Convenient synthesis of l.alpha.-hydroxy-vitamin D3

Barton, D. H. R.; Hesse, Robert H.; Pechet, Maurice M.; Rizzardo, Ezio

doi:10.1021/ja00789a090

Cited by 147 publications

(30 citation statements)

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“…This was soon confirmed (Norman et al, 1971a;Gray ef al., 1971) and shortly afterwards the chemical identity of the metabolite was established by three groups using a combination of mass spectrometry, ultraviolet absorption spectrophotometry, and specific chemical reactions, as 1,25-dihydroxycholecalciferol (Lawson et al, 1971;Norman et al, 1971b;Holick et al, 1971). The structure was soon confirmed by Haussler (1 972) and the compound has since been synthesized by several groups (Semmler et aZ., 1972;Barton et al, 1973;Uskokovic, personal communication, 1974). The extremely rapid progress that has occurred in the last few years has still to be evaluated, but it appears certain that many if not all of the actions of vitamin D3 are exerted by 1,25-dihydroxycholecalciferol.…”

Section: Historical Aspects (I) Early Observations Of the Aetiology Omentioning

confidence: 91%

Vitamin D

MacIntyre

Evans

Larkins

1977

Clinical Endocrinology

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Section: Historical Aspects (I) Early Observations Of the Aetiology Omentioning

confidence: 91%

Vitamin D

MacIntyre

Evans

Larkins

1977

Clinical Endocrinology

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“…Recently an analog of this active vitamin D derivative has been discovered: la-OH-D, (22). Preparation of this compound is less difficult and less expensive (6,18,22). The present investigation was undertaken in order to analyze the comparative biologic effects of 1.25-(OH),-D, and la-OH-D, in children with different types of D resistance, and to determine whether la-OH-D, could be a valuable substitute for 1,25-(OH),-D, in pediatric pharmacology.…”

Section: Speculationmentioning

confidence: 99%

1,25-Dihydroxyvitamin D3 and 1,α-Hydroxyvitamin D3 in Children: Biologic and Therapeutic Effects in Nutritional Rickets and Different Types of Vitamin D Resistance

et al. 1975

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ExtractDuring the past few years the metabolism of vitamin D has This investigation confirms the high level of biologic activity and the similarity of the effects of small doses of 1,25-dihydroxyvitamin D, (1,,-D,) and of its analog la-hydroxyvitamin D , (la-OH-D,) on children with nutritional rickets, "pseudodeficiency" rickets (PDR), hereditary hypophosphatemia, chronic idiopathic hypoparathyroidism, and chronic renal failure. It also shows that cystinotic patients may develop, at the end stage of the disease, a certain degree of resistance to 1,25-(OH),D,. The comparison of the therapeutic effects of long term oral administration of 1,25-(OH),-D, or la-OH-D, to two D-deficient children and two sibs with PDR demonstrates differences in sensitivity. In the patients with nutritional rickets, 0.5 pg/24 hr of either drug corrects the biochemical abnormalities, initiates healing of skeletal lesions in 28 days, and cures the metaphyseal lesions in 60 days of therapy. In contrast, it appears that doses of either drug that are curative in D deficiency rickets are only partly active in PDR. These observations indicate that the hypothesis of a deficit in 25-hydroxycholecalciferol la-hydroxylase in patients with PDR must await for confirmation more direct evidences, and that such a deficit, even if proven, may not account for all of the biochemical and skeletal alterations seen in patients with this inherited disorder. SpeculationThe similarity of action of 1,25-(OH),-D, and la-OH-D, observed in the present study presents additional evidence that la-OH-D, can be considered a valuable substitute for the hormonal form of cholecalciferol, especially for the management of children with chronic renal failure, hypoparathyroidism, or pseudodeficiency rickets. In this latter disease, the active therapeutic doses of either drug appear to be greater than the amount required for the treatment of simple nutritional rickets. This observation indicates that investigations on the pathogenesis of pseudodeficiency rickets must be continued in order to confirm or invalidate the hypothesis suggested by us and others that this inherited disorder might be related to a deficit in 25-hydroxycholecalciferol la-hydroxylase. Preliminary results obtained during this investigation established that children with P D R were sensitive to quite small doses of 1,25-(OH),-D,. These observations led us to suggest that this inherited disorder might be caused by a deficit in 25-hydroxycholecalciferol la-hydroxylase (4); a hypothesis also suggested by Fraser et al. (14), and more recently by Prader (29), Fanconi (l3), and Scriver et a/. (32). According to this hypothesis the biochemical and skeletal lesions in PDR, just as they are in simple D deficiency rickets, may be related to a deficit in 1,25-(OH),-D,. Hence, one would expect children with P D R and patients with D deficiency rickets to respond similarly to 1,25-(OH),-D, or la-OH-D, therapy. In an attempt to test the validity of this assumption our study was completed by a cornparisin of the therapeuti...

