2-Alkylidene Analogs of 19-nor-1alfa,25-(OH)2D3: Synthesis and Biological Activity

Siciński, R.

Artykuł - szczegóły

Tytuł artykułu

2-Alkylidene Analogs of 19-nor-1alfa,25-(OH)2D3: Synthesis and Biological Activity

Autorzy

Siciński R.

Identyfikatory

Warianty tytułu

Konferencja

21st Conference on Isoprenoids, 23-29 September 2005, Białystok-Białowieża, Poland

Języki publikacji

Abstrakty

D3, [1alfa,25-(OH)2D3], extends beyond calcium and phosphorus homeostasis. The vitamin was also found to regulate cellular differentiation and to play a role in immunoregulatory activity. In 1990 we reported a synthesis of the first member of the so-called 19-norvitamins D. This analog, 19-nor-1alfa,25-dihydroxyvitamin D3, was characterized by the replacement of the A-ring exocyclic methylene substituent at C-10 by two hydrogen atoms. Biological testing of this compound revealed its selective activity profile with high potency in inducing cellular differentiation and very low calcium mobilizing response. Several similar 19-norvitamins were prepared to date and the most notable among them is 19-nor-1alfa,25-dihydroxyvitamin D2 (ZemplarŽ), successfully marketed by Abbott for renal osteodystrophy. As a continuation of these studies we synthesized analogs of the natural vitamin D hormone, 1alfa,25-(OH)2D3, characterized by transposition of its A-ring exocyclic methylene group from carbon 10 to carbon 2. Among such vitamins, 2-methylene-19-nor-1alfa,25-(OH)2D3, possessing an unnatural configuration at C-20 (2MD), is most remarkable due to its unique ability to induce bone formation. 2-Methylene-substituted 19-norvitamin D compounds with truncated side chains were also prepared and two of them (2MP and 2MbisP) show great promise in the treatment of secondary hyperparathyroidism, cancer and psoriasis. In an effort to further explore the 19-nor class for pharmacologically important vitamin D compounds, the isomeric 2-ethylidene-19-nor-1alfa,25-(OH)2D3 compounds were successfully prepared. Promising biological potencies of such analogs, especially those with E-geometry of the ethylidene group, encouraged us to further explore this A-ring modification by the synthesis of 2-(3'-hydroxypropylidene)-19-nor-1alfa,25-(OH)2D3 analogs. Biological tests revealed that calcemic activity of E-geometrical isomers considerably exceeds that of the native hormone, 1alfa,25-(OH)2D3.

Słowa kluczowe

vitamins D 19-norvitamins D vitamin D analogs calcemic activity

Wydawca

Polskie Towarzystwo Chemiczne

Czasopismo

Polish Journal of Chemistry

Rocznik

2006

Tom

Vol. 80, nr 4

Strony

573--585

Opis fizyczny

Bibliogr. 59 poz., rys.

Twórcy

autor

Siciński R.

Department of Chemistry, University of Warsaw, ul. Pasteura 1, 02-093 Warsaw, Poland

