title: Calcitriol derivatives with two different side chains at C-20 III. An epimeric pair of the gemini family with unprecedented antiproliferative effects on tumor cells and renin mRNA expression inhibition.
abstract: The searches for drugs that exhibit antineoplastic activity and regulate blood pressure are among the most prevalent and compelling research activities today. Amazingly, there is ample precedence for the antiproliferative action of vitamin-D-related compounds and their role as endocrine suppressors of renin biosynthesis. We have recently synthesized a number of novel calcitriol analogs of the gemini family and originally selected for further studies an epimeric pair related to 19-nor-calcitriol whose 21-methyl group was replaced by a 5,5,5-trifluoro-4-hydroxy-4-(trifluoromethyl)-2-pentynyl group. While maintaining the acceptable calcemic responses, the IC50 concentrations of interferon-gamma release were reduced and the antiproliferative activity and inhibition of renin mRNA expression enhanced. Replacing the geminal methyl groups on the calcitriol-related side chain of these gemini compounds with trideuteriomethyl moieties further boosted the potency in the colon cancer model in mice some 10-fold, reduced NMU-induced breast cancer carcinogenesis in rats and decreased the IC(50) values for renin mRNA inhibition into the pM range.
authors.affiliation: Bioxell Inc., 340 Kingsland Street, Nutley, NJ 07110, USA. Hubert.maehr@bioxell.com
authors.forename: Hubert
authors.initials: H
authors.lastname: Maehr
authors.forename: Milan
authors.initials: M
authors.lastname: Uskokovic
authors.forename: Luciano
authors.initials: L
authors.lastname: Adorini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Penna
authors.forename: Roberto
authors.initials: R
authors.lastname: Mariani
authors.forename: Paola
authors.initials: P
authors.lastname: Panina
authors.forename: Nadia
authors.initials: N
authors.lastname: Passini
authors.forename: Elisa
authors.initials: E
authors.lastname: Bono
authors.forename: Silvia
authors.initials: S
authors.lastname: Perego
authors.forename: Mauro
authors.initials: M
authors.lastname: Biffi
authors.forename: Michael
authors.initials: M
authors.lastname: Holick
authors.forename: Catherine
authors.initials: C
authors.lastname: Spina
authors.forename: Nanjoo
authors.initials: N
authors.lastname: Suh
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006900:Hydroxylation; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D012083:Renin / Q000235:genetics* / Q000378:metabolism
chemical_list: C411462:1,25-dihydroxy-21-(3-hydroxy-3-methylbutyl)vitamin D(3); D012333:RNA, Messenger; D007371:Interferon-gamma; D012083:Renin; D002117:Calcitriol; D002118:Calcium