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Structure-activity relationship of retinoids in fetal rat bone cultures

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Summary

The structure-activity relationship of 29 retinoids was investigated in fetal rat bone organ cultures. Retinoids induced the release of proteoglycan followed by cartilage tissue breakdown. In this study the loss of RNA was used as a parameter for cartilage resorption. During 6 days of incubation RNA decreased up to 80% in presence of active retinoids. Thus the ED40 was determined from dose-response curves of the various retinoids. The new compounds, called arotinoids, which contained the retinoic acid carbon skeleton in a fixed cisoid geometric conformation, were up to 200 times more active than all-trans-β-retinoic acid. The most active compound contained a tetramethylated tetralin ring and a second aromatic ring in the side chain. Several lines of evidence indicated that the carboxylic acid end group was essential for the activity of retinoids in fetal bone cultures. The new, highly active retinoids described here might be an excellent tool to investigate whether the retinoid action is mediated by specific cellular retinoid binding proteins.

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References

  1. Bollag, W.: Retinoids and cancer, Cancer Chemother. Pharmacol.3:207–215, 1979

    Article  CAS  PubMed  Google Scholar 

  2. Stern, P. H., Mavreas, T., Trummel, C. L., Schnoes, H. K., DeLuca, H. F.: Bone resorbing activity of analogues of 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol: effects of side chain modification and stereoisomerization on responses of fetal rat bones in vitro, Mol. Pharmacol.12:879–886, 1976

    CAS  PubMed  Google Scholar 

  3. Bashor, M. M., Taft, D. O., Chytil, F.: In vitro binding of retinol to rat tissue components, Proc. Natl. Acad. Sci. U.S.A.70:3483–3487, 1973

    CAS  PubMed  Google Scholar 

  4. Bashor M. M., Chytil, F.: Cellular retinol-binding protein, Biochim. Biophys. Acta411:87–96, 1975

    CAS  PubMed  Google Scholar 

  5. Ong, D. E., Chytil, F.: Multiple retinol binding proteins in rabbit lung, Biochem. Biophys. Res. Commun.59:221–229, 1974

    Article  CAS  PubMed  Google Scholar 

  6. Ong, D. E., Chytil, F.: Specificity of cellular retinol-binding protein for compounds with vitamin A activity, Nature255:74–75, 1975

    Article  CAS  PubMed  Google Scholar 

  7. Ong, D. E., Chytil, F.: Cellular retinol-binding protein from rat liver. Purification and characterization, J. Biol. Chem.253:828–832, 1978

    CAS  PubMed  Google Scholar 

  8. Saari, J. C., Futterman, S., Bredberg, L.: Cellular retinol-and retinoic acid-binding proteins of bovine retina. Purification and properties, J. Biol. Chem.253:6432–6436, 1978

    CAS  PubMed  Google Scholar 

  9. Wiggert, B. O., Chader, G. J.: A receptor for retinol in the developing retina and pigment epithelium, Exp. Eye Res.21:143–151, 1975

    Article  CAS  PubMed  Google Scholar 

  10. Ong, D. E., Chytil, F.: Retinoic acid-binding protein in rat tissue. Partial purification and comparison to rat tissue retinol-binding protein, J. Biol. Chem.250:6113–6117, 1975

    CAS  PubMed  Google Scholar 

  11. Ong, D. E., Chytil, F.: Cellular retinoic acid-binding protein from rat testis. Purification and characterization, J. Biol. Chem.253:4551–4554, 1978

    CAS  PubMed  Google Scholar 

  12. Ong, D. E., Page, D. L., Chytil, F.: Retinoic acid-binding protein occurrence in human tumors, Science190:60–61, 1975

    CAS  PubMed  Google Scholar 

  13. Sani, B. P., Hill, D. L.: Retinoic acid: a binding protein in chick embryo metatarsal skin, Biochem. Biophys. Res. Commun.61:1276–1282, 1974

    Article  CAS  PubMed  Google Scholar 

  14. Sani, B. P., Hill, D. L.: A retinoic acid-binding protein from chick embryo skin, Cancer Res.36:409–413, 1976

    CAS  PubMed  Google Scholar 

  15. Sani, B. P., Banerjee, C. K.: Purification and properties of retinoic acid-binding protein from chick embryo skin, Biochem. J.173:643–649, 1978