Bibliografia

1. Reichle H., Koeffler H.P. and Norman A.W., N. Engl. J. Med, 320, 980 (1989).
2. Blunt J.W., DeLuca H.F. and Schnoes H.K., Biochemistry, 7, 3317 (1968).
3. Holick M.F., Schnoes H.K., DeLuca H.F., Suda T. and Cousins R.J., Biochemistry, 10, 2799 (1971).
4. Norman A.W., Vitamin D, the Calcium Homeostatic Steroid Hormone, Ed. Academic Press, New York 1979, p. 37.
5. DeLuca H.F. and Schnoes H.K., Annu. Rev. Biochem., 53, 411 (1983).
6. DeLuca H.F., FASEB J., 2, 224 (1988).
7. Bouillon R., Okamura W.H. and Norman A.W., Endocr. Rev., 16, 200 (1995).
8. Jones G., Strugnell S.A. and DeLuca H.F., Physiol Rev., 78, 1193 (1998).
9. Feldman D., Glorieux F.H. and Pike J.W., (Eds.), Vitamin D; Academic Press: San Diego, 1997.
10. First International Conference on Chemistry and Biology of Vitamin D Analogues, Steroids, 66 (special issue), 127(2001).
ll. Dai H. and Posner G.H., Synthesis, 1383 (1994).
12. Zhu G. and Okamura W.H., Chem. Rev., 95, 1877 (1995).
13. Posner G.H. and Kahraman M., Eur. J. Org. Chem., 3889 (2003).
14. Kabat M.M. and Radinov R., Curr. Opin. Drug Discovery Dev., 4, 808 (2001).
15. Perlman K.L., Siciński R.R., Schnoes H.K. and DeLuca H.F., Tetrahedron Lett., 31, 1823 (1990).
16. Paaren H.E., DeLuca H.F. and Schnoes H.K., J. Org. Chem., 45, 3253 (1980).
17. Paaren H.E., Schnoes H.K. and DeLuca H.F., J. Org. Chem., 48, 3819 (1983).
18. Bouillon R., Sarandeses L.A., Allewaert K., Zhao J., Mascarenas J.L., Mourino A., Yrielynck S., De Clercq P. and Vandewalle M., J. Bone Miner. Res., 8, 1009 (1993).
19. Perlman K.L. and DeLuca H.F., Tetrahedron Lett., 33, 2937 (1992).
20. Huang P., Sabbe K., Pottie M. and Vandewalle M., Tetrahedron Lett., 36, 8299 (1995).
21. Zhou S., Anne S. and Yandewalle M., Tetrahedron Lett., 37, 7637 (1996).
22. Mikami K., Osawa A., Isaka A., Sawa E., Shimizu M., Terada M., Kubodera N., Nakagawa K.,Tsugawa N. and Okano T., Tetrahedron Lett., 39, 3359 (1998).
23. Evans S.R.T., Schwartz A.M., Shchepotin E.I., Uskokovic M. and Shchepotin I.B., Clin. Cancer Res.,4, 2869(1998).
24. KubotaT., KoshizukaK., Koike M., Uskokovic M., Miyoshi I. and KoefflerH.P., CancerRes.,58,3370 (1998).
25. Van Gool M., Zhao X., Sabbe K. and Vandewalle M., Eur. J. Org. Chem., 2241 (1999).
26. Lee N.E., Williard P.G., Brown A.J., Campbell M.J., Koeffler H.P., Peleg S., Rao D.S. and Reddy G.S.,Steroids, 65, 252 (2000).
27. Slatopolsky E., Finch J., Ritter C., Denda M., Morrissey J., Brown A. and DeLuca H.F., Am. J. Kidney Dis., 26, 852(1995).
28. Llach F., Dialys. Transpl, 30, 654 (2001).
29. Pai A.B., Lin S., Arruda J.A.L. and Lau A.H., Int. J. Artif. Organs, 26, 484 (2003).
30. Perlman K.L., Swenson R.E., Paaren H.E., Schnoes H.K. and DeLuca H.F., Tetrahedron Lett., 32, 7663 (1991).
31. Siciński R.R., Perlman K.L. and DeLuca H.F., J. Med. Chem., 37, 3730 (1994).
32. Wecksler W.R. and Norman A.W., Steroids, 35, 419 (1980).
33. Siciński R.R., Prahl J.M., Smith C.M. and DeLuca H.F., J. Med. Chem., 41, 4662 (1998).
34. Kiegiel J., Wovkulich P.M. and Uskokovic M.R., Tetrahedron Lett., 32, 6057 (1991).
35. Siciński R.R. and DeLuca H.F., Bioorg. Med. Chem. Lett., 5, 159 (1995).
36. Binderup L., Latini S., Binderup E., Bretting C., Calverley M. and Hansen K., Biochem. Pharmacol, 42, 1569(1991).
37. Shevde N.K., Plum L.A. Clagett-Dame M., Yamamoto H., Pike J.W. and DeLuca H.F., Proc. Natl. Acad. Sci. C/S4, 99, 13487(2002).
38. Yamamoto H., Shevde N.K., Warrier A., Plum L.A., DeLuca H.F. and Pike J.W., J. Biol. Chem., 278, 31756(2003).
39. Siciński R.R., Prahl J.M., Smith C.M. and DeLuca H.F., Steroids, 67, 247 (2002).
40. DeLuca H.F., Gowlugari S. and Siciński R.R., U.S. Pat. No. 6,774,251 (August 10, 2004).
41. Plum L.A., Prahl J.M., Ma X., Siciński R.R., Gowlugari S., Clagett-Dame M. and DeLuca H.F., Proc. Natl. Acad. Sci. USA, 101, 6900 (2004).
42. Okamura W.H., Midland M.M., Hammond M.W., Abd.Rahman N., Dormanen M.C., Nemere I. and Norman A.W., J. Steroid. Biochem. Molec. Biol., 53, 603 (1995).
43. Havinga E., Experientia, 29, 1181 (1973).
44. Wing R.M., Okamura W.H., Rego A., Pirio M.R. and Norman A. W., J. Am. Chem. Soc., 97,4980 (1975).
45. Berman E., Friedman N., Mazur V. and Sheves M., J. Am. Chem. Soc., 100, 5626 (1978).
46. Eguchi T. and Ikekawa N., Bioorg. Chem., 18, 19 (1990).
47. Eguchi T., Kakinuma K. and Ikekawa N., Bioorg. Chem., 19, 327 (1991).
48. Ishida H., Shimizu M., Yamamoto K., Iwasaki Y. and Yamada S., J. Org. Chem., 60, 1828 (1995)
49. Rochel N., Wurtz J.M., Mitschler A., Klaholz B. and Moras D., Moll. Cell., 5, 173 (2000).
50. Vanhooke J.L., Benning M.M., Bauer C.B., Pike J. W. and DeLuca H.F., Biochemistry, 43,4101 (2004)
51. Siciński R.R., Rotkiewicz P., Koliński A., Sicińska W., Prahl J.M., Smith C.M. and DeLuca H.F., J.Chem., 45, 3366 (2002).
52. Johnson F., Chem. Rev., 68, 375 (1968).
53. Nasipuri D., Stereochemistry of Organie Compounds, Wiley Eastern: New Delhi, 1991; pp. 270-271.
54. Suhara Y, Nihei K., Tanigawa H., Fujishima T., Konno K., Nakagawa K., Okano T. and Takayam Bioorg. Med. Chem. Lett., 10, 1129 (2000).
55. Suhara Y, Nihei K., Kurihara M., Kittaka A., Yamaguchi K., Fujishima T., Konno K., Miyata N. Takayama H., J. Org. Chem., 66, 8760 (2001).
56. Głębocka A., Siciński R.R. and DeLuca H.F., J. Steroid Biochem. Mol. BioL, 89-90, 25 (2004).
57. DeLuca H.F., Siciński R.R., Głębocka A. and Plum L.A., US Pat. Appl. No 20040229851 (Noven 18,2004).
58. Yoshida A., Ono K., Suhara Y, Saito N., Takayama H. and Kittaka A., Synlett, 8, 1175 (2003).
59. Ono K., Yoshida A., Saito M., Fuishima T, Honzawa S., Suhara Y, Kishimoto S., Sugiura T, Waku Takayama H. and Kittaka A., J. Org. Chem., 68, 7407 (2003).

Typ dokumentu

Bibliografia

Identyfikator YADDA

bwmeta1.element.baztech-article-BUJ3-0006-0055