Robert H. Hesse

Regulation of bone resorption and formation: Influences of thyrocalcitonin, parathyroid hormone, neutral phosphate and vitamin D3

Abstract The destruction of bone collagen and dissolution of bone mineral induced by parathyroid hormone administration is accompanied by a concomitant renal action of the hormone, causing decreased tubular reabsorption of phosphorus and increased reabsorption of calcium and magnesium. The hormone also acts on soft tissue cells, resulting in a shift of phosphorus, potassium and magnesium from cells. Thyrocalcitonin inhibits bone resorption and the action of parathyroid hormone on bone resorption and may also stimulate osteoblastic activity. The effect of thyrocalcitonin on phosphorus excretion is influenced by the ratio of calcium to magnesium cations perfusing the kidney. Minimal amounts of parathyroid hormone are required for the action of vitamin D 3 upon bone, and bone resorption induced by the vitamin is suppressed by thyrocalcitonin. Since the hormone is required for the action of the vitamin on bone, cases of hypoparathyroidism resistant to vitamin D may respond to treatment with the combination of vitamin plus hormone. Although thyrocalcitonin protects against hypercalcemia the physiologic significance of this is unknown. Another important function of the hormone may be in the regulation of bone remodeling. Administration of neutral phosphate stimulates bone formation and bone mineralization. A combination of neutral phosphate with thyrocalcitonin may prove to be useful in the treatment of osteoporosis.

Response of Adult Patients with Osteomalacia to Treatment with Crystalline 1α-Hydroxy Vitamin D3

Abstract Preparation of synthetic sterols with hydroxyl groups in key positions on the sterol molecule opens the possibility of developing new antirachitic sterols to treat metabolic bone disease i...

Metabolic and clinical effects of pure crystalline 1α-hydroxyvitamin D3 and 1α,25-dihydroxyvitamin D3: Studies of intestinal calcium transport, renal tubular function and bone metabolism

Abstract In thyroparathyroidectomized rats, crystalline 1α-hydroxyvitamin d 3 (1α-(OH)D 3 ) was more potent in increasing serum calcium concentration and urinary calcium and hydroxyproline excretion than 1α,25-dihydroxyvitamin D 3 (1α,25-(OH) 2 D 3 ); the effects of 1α-(OH)D 3 appeared and disappeared earlier than those of 1α,25-(OH) 2 D 3 . Concomitant administration of calcium with either analog augmented the decrease in urinary phosphorus. Both analogs were antagonistic to the phosphaturic action of parathyroid hormone (PTH). A direct action of the analogs on renal tubular reabsorption of phosphorus, that is mediated by tubular calcium ion concentration, has been demonstrated. Vitamin D 3 induced a rapid response. In the anephric rat, vitamin D 3 was effective in increasing serum calcium, as were the analogs; however, vitamin D 3 and its analogs were ineffective in reestablishing a normal serum calcium level. These results are at variance with the prevailing concept that prior transformation of vitamin D 3 into an active metabolite is necessary for expression of its biologic activity. Crystalline 1α-(OH)D 3 induced a therapeutic response in patients with osteomalacia as demonstrated by metabolic balance studies; bone biopsy studies before and after therapy demonstrated mineralization of osteoid tissue and an increase in both bone resorption and bone formation. In man, 1α-(OH)D 3 is active orally as well as parenterally. The rapid onset and cessation of activity contrast markedly with the response to vitamin D 3 and suggest that therapy with 1α-(OH)D 3 may be associated with less toxicity.

Electrophilic fluorination of some steroidal α,β-unsaturated ketones

3β-Acetoxy-5α,6β-dichloropregn-16-en-20-one (1), on treatment with elemental fluorine at low temperature, gave the 16α,17α-difluoro-adduct (2) and, by rearrangement, the 13α,16α-difluoro-17β-methyl derivative (3). The adduct (2) was subsequently converted via a short, efficient synthetic sequence into 16α,17α-difluoroprogesterone (5). In contrast, fluorination of 21-acetoxypregna-1,4,16-triene-3,11,20-trione (6) afforded the corresponding 16α,17α-difluoro-adduct (8) in low yield. Similarly, androsta-1,4,6-triene-3,17-dione (9) was converted into the 6α,7α-difluoro-adduct (11). Fluorination with CF3OF led to an increased yield of the adduct (11) and also afforded the 6α-trifluoromethoxy-7α-fluoro-adduct (12). Dehydrofluorination of the latter gave 6-trifluoromethoxyandrosta-1,4,6-triene-3,17-dione (13). 21-Acetoxy-11β,17α-dihydroxypregna-1,4,6-triene-3,20-dione (5) was prepared by stepwise dehydrogenation of cortisol acetate (14). Subsequent low temperature treatment with CF3OF resulted in two major products, formulated as the adducts (17) and (18).

