title: Chemical synthesis, cytotoxicity, selectivity and bioavailability of 5α-androstane-3α,17β-diol derivatives.
abstract: Aminosteroid derivatives represent a new family of compounds with promising antiproliferative activity over different cancer cell lines. Among all the aminosteroid derivatives synthesised in our laboratory, we have identified E-37P as one of the more potent when tested in vitro. Unfortunately, the pharmacokinetic properties of E-37P decrease its effectiveness when tested in vivo. To improve the bioavailability and increase the efficiency of aminosteroid E-37P, two series of analog compounds were synthesised by classic chemical synthesis, they were then characterized, and the concentration that inhibits 50% of cell proliferation (IC50) was determined on different cell lines. RM-133, a 5α-androstane-3α,17β-diol derivative with a quinoline nucleus at the end of the piperazine-proline side-chain at position 2β and an ethinyl at position 17α, showed very good antiproliferative activity among the five cancer cell lines studied (IC50=0.1, 0.1, 0.1, 2.0 and 1.1 μM for HL-60, MCF-7, T-47D, LNCaP and WEHI-3, respectively). Moreover, the plasmatic concentration of RM-133 at 3h, when injected subcutaneously in rats, was 2.3-fold higher than that of E-37P (151 vs 64.8 ng/mL). Furthermore, RM-133 weakly inhibited the two representative liver enzymes, CYP3A4 and CYP2D6, indicating a very low risk of drug-drug interactions. The cytotoxicity of RM-133 against normal cells was tested on peripheral blood lymphocytes (PBL) obtained from different donors and previously activated with phytohemagglutinin-L. PBL responded differently to treatment with RM-133, we observed a stimulation of cell proliferation and/or cytotoxicity in a dose-dependent manner. Based on these results, additional studies are currently underway to evaluate the selectivity of our lead compound against normal cell lines in a more detailed fashion.
authors.affiliation: Laboratory of Medicinal Chemistry, CHU de Québec-Research Center (CHUL, T4-42) and Université Laval (Faculty of Medicine), 2705 Laurier Boulevard, Québec (Québec) G1V 4G2, Canada.
authors.forename: Diana
authors.initials: D
authors.lastname: Ayan
authors.affiliation: Laboratory of Medicinal Chemistry, CHU de Québec-Research Center (CHUL, T4-42) and Université Laval (Faculty of Medicine), 2705 Laurier Boulevard, Québec (Québec) G1V 4G2, Canada.
authors.forename: René
authors.initials: R
authors.lastname: Maltais
authors.affiliation: Laboratory of Medicinal Chemistry, CHU de Québec-Research Center (CHUL, T4-42) and Université Laval (Faculty of Medicine), 2705 Laurier Boulevard, Québec (Québec) G1V 4G2, Canada.
authors.forename: Audrey
authors.initials: A
authors.lastname: Hospital
authors.affiliation: Laboratory of Medicinal Chemistry, CHU de Québec-Research Center (CHUL, T4-42) and Université Laval (Faculty of Medicine), 2705 Laurier Boulevard, Québec (Québec) G1V 4G2, Canada. Electronic address: donald.poirier@crchul.ulaval.ca.
authors.forename: Donald
authors.initials: D
authors.lastname: Poirier
mesh_terms: D000736:Androstenes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D001682:Biological Availability; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002777:Cholestanols / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000633:toxicity; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D018922:HL-60 Cells; D006207:Half-Life; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010879:Piperazines / Q000737:chemistry; D011392:Proline / Q000737:chemistry; D011804:Quinolines / Q000737:chemistry; D051381:Rats
chemical_list: D000736:Androstenes; D002777:Cholestanols; D010879:Piperazines; D011804:Quinolines; C000594943:RM-133 aminosteroid; D011392:Proline; C037219:quinoline; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A
keywords: Aminosteroid; Cancer; Cytotoxicity; Lymphocytes; Selectivity