    CAS  PubMed  Google Scholar 

  16. Jetten, A. M., Jetten, M. E. R.: Possible role of retinoic acid binding protein in retinoid stimulation of embryonal carcinoma cell differentiation, Nature278:180–182, 1979

    Article  CAS  PubMed  Google Scholar 

  17. Kistler, A.: Inhibition of vitamin A action in rat bone cultures by inhibitors of RNA and protein synthesis, Experientia34:1159–1161, 1978

    Article  CAS  PubMed  Google Scholar 

  18. Kistler, A., Galli, B.: Retinoic acid-induced proteoglycan release and cartilage resorption in rat bone cultures are age dependent and inhibited by EDTA, Wilhelm Roux's Arch. Dev. Biol.187:59–71, 1979

    Article  CAS  Google Scholar 

  19. Loeliger, P., Bollag, W., Mayer, H.: Arotinoids, a new class of highly active retinoids, Eur. J. Med. Chem.15:9–15, 1980

    CAS  Google Scholar 

  20. Ceriotti, G.: Determination of nucleic acids in animal tissues, J. Biol. Chem.214:59–70, 1955

    CAS  PubMed  Google Scholar 

  21. Whiteman, P.: The quantitative measurement of alcian blue-glycosaminoglycan complexes, Biochem. J.131:343–350, 1973

    CAS  PubMed  Google Scholar 

  22. Hänni, R., Hervouet, D., Busslinger, A.: Determination of an aromatic retinoid and its main metabolite by high-performance liquid chromatography, J. Chromatogr.162:615–621, 1979

    PubMed  Google Scholar 

  23. Fell, H. B., Mellanby, E.: The effect of hypervitaminosis A on embryonic limb-bones cultivated in vitro, J. Physiol.116:320–349, 1952

    CAS  PubMed  Google Scholar 

  24. Goodman, D. S., Smith, J. E., Hembry, R. M., Dingle, J. T.: Comparison of the effects of vitamin A and its analogs upon rabbit ear cartilage in organ culture and upon growth of the vitamin A-deficient rat, J. Lipid Res.15:406–414, 1974

    CAS  PubMed  Google Scholar 

  25. Bard, D. R., Lasnitzki, I.: Toxicity of anti-carcinogenic retinoids in organ culture, Br. J. Cancer35:115–119, 1977

    CAS  PubMed  Google Scholar 

  26. Wilkoff, L. J., Chopra, D., Peckham, J. C.: Effect of retinoids on the differentiation of chick embryo metatarsal skin explants, J. Invest. Dermatol.72:11–16, 1979

    Article  CAS  PubMed  Google Scholar 

  27. Adamo, S., De Luca, L. M., Akalovsky, I., Bhat, P. V.: Retinoid-induced adhesion in cultured, transformed mouse fibroblasts, J. Natl. Cancer Inst.62:1473–1478, 1979

    CAS  PubMed  Google Scholar 

  28. Jetten, A. M., Jetten, M. E. R., Shapiro, S. S., Poon, J. P.: Characterization of the action of retinoids on mouse fibroblast cell lines, Exp. Cell Res.119:289–299, 1979

    Article  CAS  PubMed  Google Scholar 

  29. Bollag, W.: Therapeutic effects of an aromatic retinoic acid analog on chemically induced skin papillomas and carcinomas of mice, Eur. J. Cancer10:731–737, 1974

    CAS  PubMed  Google Scholar 

  30. Kleiner-Bössaler, A., DeLuca, H. F.: Formation of retinoic acid from retinol in the kidney, Arch. Biochem. Biophys.142:371–377, 1971

    Article  PubMed  Google Scholar 

  31. Oppenheimer, J. H., Dillmann, W. H.: Nuclear receptors for triiodothyronine: A physiological perspective. In: L. Birnbauer, B. W. O'Malley (eds.): Receptors and Hormone Action, Vol. III, pp. 1–33. Academic Press, New York, 1978

    Google Scholar 

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  1. Biological Pharmaceutical Research Department, F. Hoffmann-La Roche & Co. Ltd., CH-4002, Basel, Switzerland

    Andreas Kistler

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  1. Andreas Kistler
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Kistler, A. Structure-activity relationship of retinoids in fetal rat bone cultures. Calcif Tissue Int 33, 249–254 (1981). https://doi.org/10.1007/BF02409445

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