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“…The importance of. the lai-hydroxyl to biological activity is further emphasized by the observed high biological activity of the chemically synthesized analogs, 3-deoxy-la-OH-vitamin D3 (3-d-la-OH-D3) (20) and la-hydroxyvitamin D3 (la-OHD3) (21)(22)(23)(24)(25), and the pseudo-la-hydroxyl § analogs, 5,6-trans-vitamin D3 (5,6-t-D3) (26), dihydrotachysterol3 (H2T3) (27)(28)(29), and isotachysterol3 (i-T3) (30). (See Fig.…”

mentioning

confidence: 99%

Vitamin D: Concerning the Relationship Between Molecular Topology and Biological Function

Okamura

Norman

Wing

1974

Proc. Natl. Acad. Sci. U.S.A.

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Structure-function relationships for vitamin D1, its metabolites, and analogs are discussed with particular emphasis on the A-ring conformation. It is emphasized that the A-ring of these seco-steroids consists of a pair of rapidly equilibrating chair conformers. As a consequence, different chair conformations produce different orientations of substituent groups in the A-ring. It is propbsed that the la-hydroxyl of la,25-dihydroxyvitamin D3 or its geometric equivalent in analogs must occupy the equatorial, as opposed to the axial, orientation for optimization of biological activity. This proposal is discussed in relation to existing published data on struc- (0,10). The biochemical mode of action of la,25-(OH)2D3 (11) is believed to occur as a consequenee of association with cytoplasmic and nuclear receptors, as is the case for other classical steroid hormones (12, 13) such as estrogen (14), hydrocortisone (15), aldosterone (16), or Abbreviations: D3, vitamin D3; 25-OHD3, 25-hydroxyvitamin D3; 1a,25-(OH)2D3, la,25-dihydroxyvitamin D3; la-OHD3, lahydroxyvitamin D3; 5,6-t-D3, 5,6-trans-vitamin D3; H2T, dihydrotachysterol; i-T, isotachysterol; H2V-IV, dihydrovitamin D-IV; 3-d-la-OHD3, 3-deoxy-lc-hydroxyvitamin D3; 3-d-la,25-(OH)2D3, 3-deoxy-la,25-dihydroxyvitamin D3; 3a!-or 3,8-Me-3-d-la-OHD3, 3a-or 3,3-methyl-3-deoxy-1a-hydroxyvitamln D3; the subscript 3 or 2 after the letters D, T, and V refer to vitamin D-like molecules containing the cholesterol side-chain carbon skeleton as in vitamin D3 or the ergosterol side-chain carbon skeleton as in vitamin D2, respectively. The abbreviation H2T instead of DHT for dihydrotachysterol is used since the former is more in keeping with the rules of IUB and IUPAC.* Send all correspondence to the first author. A preliminary account of this work was presented at the 1974 meetings of the American Society of Biological Chemists in Minneapolis, Minn. (see ref. 20). This is paper V in the series, "Studies on Vitamin D and Its Analogs." Paper IV is Norman, A. W., Mitra, M. N., Okamura, W. H. & Wing, R. M., "Vitamin D: 3-Deoxy-lahydroxyvitamin D3, a biologically active analog of la,25-dihydroxyvitamin D3," Science, in press. testosterone (17). In fact, the fat-soluble vitamin D3 should be considered a steroid hormone both from a structural and a functional point of view (18).The unusual importance of the 1a-hydroxyl to the active metabolite was emphasized by the observation that neither the parent vitamin D3 nor the intermediate 25-hydroxyvitamin D3 (25-OHD3) weie able to produce any stimulation of intestinal calcium transport in nephrectomized rats, while 1a,25-(OH)2D3 was fully active (19). The importance of. the lai-hydroxyl to biological activity is further emphasized by the observed high biological activity of the chemically synthesized analogs, 3-deoxy-la-OH-vitamin D3 (3-d-la-OH-D3) (20) and la-hydroxyvitamin D3 (la-OHD3) (21-25), and the pseudo-la-hydroxyl § analogs, 5,6-trans-vitamin D3 (5,6-t-D3) (26), dihydrotachysterol3 (H2T3) (27-29), and isotachysterol3 (i-T3) (30)...

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Convenient synthesis of l.alpha.-hydroxy-vitamin D3

Cited by 147 publications

References 2 publications

Vitamin D

Vitamin D

1,25-Dihydroxyvitamin D3 and 1,α-Hydroxyvitamin D3 in Children: Biologic and Therapeutic Effects in Nutritional Rickets and Different Types of Vitamin D Resistance

Vitamin D: Concerning the Relationship Between Molecular Topology and Biological Function

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