Solid-phase chemical synthesis and in vitro biological evaluation of novel 2β-piperazino-(20R)-5α-pregnane-3α,20-diol N-derivatives as anti-leukemic agents.
The steroid nucleus is an interesting scaffold for the development of new therapeutic agents. Within the goal of identifying anticancer agents, new pregnane derivatives were prepared by using a sequence of liquid and solid-phase reactions. After we dehydrated epi-allopregnanolone in one step with diethylaminosulfur trifluoride and generated a 2,3α-epoxide, the regio- and stereo-selective aminolysis of this epoxide enabled us to obtain a 2β-piperazino-pregnane, whose secondary amine was protected as N-Fmoc-derivative. Using the difference in reactivity between OHs 3 and 20, we linked the pregnane nucleus-selectively on the polystyrene diethylbutylsilane resin via the OH in position 20. We next achieved in parallel the coupling of an amino acid (1st level of diversity) and the coupling of a carboxylic acid (2nd level of diversity) to generate two libraries of pregnane derivatives. The compounds inhibited the HL-60 leukemia cell growth and the most potent were three compounds (PD, LPC-37 and LPC-48) with a l-proline as first level of diversity and a cyclohexyl-carbonyl, a naphthalene-2-carbonyl or a 3-acetylbenzoyl as second level of diversity. LPC-48 efficiently inhibited HL-60 cell proliferation with IC(50) value of 1.9 μM and exhibited a low toxicity on normal peripheral blood lymphocytes (IC(50)=31 μM). These results encouraged us to further evaluate the biological activity of these new aminosteroids by investigating their preliminary mechanism of action.
Laboratory of Medicinal Chemistry, Oncology and Genomic Unit, CHUQ-CHUL Research Center and Laval University, Québec, Canada.
Hajer
H
Jegham
René
R
Maltais
Philippe
P
Dufour
Jenny
J
Roy
Donald
D
Poirier
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004048:Diethylamines / Q000737:chemistry; D005461:Fluorine / Q000737:chemistry; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology*; D011278:Pregnanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D060327:Solid-Phase Synthesis Techniques
D000970:Antineoplastic Agents; D004048:Diethylamines; D011278:Pregnanes; D054852:Small Molecule Libraries; D005461:Fluorine; C040394:diethylaminosulfur trifluoride