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

Siciński R.

Polish Journal of Chemistry

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2006

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Vol. 80, nr 4

573-585

EN

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.

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19-Methyl Analogs of Vitamin D3: Synthesis and Structure Elucidation by 1HNMR

Szoka P., Siciński R.

Polish Journal of Chemistry

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2006

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Vol. 80, nr 7

1155-1168

EN

Synthesis of three isomeric 19-methylated vitamin D3 derivatives is described. Two different synthetic paths were used, both involving 3,5-cyclovitamin D precursors easily obtainable from commercial vitamin D3. The crucial step of the first route consisted of an acid-catalyzed cycloreversion of isomeric 19-methyl-3,5-cyclovitamin D3 compounds, whereas in the other it involved a Wittig reaction of 10-oxo-19-norvitamin analogs. Neither iodine-catalyzed nor thermal isomerization of the 5Z,10E-isomer provided detectable quantities of the fourth possible isomeric vitamin with a 5Z,10Z-configuration. Structures, stereochemistries and A-ring conformations of the final 19-methyl vitamin D3 analogs were tentatively established on the basis of their 500-MHz 1H NMR spectra and conformational analysis. Application of 1H NOE difference spectroscopy andmolecular modeling studies allowed for the assignment of preferred solution conformations of the 3,5-cyclovitamin D3 intermediates.

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Synthesis of the Enantiomer of 1alfa,25-Dihydroxy Vitamin D3(calcitrol) and a Diastereomer of 1alfa,25-Dihydroxy Vitamin D3, Differing from Natural Product in Configuratoion at All but One Asymmetric Carbon Atoms

Achmatowicz B., Przezdziecka A., Wicha J.

Polish Journal of Chemistry

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2005

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Vol. 79 / nr 2

413-428

EN

Convergent synthesis of ent-1alfa,25-dihydroxyvitamin D3 (ent-calcitriol, 2) and (1S,3S, 13S,14S,17S,20S) - 1alfa,25-dihydroxyvitamin D3 (5) using the ring A building blocks, 6 and 7, respectively, and rings CD building block8, is described. Building block 6 was obtained starting from vitamin D3 via dihydroxylation of the C7-C8 double bond, Mitsunobu inversion at C3, diastereoselective hydroxylation at C1 and cleavage of the C7-C8 bond. Building block 7 was prepared from known synthetic intermediate, 16a(1R,3S) via benzylation of the primary hydroxy group, mono-deprotection of bis-silyl ether 16b and Mitsunobu inversion of the configuration at C3 in 19. Synthetic building blocks were combined using Julia-Kocienski olefination reaction. Key words:Vitamins D, convergent synthesis, Mitsunobu reaction, olefination reaction