Vitamin D derivative

The D vitamins are methylated frans-hydrindane derivatives with an isoprenoid side chain. A system of two conjugated double bonds and a hydroxylated cyclohexane ring are attached to the hydrindane moiety. The latter is substituted by a methylene group. Most important are vitamin Dg (cholecalciferol) and vitamin Dg (calciferol). 

Compounds of the vitamin D group are synthesized in animals, certain higher plants, mushrooms, and algae. 

The D vitamins originate from zJ -unsaturated sterols, e.g., 7-dehydrocholesterol or ergosterol (D 6.4.1), by opening of ring B. This nonenzymatic reaction is mediated by UV light(A 260-285 nm). In animals D vitamins are hydroxylated 

1 Nonenzymatic reactions 2 vitamin D 25-monooxygenase 3 25-hydroxycholecalciferol-1-monooxygenase 

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The concept of using diazaquinones for diene system protection was accomplished in the case of some vitamin D derivatives, as shown in Scheme 37 (86JOC4819). Acetyl vitamin D2152 was protected with phtha-lazinedione 83a, providing a mixture of both possible stereoisomeric adducts from which 153 was isolated. Then usual ozonolysis procedure afforded aldehyde 154, which after the Wittig coupling and hydrogenation provided 155. The most difficult part of the sequence proved to be the deprotection of this compound, but this transformation was accomplished... 

Calcitonin is a polypeptide hormone that (along with PTH and the vitamin D derivative, 1,25-dihydroxycholecalciferol) plays a central role in regulating serum ionized calcium (Ca2+) and inorganic phosphate (Pi) levels. The adult human body contains up to 2 kg of calcium, of which 98 per cent is present in the skeleton (i.e. bone). Up to 85 per cent of the 1 kg of phosphorus present in the body is also found in the skeleton (the so-called mineral fraction of bone is largely composed of Ca3(P04)2, which acts as a body reservoir for both calcium and phosphorus). Calcium concentrations in human serum approximate to 0.1 mg ml-1 and are regulated very tightly (serum phosphate levels are more variable). 

Calcitriol and tacalcitol are other vitamin D derivatives that have been studied for treatment of psoriasis. 

An efficient synthetic route to (10Z)- and (10 )-19-lluoro-la,25-dihydroxy vitamin D3 has been developed (488). The key feature of this pathway is the introduction of a 19-fluoromethylene group to a (5 )-19-nor-10-oxo-vitamin D derivative. The 10-oxo compound 445 has been obtained via a 1,3-dipolar cycloaddition reaction of (5 )-la,25-dihydroxyvitamin D with in situ generated nitrile oxide, followed by ring cleavage of the formed isoxazoline moiety with molybdenum hexacarbonyl. Conversion of the keto group of (5 )-19-nor-10-oxo-vitamin D to the E and Z fluoromethylene group has been achieved via a two-step sequence, involving a reaction of lithiofluoromethyl phenyl sulfone, followed by the reductive de-sulfonylation of the u-lluoro-j3-hydroxysulfone. The dye-sensitized photoisomerization of the (5 )-19-fluorovitamin D affords the desired (5Z)-19-fluorovitamin D derivatives, (10Z)- and (10 )-19-fluoro-la,25-dihydroxy-vitamin D3. 

Halket and Lisboa (25) examined several Vitamin D derivatives by capillary gas chromatography coupled with mass spectrometry. This technique offered the advantages of great sensitivity and separating power. Retention times and fragmentation patterns for ergocalciferol, cholecalciferol and calcitriol were reported. 

Calcipotriol is a vitamin D derivative used topically for psoriasis. It does not cause skin discoloration and does not stain clothes. 

Calcipotriol, a vitamin D derivative without vitamin D activity is used to treat psoriasis. 

Studies of the effects of oral contraceptives on serum concentrations of vitamin D derivatives have given variable results. 

The time of year and the point during the menstrual cycle during which vitamin D derivatives are measured may be important. In seven women there was a two-fold rise in the serum concentration of 1,25-dihydroxycolecalci-ferol on day 15 of the menstrual cycle compared with days 1 and 8, without a detectable change in the serum calcium concentration (187). This increase did not occur in five women taking oral contraceptives, and there was a small but significant fall in the serum calcium concentration. 

Vitamin D. Vitamin D is a steroidlike hormone that can be obtained from dietary sources or synthesized in the skin from cholesterol derivatives in the presence of ultraviolet light. Vitamin D produces several metabolites that are important in bone mineral homeostasis.27,31 In general, vitamin D derivatives such as 1,25 dihydroxyvitamin D3 increase serum calcium and phosphate levels by increasing intestinal calcium and phosphate absorption and by decreasing renal calcium and phosphate excretion.27,46... 

Systematic nomenclature of vitamin D derivatives utilizes the obvious relationship to steroids, and the term seco (ring opened) is incorporated into the root name (compare secologanin as a... 

Two vitamin D derivatives, calcipotriol and tacalcitol (Figure 5.107) are widely used in the topical treatment of psoriasis, to inhibit the cell proliferation characteristic of this condition. 

Determine the configuration of the chirality centres and double bonds in the vitamin D derivative maxacalcitol, and indicate whether the structural formula represents the s-cis or the s-trans isomer. 

Two types of human hormone are steroidal—the sex hormones such as oestradiol and testosterone and the adrenal hormones such as cortisone. Cholesterol is a steroid too, as is vitamin D, derived from ergosterol. 

