Synthetic Studies of Vitamin D Analogues. XI. Synthesis and Differentiation-Inducing Activity of 1.ALPHA.,25-Dihydroxy-22-oxavitamin D3 Analogues.

Abstract

Six analogues of 1 alpha,25-dihydroxy-22-oxavitamin D3 (OCT) (2), 26,27-dimethyl OCT (5), 26,27-diethyl OCT (6), 24-norOCT (7), 24-homoOCT (8), 24-dihomoOCT (9), and 24-trihomoOCT (10) were synthesized from the 20(S)-alcohol (11) as the common starting material. In the activity inducing differentiation of human myeloid leukemia cells (HL-60) into macrophages, 26,27-dimethyl OCT (5) and 24-homoOCT (8) showed the highest activities. The binding properties of these analogues to the chick embryonic intestinal 1 alpha,25-dihydroxyvitamin D3 (1) receptor are also described.

Dose‐response Study of 22‐Oxacalcitriol in Patients with Secondary Hyperparathyroidism

“…1). Initially, OCT was found to mimic certain biological actions of calcitriol such as suppression of tumor and epithelial cell proliferation, differentiation of leukemia, tumor and epithelial cells and regulation of the immune system (4–7). It was soon recognized, however, that OCT had low calcemic properties and might therefore be used to treat hyperparathyroidism.…”

Noncalcemic, Antiproliferative, Transcriptionally Active, 24-Fluorinated Hybrid Analogues of the Hormone 1α,25-Dihydroxyvitamin D3. Synthesis and Preliminary Biological Evaluation

“…[3][4][5][6][7][8][9][10][11][12] Some synthetic analogues exhibiting such selective physiological activities, like Hoffmann-La Roche's 16-ene-26,27-hexafluorinated compound 2, 13 have been shown to possess very desirable pharmacological properties with good potential as new drug candidates for the treatment of proliferative and immunological diseases. [3][4][5][6][7][8][9][10][11][12][13] As part of our research program to prepare analogues of 1,25D 3 carrying a 1-hydroxymethyl group to diminish calcemic activity and carrying also a potently prodif-ferentiating side chain (i.e., hybrid analogues), we have already succeeded in synthesizing several selectively active lead compounds; [14][15][16] some of these new hybrid analogues are serving also as effective molecular probes to elucidate the mechanistic details of the selective biological responses that they stimulate. [17][18][19] Now, we report on a new set of 1-hydroxymethyl hybrid analogues 3 and 4 bearing two fluorine atoms at side-chain position 24.…”

“…Because of its extraordinarily high potency in regulating diverse biochemical events vital to good health in humans, 1α,25-dihydroxyvitamin D 3 (1,25D 3 , calcitriol, 1 ) has stimulated the interest worldwide of medical researchers, molecular biologists, pharmacologists, and medicinal and organic chemists . A major chemical challenge has been to design and synthesize analogues of 1,25D 3 that retain potent antiproliferative and pro-differentiating activities but that lack hypercalcemic activity. − Some synthetic analogues exhibiting such selective physiological activities, like Hoffmann-La Roche's 16-ene-26,27-hexafluorinated compound 2 , have been shown to possess very desirable pharmacological properties with good potential as new drug candidates for the treatment of proliferative and immunological diseases. −

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Organic Chemistry of Vitamin D Analogues (Deltanoids)

“…Thus, C‐20 ketone 6 is derived from C‐22 aldehyde 7 , which is prepared by ozonolysis of triene‐protected steroidal vitamin D 2 followed, ultimately, by allylic 1‐hydroxylation 11. Likewise, C‐20 alcohol 8 is prepared from the steroid dehydroepiandrosterone (DHEA) 12. The major advantage of preparing new deltanoids from almost whole steroid precursors is that most of the deltanoid skeleton, including its absolute stereochemistry, is available without needing costly and time‐consuming multistep syntheses.…”