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

Hubert Maehr, Milan Uskokovic, Luciano Adorini, Giuseppe Penna, Roberto Mariani, Paola Panina, Nadia Passini, Elisa Bono, Silvia Perego, Mauro Biffi, Michael Holick, Catherine Spina, Nanjoo Suh

Research output: Contribution to journalArticle

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-γ 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 IC50 values for renin mRNA inhibition into the pM range.

Original languageEnglish
Pages (from-to)277-281
Number of pages5
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume103
Issue number3-5
DOIs
Publication statusPublished - Mar 2007

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Keywords

  • Antineoplastic activity
  • Gemini
  • Renin mRNA
  • Vitamin-D analogs

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology

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