecular Endocrinology Laboratory, CHUL Research Center (CHUQ-Pavillon CHUL) and Université Laval, 2705 Laurier Boulevard, Que., Canada G1V 4G2.
authors: Dominic
authors: D
authors: Thibeault
authors: Jenny
authors: J
authors: Roy
authors: Patrick
authors: P
authors: DeRoy
authors: Donald
authors: D
authors: Poirier
mesh_terms: D015113:Androstane-3,17-diol / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D008968:Molecular Conformation; D013237:Stereoisomerism; D013256:Steroids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D013256:Steroids; D015113:Androstane-3,17-diol