Novel 2-alkyl-1α,25-dihydroxy-19-norvitamin D3: Efficient synthesis with Julia olefination, evaluation of biological activity and development of new analyzing system for co-activator recruitment

Midori A. Arai, Atsushi Kittaka

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

New 2-alkyl-1α,25-dihydroxy-19-norvitamin D3 analogs were efficiently synthesized. The C2-alkyl-A-ring precursors were prepared as (3R,5R)-4-alkyl-3,5-dihydroxycyclohexanones from (-)-quinic acid based on radical allylation at the C4 position of methyl (-)-quinicate. The novel CD-ring coupling partner, with the elongated two carbon unit, was synthesized from 25-hydroxy Grundmann's ketone, and applied to modified Julia olefination to construct a diene unit between the A-ring and the CD-ring. The coupling yields, including a deprotection step, were moderate (47-62%). After the separation of the diastereomers based on C2 stereochemistry using HPLC, the structure (2α or 2β) was determined by 1H NMR studies including NOE (nuclear Overhauser effect) experiments. It was also found that H NMR chemical shifts on the A-ring showed good correlation with DeLuca's 2-methyl- and 2-ethyl-1α,25-dihydroxy-19-notvitamin D3 analogs. Among the synthesized 19-norvitamin D3 analogs, 2α-(3-hydroxypropyl)- 1α,25-dihydroxy-19-norvitamin D3 (8a) showed almost the same potency in binding to the bovine thymus vitamin D receptor (VDR) as the natural hormone (1), while its β-isomer had only a 3% affinity. Both 2α-allyl- and 2α-propyl-1α,25-dihydroxy-19-norvitamin D 3 and their 2β-analogs possessed a weak affinity for the VDR. The strong VDR ligand 8a was ca. 36-fold more potent in induction of HL-60 cell differentiation than 1 and, interestingly, even the weaker ligand, 2β-(3-hydroxypropyl)-1α,25-dihydroxy-19-norvitamin D3 (8b), showed a 6.7-fold higher potency in cell differentiation activity than that of 1. Next, a novel rapid analyzing system of ligand-induced co-factor recruitment on VDR was developed using fluorophore labelled CoA and HCHO fixing of the complex. The efficiency of recruitment of co-activators would explain the discrepancy between the biological activity and the VDR affinity of the ligand.

Original languageEnglish
Pages (from-to)2621-2631
Number of pages11
JournalAnticancer research
Volume26
Issue number4 A
Publication statusPublished - 2006 Jul 1
Externally publishedYes

Keywords

  • 19-norvitamin D
  • Co-activator
  • High-throughput screening
  • Julia olefination
  • Synthesis
  • Vitamin D receptor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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