There are many endogenous substrates, of widely different chemical structure, that are metabolized through oxidative, peroxidative, and reductive changes introduced by P450 enzymes. These include saturated and unsaturated fatty acids, eicosanoids, sterols and steroids, bile acids, vitamin D derivatives, retinoids, and uroporphyrinogens (Tables 9.4 and 9.5). 

Many syntheses have been reported for variously hydroxylated cholestanes, the objective in many cases being the eventual conversion of these steroids into their hydroxylated vitamin D derivatives. 1 a -Hydroxycholest- 5 -ene has been synthesized by way of the epoxy-dienone (261), itself derived from cholesterol by successive... 

Mega Cal calcium with vitamin D, 1 tablet supplied 500 mg calcium and 100 mg vitamin D, derived from egg shells, oyster shells, calcium lactate, calcium gluconate, calcium carbonate, non-fat dried milk, malted milk and dairy sweet whey. Holistic Products Corp. East Rutherford, NJ 07073. 

The discovery that vitamin D3 (1), also called calciol [I], is actually a pro-hormone and not a vitamin as previously assumed has induced intense worldwide research activities within the last 20 years. Nowadays, it is known that the prohormone is transformed in liver and kidney into physiologically much more active metabolites by hydroxylation. In particular, the la,25-dihy-droxylated derivative, calcitriol (3), performs a key function in the regulation of different physiological events [2]. Some hydroxylated vitamin D derivatives and structural analogs are currently being clinically tested as drugs for the treatment of a range of human diseases such as cancer, psoriasis or immune defects. 

Since the completion of the first total synthesis of calciol (1) by H. H. Inhoffen, H. Burkhardt and G. Quinkert in 1959 [3], several research groups have focussed their activities on the synthesis of vitamin D derivatives [4]. In the course of these investigations, two particularly powerful strategies have been identified, which still today [5J form the basis of many syntheses of la-hydro-xylated vitamin D derivatives (Schemel). 

An auxiliary-directed asymmetric Simmons-Smith reaction was used by a Hoff-mann-La Roche group88 for the synthesis of an ethynyl cyclopropane that served as the A-ring precursor to Vitamin D derivatives [Scheme 2.41]. High diastereoselectivity was achieved with the aid of the dioxolane ring prepared from (/ft/f)-(-)-butane-2,3-diol. The acid conditions for hydrolysis of the dioxolane ring were mild enough to leave the cyclopropane ring unperturbed. Dia-stereoselective cyclopropanation of acetals derived from 1,2-di-O-benzyl-L-threi-tol have also been reported 90... 

A synthesis of the Inhoffen-Lythgoe diol (46.7, Scheme 2.46), a useful intermediate in the synthesis of Vitamin D derivatives, demonstrates the use of a chiral acetal in an asymmetric tandem cyclisation reaction.102 Once again, Lewis acid co-ordination to the less hindered oxygen of the acetal 46.1 initiated a Prins-like cyclisation that terminated by attack of the propargylsilane on an incipient tertiary carbocation. After removal of the chiral auxiliary, the allene function in the alcohol 46.4 was transformed into the side chain of 46.7 with the creation of two new stereogenic centres. 

The hypocalcaemia of hypoparathyroidism may require ergocalciferol in doses up to 2.5 mg (100 000 units) daily to achieve normocalcaemia but the dose is difficult to titrate and hypercalcaemia from overdose may take weeks to resolve. The synthetic vitamin D derivatives, alfacalcidol and... 

Bones are constantly dissolved by osteoclasts and remineralized by osteoblasts in response to mechanical forces. Osteoclasts possess an acidic compartment and pass demineralized bone products to the periosteum (Sect. 1). They develop in stress-induced bony microcracks and are activated by differentiation factors secreted by osteoblasts, especially after menopause. Menopausal osteoporosis is controlled by drugs that are a stable form of pyrophosphate (bisphosphonate) or cathepsin K inhibitors (Sect. 2). The calcium ion concentration of blood is raised by parathyroid hormone and a vitamin D derivative called calcitriol. Parathyroid hormone causes kidneys to excrete phosphate, retain calcium, and activate calcitriol production (Sect. 3). Calcitriol induces calcium transporter proteins in osteoclasts and intestinal epithelium, where they move calcium from bone or diet into blood (Sect. 4). The chapter concludes with a discussion of calcitonin which lowers blood calcium concentrations by reversing parathyroid hormone effects on the kidney and inhibiting osteoclast activity (Sect. 5). 

Vitamin D is a fat soluble vitamin derived from cholesterol. In the human epidermis (skin), sunlight spontaneously oxidizes cholesterol to 7-dehydrocholesterol (Fig. 10.10a). The 7-dehydrocholesterol leaks into the blood where it isomerizes to cholecalciferol (vitamin D3, Fig. 10.10b and c). Cholecalciferol is enzymatically hydroxylated at C25 in the liver (25-cholecalciferol) and then passes to the kidney where another enzyme is activated by parathyroid hormone to hydroxylate it at Cl, forming calcitriol (Fig. lO.lOd). The kidney hydroxylase is sensitive to feedback inhibition. As the amount of calcitriol increases, it binds to the hydroxylase and alters the specificity of the kidney enzyme. Additional 25-cholecal-ciferol is hydroxylated to 24,25-dihydroxycholecalciferol (inactive calcitriol) instead of 1,25 dihydroxycholecalciferol (calcitriol). Other vitamin D derivatives that can be converted to calcitriol are obtained enzymatically from cholesterol in other vertebrates. The most common of these are vitamin D3 (lamisterol) and D2 (ergosterol) from cold-water fish such as cod, where their presence keeps membranes fluid at low body temperatures 10-20°C. 

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