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  • Title: Chemical synthesis of 2beta-amino-5alpha-androstane-3alpha,17beta-diol N-derivatives and their antiproliferative effect on HL-60 human leukemia cells.
    Author: Thibeault D, Roy J, DeRoy P, Poirier D.
    Journal: Bioorg Med Chem; 2008 May 01; 16(9):5062-77. PubMed ID: 18375126.
    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.
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