Skip to main content
SpringerLink
Log in

Calcium regulating activity of 24a-homo-24,24-difluoro-1α,25-dihydroxyvitamin D3 and 26,27-dimethyl-24,24-difluoro-1α,25-dihydroxyvitamin D3

  • Laboratory Investigations
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Summary

Two fluoro analogs of 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], 24a-homo-24,24-difluoro-1α,25-dihydroxyvitamin D3 [24aF2-homo-1,25(OH)2D3], and 26,27-dimethyl-24,24-difluoro-1α,25-dihydroxyvitamin D3 [24F2-1,25(OH)2(Me)2D3] were examined for calcium (Ca)-regulating activity. The objective of the present study was to determine whether or not fluoro substitution at 24-position would alter activities of the original compounds, that is, 26,27-dimethyl 1α, 25-dihydroxyvitamin. D3[1,25(OH)2 (Me)2D3] and 24-homo-1α,25-dihydroxyvitaminD3[24homo-1,25(OH)2D3], respectively. The relative activities of 24aF2-homo-1,25(OH)2D3, 24F2-1,25(OH)2(Me)2D3, and 1,25(OH)2D3 in competing with 1,25(OH)2D3 for binding to chick intestinal cytosol receptor were 0.28:0.5:1.0. The relative potencies of the same series of compounds in competition for the vitamin D-deficient rat serum binding sites were 0.04:0.15:1. Bone-resorbing activities of two fluoro analogs in cultures of neonatal mouse parietal bones were more potent than that of 1,25(OH)2D3. Similar results were recognized in stimulating activities of osteoclast-like cell formation. Responses of two fluoro analogs to intestinal Ca absorption were similar to that of 1,25(OH)2D3. The potencies of 1,25(OH)2D3. and its fluoro analogs in bone Ca mobilization were the highest with 1,25(OH)2D3. followed by 24F2 1,25(OH)2(Me)2D3 and 24aF2-homo-1,25(OH)2D3, in that order. From these results and the data of Paulson et al. [24], fluoro substitution in 24-position of 1,25(OH)2D3. apparently does not alter their activities, hence, the fluoro substitution at 24-position of 1,25(OH)2D3. and the elongation of side chain of 1,25(OH)2D3. may not intensify Ca-regulating activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. DeLuca HF, Schones HK (1983) Vitamin D: recent advances. Annu Rev Biochem 52:411

    Google Scholar 

  2. Abe E, Miyaura C, Sakagami H, Takeda M, Konno K, Yamazaki T, Yoshiki S, Suda T (1981) Differentiation of mouse myeloid leukemia cells induced by 1α,25-dihydroxyvitamin D3. Proc Natl Acad Sci USA 78:4990–4994

    Google Scholar 

  3. Okamoto S, Tanaka Y, DeLuca HF, Kobayashi Y, Ikekawa N (1983) Biological activity of 24,24-difluoro-1,25-dihydroxyvitamin D3. Am J Physiol 244:E159-E163

    Google Scholar 

  4. Tanaka Y, DeLuca HF, Kobayashi Y, Ikekawa N (1984) 26,26,26,27,27,27-Hexafluoro-1,25-dihydroxyvitamin D3: a highly potent, long-lasting analog of 1,25-dihydroxyvitamin D3. Arch Biochem Biophys 229:348–354

    Google Scholar 

  5. Gill HS, Londowski JM, Corrodino RA, Zmsmeister AR, Kumar R (1988) The synthesis and biological activity of 25dihydroxy-26,27-dimethyl-vitamin D and 1,25-dihydroxy-26,27dimethyl-vitamin D: highly potent novel analogs of vitamin D. J Steroid Biochem 31:147–160

    Google Scholar 

  6. Eguchi T, Ikekawa N, Sumitani K, Kumegawa M, Higuchi S, Otomo S (1990) Effect on carbon lengthening at the side chain terminal of 1α,25-dihydroxyvitamin D3 for calcium regulating activity. Chem Pharm Bull (Tokyo) 38:1246–1249

    Google Scholar 

  7. Ostrem VK, Lau WF, Lee SH, Perlman K, Prahl J, Schones HK, DeLuca HF (1987) Induction of monocytic differentiation of HL-60 cells by 1,25-dihydroxyvitamin D analogs. J Biol Chem 262:14164–14171

    Google Scholar 

  8. Ostrem VK, Tanaka Y, Prahl J, DeLuca HF, Ikekawa N (1987) 24- and 26-homo-1,25-dihydroxyvitamin D3: preferential activity in inducing differentiation of human leukemia cells HL-60 in vitro. Proc Natl Acad Sci USA 84:2610–2614

    Google Scholar 

  9. Perlman K, Kutner A, Prahl J, Smith C, Inaba M, Schones HK, DeLuca HF (1990) 24-homologated 1,25-dihydroxyvitamin D3 compounds: separation of calcium and cell differentiation activities. Biochemistry 29:190–196

    Google Scholar 

  10. Miyahara T, Harada M, Miyata M, Sugure A, Ikemoto Y, Takamura T, Higuchi S, Otomo S, Kozuka H, Ikekawa N (1992) Calcium regulating activity of 26,27-dialkyl analogs of 1,25-dihydroxyvitamin D3. Calcif Tissue Int 51:218–223