Convenient synthesis of crystalline 1α,25-dihydroxyvitamin D3

Crystalline 1α,25-dihydroxyvitamin D3 has been prepared from 25-hydroxycholesterol through an efficient eight-step synthesis.

Preparation and reactions of α,β-unsaturated and cross-conjugated diene thiones

Δ1,4-Diene-3-thiones were prepared from corticosterone-1,4-dien-3-ones and phosphorus pentasulphide. Reaction-with diphenyldiazomethane or 2-nitrobenzenesulphenyl chloride gave respectively the derived 3-diphenylmethylene-Δ1,5-dienes and 3-(2-nitrobenzenesulphenylthio)-Δ1,3,5-trienes. The less stable steroid Δ4-ene-3-thiones were trapped with 2-nitrobenzenesulphenyl chloride as 3-(2-nitrobenzenesulphenylthio)-Δ3,5-dienes. Subsequent thiol exchange gave 3-ethane- and 3-benzene-sulphenylthio-Δ3,5-dienes. Warfarin and cyclocumarol were thionated with P4S10 giving mono- and dithio-derivatives. Griseofulvin gave a stable enethione and thence with diphenyldiazomethane the diphenylmethylene derivative.

The mechanism of the barton reaction

Photolysis of 6β-nitroso-oxy-5α-cholestan-3β-yl acetate gave the 19-oxime, 6β,19-oxide, 6-oxo-5α-cholestan-3β-yl apetate, and 6β-hydroxy-5α-cholestan-3β-yl acetate. The 6β.19-oxide was formed from the C-19 nitrosodimer by a novel photochemical reaction involving nitric oxide and with subsequent displacement of the presumed 19-diazonium salt by the 6β-hydroxy-function. The formation of ketone was coupled with the appearance of hyponitrous acid. The alcohol was formed by intermolecular hydrogen atom abstraction by the intermediate C-19 alkyl radical in a reaction not related to ketone formation. Evidence for the intermediacy of peroxynitrites in the formation of nitrate esters by nitrite photolysis under oxygen is presented. Hydroperoxides and nitrosyl chloride gave the derived nitrates. Attention is drawn to the formation of androst-4-ene-3,17-dione (59%) from reaction of trifluoroacetic anhydride and 17α-hydroperoxyprogesterone.

Improved syntheses of aldosterone

A convenient synthesis of 1,2-didehydroaldosterone acetate, from 11β-hydroxypregna-1,4-dien-3-one, is described. Photolysis of the 11-nitrite of the latter compound gives only the desired attack at C-18. The resulting 18-oxime is cyclised to the nitrone, and the oxidation level of the latter is conveniently used for the introduction of a 21-acetoxy-group. Similar experiments with 11β-hydroxypregna-1,4,6-trien-3-one afford 1,2,6,7-tetradehydroaldosterone acetate. Selective hydrogenation of 1,2-didehydro- or of 1,2,6,7-tetradehydroaldosterone acetate gives aldosterone acetate in unlabelled or labelled (tritium) form.An interesting cleavage of steroid 18,20-nitrones with chromic acid (Jones reagent) has been discovered and shown to regenerate the masked aldehyde function of aldosterone-type compounds.A systematic study of the photolysis of 11β-nitrites has defined the best solvent and other conditions for this reaction.

Organic reactions of fluoroxy compounds–fluorination of imines

Schiffs bases react smoothly with CF3OF to afford, in alcoholic media, NN-difluoroamines; the reaction provides a convenient conversion of amines into NN-difluoroamines under mild conditions.

The biological activities of pure crystalline 1α-hydroxy vitamin D3 and 1α,25-dihydroxy vitamin D3

The biological activities of crystalline 1α-hydroxy Vitamin D3 (melting point 132–133 °C) and crystalline la,25-dihydroxy Vitamin D3 (melting point of monochloroform solvate 106–112 °C) have been compared in thyroparathyroid-ectomized rats. Both crystalline analogs are much more effective in bone calcium mobilization than the parent Vitamin D3. The onset of biological activities is more rapid for both analogs than for the parent Vitamin D3, however, the 1α-hydroxy Vitamin D3 induces a more rapid effect than the 1α,25-dihydroxy Vitamin D3 and the termination of the biologic effects with the 1α-analog occurs at an earlier time than that with the 1α,25-analog.