title: 2beta-(N-substituted piperazino)-5alpha-androstane-3alpha,17beta-diols: parallel solid-phase synthesis and antiproliferative activity on human leukemia HL-60 cells.
abstract: Leukemia is the most common cancer affecting children. A steroid possessing a methylpiperazine nucleus was recently reported to inhibit the proliferation of HL-60 leukemia cells. To speed up the development of this promising potential new drug, we generated libraries of analogues using parallel solid-phase organic synthesis (SPOS). A 6-step sequence of reactions, starting from dihydrotestosterone, afforded a steroidal 2,3alpha-epoxide, which was selectively opened to give, after N-Fmoc protection, a diol with suitable stereochemistry. The difference of reactivity between 3alpha-OH and 17beta-OH was then used to allow the regioselective coupling of 17beta-OH to chloro-activated butyldiethylsilane polystyrene. We next generated three libraries of 2beta-piperazinyl-5alpha-androstane-3alpha,17beta-diol N-derivatives with 1, 2, or 3 levels of molecular diversity in acceptable yields and purities for our biological screening assay. Several members of these libraries were more potent than the lead compound, especially five members with a proline as the first level of diversity and a cyclohexylcarbonyl, methylbutyryl, cyclohexylacetyl, cyclopentylpropionyl, or hexanoyl as the second level of diversity. They efficiently inhibited HL-60 cell proliferation with IC50 values of 0.58, 0.66, 1.78, 1.98, and 2.57 microM, respectively. The present work demonstrates the potential of our SPOS approach for the optimization of a new class of cytotoxic agents.
authors: Medicinal Chemistry Division, Oncology and Molecular Endocrinology Research Center, Centre Hospitalier Universitaire de Québec (CHUQ) and Université Laval, Québec G1V 4G2, Canada.
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; D049109:Cell Proliferation / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D010879:Piperazines; D015113:Androstane-3,17-diol