    Google Scholar 

  11. Ikekawa N, Eguchi T, Hara N, Takatsuto S, Honda A, Mori Y, Otomo S (1987) 26,27-diethyl-1α,25-dihydroxyvitamin D3 and 24,24-difluoro-24-homo-1(x,25-dihydroxyvitamin D3: highly po tent inducer for differentiation of human leukemia cells HL-60. Chem Pharm Bull 35:4362–4365

    Google Scholar 

  12. Shigeno C, Yamamoto I, Dokoh S, Hino M, Aoki J, Yamada K, Morita R, Kaneyama M, Torizuka K (1985) Identification of 1,24(R)-dihydroxy-vitamin D3 like bone resorbing lipid in a patient with cancer-associated hypercalcemia. J Clin Endocrinol Metab 61:761–768

    Google Scholar 

  13. Takahashi N, Yamana H, Yoshiki S, Roodman GD, Munday GR, Jones ST, Boyde A, Suda T (1988) Osteoclast-like cell formation and its regulation by osteotropic hormones in mouse bone marrow cultures. Endocrinology 122:1373–1382

    Google Scholar 

  14. Burstone MS (1958) Histochemical demonstration of acid phosphatase with naphthol AS-phosphates. J Natl Cancer Inst 21:523–539

    Google Scholar 

  15. Suda T, DeLuca HF, Tanaka Y (1970) Biological activity of 25-hydroxy-ergocalciferol in rats. J Nutr 100:1049–1052

    Google Scholar 

  16. Connerty HV, Briggs AR (1966) Determination of serum calcium by means of orthocresolphthalein complexone. Am J Clin Pathol 45:290–296

    Google Scholar 

  17. Omdahl J, Holick MF, Suda T, Tanaka Y, DeLuca HF (1971) Biological activity of 1,25-dihydroxycholecalciferol. Biochemistry 10:2935–2940

    Google Scholar 

  18. Okumura H, Yamamuro T, Higuchi S, Harada M, Takamura T, Otomo S, Aihara H, Ikekawa N, Kobayashi (1990) 26,27-hexafluoro-1,25-dihydroxyvitamin D3(F6-1,25(OH)2D3) prevents osteoporosis induced by immobilization combined with ovariectomy in the rat. Bone Miner 9:101–109

    Google Scholar 

  19. Seino Y, Yamaoka K, Ishida M, Yabuuchi H, Ichikawa M, Ishige H, Yoshino H, Avioli LV (1982) Biochemical characterisation of 1,25-dihydroxyvitamin D receptor in chick embryonal duodenal cytosol. Calcif Tissue Int 34:265–269

    Google Scholar 

  20. Haddad JG, Chyu KJ (1971) Competitive protein-binding radioassay for 25-hydroxycholecalciferol. J Clin Endocrinol 33:992–995

    Google Scholar 

  21. Corradino RA, Ikekawa N, DeLuca HF (1981) Induction of calcium-binding protein in organ-cultured chick intestine by fluoro analogs of vitamin D3. Arch Biochem Biophys 208:273–277

    Google Scholar 

  22. Evans DB, Thavarajah M, Uskokovic MR, Kanis JA (1990) Increased potency of 1,25-dihydroxyvitamin D3 on human osteoblast-like cells following structural side-chain modification. Bone 11:439–443

    Google Scholar 

  23. Bouillon R, Allewaert K, Xiang DA, Tan BK, Baelen HV (1991) Vitamin D analogs with low affinity for the vitamin D binding protein: enhanced in vitro and decreased in vivo. J Bone Miner Res 6:1051–1057

    Google Scholar 

  24. Paulson SK, Perlman K, DeLuca HF, Stern PH (1990) 24- and 26-homo-1,25-dihydroxyvitamin D3 analogs potencies on in vitro bone resorption differ from those reported for cell differentiation. J Bone Miner Res 5:201–206

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Research Center, Taisho Pharmaceutical Co., Ltd., Yoshino-cho, Ohmiya, 1-403, Saitama, 330, Japan

    Masahiro Harada, Akemi Sugure, Yumi Ikemoto, Sumiyo Kondo, Tadanobu Takamura, Shohei Higuchi & Susumu Otomo

  2. Department of Toxicology, Faculty of Pharmaceutical Sciences, Toyama Medical & Pharmaceutical University, Toyama, Japan

    Tatsuro Miyahara, Masaki Miyata, Hiroko Komiyama & Hiroshi Kozuka

  3. Department of Sciences & Technology, Iwaki Meisei University, Iwaki, Japan

    Nobuo Ikekawa

Authors
  1. Masahiro Harada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tatsuro Miyahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masaki Miyata
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroko Komiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Akemi Sugure
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yumi Ikemoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sumiyo Kondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tadanobu Takamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Shohei Higuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Susumu Otomo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hiroshi Kozuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Nobuo Ikekawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Harada, M., Miyahara, T., Miyata, M. et al. Calcium regulating activity of 24a-homo-24,24-difluoro-1α,25-dihydroxyvitamin D3 and 26,27-dimethyl-24,24-difluoro-1α,25-dihydroxyvitamin D3 . Calcif Tissue Int 53, 318–323 (1993). https://doi.org/10.1007/BF01351836

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01351836

Key words

Search

Navigation