Synthesis of 24,24-difluoro- and 24ξ-fluoro-25-hydroxyvitamin D3

Kobayashi, Yoshiro; Taguchi, Takeo; Terada, T.; Oshida, Jun-ichi; Morisaki, Masuo; Ikekawa, Nobuo

doi:10.1016/s0040-4039(01)86253-5

Cited by 41 publications

(22 citation statements)

References 13 publications

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“…We next investigated the effect of cysteamine on dispersed anterior pituitary cells in culture (11). Pituitaries were harvested from male CD rats (Charles River) weighing 225 to 250 g; all tests were done on day 4 or 5 in culture.…”

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confidence: 99%

Cysteamine: a Potent and Specific Depletor of Pituitary Prolactin

Sagar

Landis

et al. 1982

Science

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confidence: 99%

Cysteamine: a Potent and Specific Depletor of Pituitary Prolactin

Sagar

Landis

et al. 1982

Science

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“…Treatment of the secondary hydroxyl group with DAST afforded fluorine-substituted vitamin Ds, however, in this case, the configuration at position C1 remained uncertain. The potency of 25-fluoro-1 -hydroxyvitamin D 3 (20) was estimated to be as active as 1 -hydroxyvitamin D 3 [28]. On the other hand, doubly substituted analogue 21 showed virtually no vitamin D activity [29].…”

Section: Vitamin D Analogues Having Fluorine Instead Of Hydroxyl Groupsmentioning

confidence: 99%

“…(3) depicts those analogues designed to slow or resist side-chain hydroxylation by CYP24A1, which is regarded as the key enzyme for breaking down the hormone 1. Synthesis of 7, based upon a classical steroidal approach starting from lithocholic acid (11), is outlined in Scheme 1 [18][19][20]. Side-chain fluorine atoms were introduced at an early stage by reaction of 12 with (diethylamido)sulfur trifluoride (DAST) in 75% yield.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Activity of Fluorinated Vitamin D

Fujishima¹,

Fujii²,

Harayama

2010

COC

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The active metabolite of vitamin D, 1 ,25-dihydroxyvitamin D3 (1), has a wide range of biological activities, making its analogues promising therapeutic agents for the treatment of cancer, psoriasis and osteoporosis. In particular, the stability of the carbonfluorine bond to oxidation has aided in the development of fluorinated vitamin D analogues as catabolism inhibitors. The analogues were synthesized either by classical steroidal approaches or by convergent methods, depending on the sites of fluorination. The incorporation of fluorine has provided numerous advantages for studying the structurally flexible hormone 1 ,25-dihydroxyvitamin D3 1, including helping to define its molecular mode of actions. Biological evaluation of the fluorinated analogues suggested that fluorine substitution would not only change the metabolism, but also have direct effects on the vitamin D receptor, resulting in compounds with unique activity profiles.

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“…Vitamin D3, or cholecalciferol, is metabolically activated by a series of hydroxylations prior to exerting its biological activity. Vitamin D a is first hydroxylated at the 25 position in the liver to form 25-hydroxyvitamin D3 (25-OH-D3) and then further hydroxylated in the kidney to form 1,25-dihydroxyvitamin D z (1,25-(OH)2D3) or 24,25-dihydroxyvitamin D3 (24,25-(OH)2D3) [1,2]. 24-Hydroxylation also takes place elsewhere [1,2].…”

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“…Investigations into the biological importance of 24-hydroxylation of the vitamin D molecule led to the recent synthesis of a 25-OH-D3 analog which is blocked in the 24 position by 2 fluorine atoms [24,25]. The resultant molecule, 24,24-difluoro-25-hydroxyvitamin D3 (24,24-difluoro-25-OH-D3) is similar to 25-OH-D3 except that it cannot be hydroxylated in the 24 position due to the stable carbon-fluorine bonds.…”

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Studies on the role of 24-hydroxylation of vitamin D in the mineralization of cartilage and bone of vitamin D-deficient rats

et al. 1981

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Summary. To test the importance of 24-hydroxylation of vitamin D 3 on bone mineralization, rat pups born to vitamin D-deficient females were given either 25-hydroxyvitamin D3 or 24,24-difluoro-25-hydroxyvitamin Da for 16 days beginning at the time of weaning. Following such treatment analysis of blood samples revealed no detectable 24R,25-(OH)2Dz and 1,25-(OH)2Dz in the rats given the difluoro compound while revealing the expected 24,24-difluoro-25-hydroxyvitamin D3 and 24,24-difluoro-l,25-dihydroxyvitamin Da. The rats given 25-hydroxyvitamin D3 had the expected levels of 25-hydroxyvitamin D3, 24,25-dihydroxyvitamin D3, and 1,25-dihydroxyvitamin D 3. Following sacrifice at day 17, postweaning bone mineralization and modeling were studied in long bones using histological methods. Bones taken from vitamin Ddeficient rats at the beginning and end of the experimental period had lesions typical of rickets. These included wide growth plates, excessive amounts of osteoid, and metaphyseal fibrosis. Following treatment with either 25-hydroxyvitamin D3 or 24,24-difluoro-25-hydroxyvitamin D3, bone mineralization returned to normal. Growth plate widths and the amount of osteoid on bone surfaces were both substantially reduced and to a similar degree in both treatment groups. Normal cartilage core formation and trabecularization of the metaphyseal primary spongiosa were also restored to a similar degree in both groups. In effect, no difference was observed in any bone parameter studied between the 25-hydroxyvitamin D3-and the 24,24-difluoro-25-hydroxyvitamin Dz-treated animals. These results provide strong evidence that 24-hydroxylation of the vitamin D molecule plays little or no role in the modeling and mineralization of bone.Send offprint requests to H. F. DeLuca at the above address.Key words: Vitamin D-Vitamin D deficiencyCartilage --Bone.The importance of the vitamin D endocrine system in the maintenance of serum calcium and phosphorus levels and the promotion of bone mineralization is well established [1-3]. Vitamin D3, or cholecalciferol, is metabolically activated by a series of hydroxylations prior to exerting its biological activity. Vitamin D a is first hydroxylated at the 25 position in the liver to form 25-hydroxyvitamin D3 (25-OH-D3) and then further hydroxylated in the kidney to form 1,25-dihydroxyvitamin D z (1,25-(OH)2D3) or 24,25-dihydroxyvitamin D3 (24,25-(OH)2D3) [1,2]. 24-Hydroxylation also takes place elsewhere [1,2]. The formation of 24,25-(OH)2D3 is related in a reciprocal fashion to the formation of 1,25-(OH)2Dz in the kidney [4]. It has been demonstrated that the synthesis of 1,25-(OH)2Dz from 25-OH-Dz decreases with increasing serum calcium levels while the synthesis of 24,25-(OH)2Dz increases [5]. Thus the circulating levels of these metabolites are influenced indirectly by plasma calcium concentrations via the parathyroid hormone [6][7][8]. Although 25-OH-D z and 24,25-(OH)2Dz are, under normal circumstances, the dominant metabolites found in the serum [9], it is well established that 1,25-(OH)2D...

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Synthesis of 24,24-difluoro- and 24ξ-fluoro-25-hydroxyvitamin D3

Cited by 41 publications

References 13 publications

Cysteamine: a Potent and Specific Depletor of Pituitary Prolactin

Cysteamine: a Potent and Specific Depletor of Pituitary Prolactin

Synthesis and Biological Activity of Fluorinated Vitamin D

Studies on the role of 24-hydroxylation of vitamin D in the mineralization of cartilage and bone of vitamin D-deficient rats

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