1α,25-Dihydroxyvitamin D3-3β-bromoacetate, a potential cancer therapeutic agent: Synthesis and molecular mechanism of action

Abstract

Synthesis of 1α,25-dihydroxyvitamin D 3 -3β-bromoacetate (1,25(OH) 2 D 3 -3-BE), a potential anticancer agent is presented. We also report that mechanism of action of 1,25(OH) 2 D 3 -3-BE may involve reduction of its catabolism, as evidenced by the reduced and delayed expression of 1α,25-dihydroxyvitamin D 3 -24-hydroxylase (CYP24) gene in cellular assays. Keywordssynthesis of 1,25(OH) 2 D 3 -3-BE; anti-cancer agent; mechanism of action of 1,25(OH) 2 D 3 -3-BE; 1α,25-dihydroxyvitamin D 3 -24-hydroxylase (CYP24)The awareness of the potential beneficial effect of vitamin D in a number of diseases, and general good health has increasingly become a public health issue [1]. In addition, the therapeutic potential of 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), the dihydroxylated metabolite of vitamin D 3 , on established tumors was realized when the potent antiproliferative property of 1,25(OH) 2 D 3 was discovered in the early 1980's in leukemic cells [2]. Since then the antiproliferative and pro-differentiative effects of 1,25(OH) 2 D 3 has been studied in various cancer cell lines, and as a result, 1,25(OH) 2 D 3 has been investigated as a potential anti-cancer agent [3]. However, clinical trials have demonstrated strong calcemic and calciuric effects at pharmacological doses (of 1,25(OH) 2 D 3 ) [4]. This limitation provided the search for structural analogs of 1,25(OH) 2 D 3 with potent antiproliferative yet low calcemic properties [4]. This effort, based solely on a Specific Estrogen Receptor Modulator (SERM)-like concept adopted the idea that these analogs would change the conformation of nuclear vitamin D receptor (VDR), the chief modulator of the biological actions of 1,25(OH) 2 D 3 sufficiently from the parent hormone to separate cell-regulatory properties from calcemic property. Numerous such 'non-calcemic' analogs (of 1,25(OH) 2 D 3 ) have been synthesized based on this concept with the hope of achieving a favorable antiproliferative/toxicity index, yet clinical results are largely disappointing [5,6].On the other hand, recent clinical trials of 1,25(OH) 2 D 3 either alone or in combination with common cancer therapeutic drugs have produced strongly encouraging results, and brought © 2011 Elsevier Ltd. All rights reserved. * Communicating author: Boston University School of Medicine, 85 East Newton Street, Boston, MA 02118, telephone: 617-638-8199, FAX: 617-638-8194, bapi@bu.edu . Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. and converting the crude into the tert.butyldimethylsilylether (TBDMS) derivative (C) (Scheme 1) in good yield. NIH Public AccessS...

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