title: Explorative study on the anticancer activity, selectivity and metabolic stability of related analogs of aminosteroid RM-133.
abstract: RM-133 is a key representative of a new family of aminosteroids reported as potent anticancer agents. Although RM-133 produced interesting results in 4 mouse xenograft cancer models when injected subcutaneously, it needs to be improved to increase its in vivo potency. Thus, to obtain an analog of RM-133 with a better drug potential, a structure-activity relationship study was conducted by synthesizing eleven RM-133-related compounds and addressing their antiproliferative activity on 3 human cancer cells (HL-60, OVCAR-3 and PANC-1) and 3 human normal cell lines (primary ovary, pancreas and renal proximal tubule) as well as their metabolic stability in human liver microsomes. When the 2β-tertiary amine of RM-133 was transformed into a salt or moved to position 3β, the anticancer activity was lost. Modifying the orientation of the side chain of RM-133 increased anticancer activity and selectivity, but led to a drastic loss of stability. The protection of the 3α-hydroxyl of RM-133 by the formation of an ester or a carbamate stabilized the molecule against the phase I metabolic enzymes without affecting its anticancer activity. In comparison to RM-133, the 3-dimethylcarbamate derivative 3 is more selective for cancer cells over normal cells and is much more stable in liver microsomes. Those results support the use of a pro-drug strategy targeting the 3α-hydroxyl of RM-133 as an approach to improve its drug properties. The work presented will enable the development of an optimized anticancer drug of the aminosteroid family that is suitable for a future phase I clinical trial.
authors.affiliation: Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center, Québec (Québec), Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Perreault
authors.affiliation: Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center, Québec (Québec), Canada.
authors.forename: René
authors.initials: R
authors.lastname: Maltais
authors.affiliation: Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center, Québec (Québec), Canada.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Dutour
authors.affiliation: Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center, Québec (Québec), Canada; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec (Québec), Canada. Electronic address: donald.poirier@crchul.ulaval.ca.
authors.forename: Donald
authors.initials: D
authors.lastname: Poirier
mesh_terms: D000736:Androstenes / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000736:Androstenes; D000970:Antineoplastic Agents; C000594943:RM-133 aminosteroid
keywords: Anticancer agent; Drug; Metabolic stability; Selective cytotoxicity; Steroid