Thesis (Ph. D.)--Louisiana State University, Baton Rouge, 2008. / Title from document title page.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1956. / Typescript. Vita. Includes (as Chapter II): Effect of pregnancy and lactation on granuloma tissue formation and joint permeability in rats / Roland K. Meyer, Jacob C. Stucki, and K.A. Aulsebrook, reprinted from Proceedings of the society for experimental biology and medicine, v. 84 (1953), p. 624-628. Includes bibliographical references.

The 16α-alkylation was achieved via treatment of 3-methoxyestra-1,3,5(10)-trien-17-one-N,N-dimethylhydrazone (118) with n-butyllithium and the appropriate haloalkane to afford exclusive 16α-substitution (119). Subsequent, cupric ion-catalysed hydrolysis, 17-ketone reduction and removal of the 3-hydroxyl protecting group, furnished 16α-methylestra-1,3,5(10)-trien-3,17β-diol (122a) and 16α-ethylestra-1,3,5(10)-trien-3,17β-diol (122b). An alternative sequence to the 16α-ligands, by direct alkylation of the 17-keto-estrone enolate, was also investigated. In this manner 16α-allylestra-1,3,5(10)-trien-3,17β-diol (122c) and 16α-benzylestra-1,3,5,(10)-trien-3,17β-diol (122d) were obtained.

Alteration of serum tryptophan leads to parallel alterations in brain tryptophan levels. Such changes in brain tryptophan levels has been shown to lead to mood disturbances. The primary enzyme responsible for altering serum tryptophan levels is the liver cytosolic enzyme, tryptophan pyrrolase. Activation of this enzyme is responsible for the enhanced catabolism of circulating tryptophan. The purpose of the present study was firstly to establish whether there is a link between sex steroids and tryptophan pyrrolase activity especially since sex steroids are also known to cause mood disturbances and secondly to determine the effects of sex steroids on brain indolamine metabolism. The results show that all three sex steroids induce the activity of tryptophan pyrrolase implying that they decrease serum tryptophan levels by the activation of tryptophan pyrrolase, thus making less tryptophan available for uptake by the brain. It was also shown that the sex steroids enhance the uptake of ¹⁴C-tryptophan by brain synatopsomes. In addition, the sex steroids influenced the pattern of metabolism of serotonin by organ cultures of rat pineal glands. It is possible that the sex steroids regulate the availability and uptake of indoleamines in the brain.

The ozonization of 7-ketocholesteryl acetate has yielded 5-keto-5, 7-seco-6-nor-3-cholesten-7-oic acid, an intermediate useful in the preparation of 6-azacholestane. Catalytic hydrogenation converted this intermediate to 5-keto-5,7-seco-6-norcholestan-7-oic acid which, upon treatment with benzyl amine, gave N-benzyl-6-aza-4-cholesten-7-one. Catalytic reduction of this enol-lactam yielded N-benzyl-6-azacholestan-7-one which was reduced with lithium aluminum hydride to N-benzyl-6-azacholestane. The generality of this route was shown when it was applied to compounds of the androstane series. Ozonization of 3β,17β-dihydroxy-5-androsten-7-one diacetate gave 17β-hydroxy-5-keto-5,7-seco-6-nor-3-androsten-7-oic acid which was hydrogenated catalytically to 17β-hydroxy-5-keto-5,7-seco-6-norandrostan-7-oic acid. This saturated acid ring—closed with benzyl amine to yield 17β-hydroxy-N-benzyl-6-aza-4-androsten-7-one. Catalytic hydrogenation of this enol-lactam gave 17β-hydroxy~N-benzyl-6-azandrostan-7-one which was reduced with lithium aluminum hydride to N-benzyl-6-azaandrostan-17β-ol. A mild chromic acid oxidation converted the alcohol to the keto compound, N-benzyl-6-azaandrostan-17-one. / Science, Faculty of / Chemistry, Department of / Graduate

In Part I, the C.D. spectra of a number of 3-keto and 20-keto steroids are reported. The 3-keto steroids were comprised of two series of compounds. For one series, the conformationally transmitted effects of olefinic centers located in, or exocyclic to, rings B and C were investigated. It was found that these effects were reflected in the C.D. spectra when the double bond was located in ring B, but not when the double bond was located in ring C. Further, no correlation could be made between the relative rates of alkali-catalyzed benzaldehyde condensation and the C.D. data. For the other series, the conformations of ring A in a number of steroids substituted at the 2- and 4- positions are discussed. The C.D. results are in agreement with other evidence on this subject, and suggest that a 1,3-diaxial methyl interaction leads to flattening of ring A. For the Δ⁵- 4,4-dimethyl-3-keto steroids, a non-chair conformation is indicated, but a distinction between a boat and a flat chair conformation cannot be made . For 2 α -bromo-4,4-dimethylcholest-5-en-3-one, a conformational equilibrium is suggested. The 20-keto steroids were comprised of a large number of 16-substituted pregnanone and 17 α -pregna-none derivatives. The C.D. spectra of the 16,17 trans compounds and the 16α , 17α -cis-compounds were similar to those of the 16-unsubstituted parent compounds. Modifications in rings A and B had little effect upon the dichroism of the 20-keto group. The C.D. spectra of the 16β, 17β-compounds were very sensitive to the nature of the 16β -substituent, These results are interpreted in terms of the preferred conformation of the 17β -acetyl group. Finally, the C.D. spectra of a number of 16, 17-epoxy-20-keto steroids are reported and discussed with reference to the "reversed octant rule". In Part II, the structural determination of the mould metabolite, hirsutic acid C, is reported. The functional groups were established from chemical information; however the X-ray analysis of the p-bromo-phenacyl ester was required to reveal the novel ring system. During the X-ray irradiation an unusual solid-phase rearrangement occurred, transforming the α-epoxy hydroxyl system of p-bromophenacyl hirsutate to a β -hydroxy ketone system without disrupting the crystal structure. The X-ray analysis revealed a 50:50 mixture of starting material and rearrangement product. A combination of the X-ray and the chemical data was required to complete the structural determinations of both products. The generality of the rearrangement process was investigated. It occurred with methyl hirsutate and dihydromethylhirsutate, but not with hirsutic acid. It could not be induced thermally. It did not occur with the steroids 3 α - and 3 β -hydroxy-4 β, 5-epoxy-5β-cholestane. The rearrangement process is probably controlled by the nature of the molecular packing and hydrogen-bond formation. In Part III, the biogenetic-type syntheses of a number of acetate-derived aromatic compounds are reported. A discussion of the preparation of the condensed polypyrone intermediates is given, and in particular the synthesis of the tetrapyrone, 4-hydroxy-9-methyl-2,5,7,12-tetraketo 1,6,8,11-tetra-oxachrysene from the condensation of bis (2,4-dichlorophenyl) malonate and the tripyrone, 7-methyl-1-hydroxy-3,5,10-triketo 4,6,9-trioxaphenanthrene is reported. Treatment of the tripyrone with methanolic potassium hydroxide solution resulted in ring opening to form a poly- β-keto chain, and subsequent aldol-type condensation to give aromatic compounds representative of the naturally-occurring 6,8 dihydroxy-isocoumarins and C-acetylorsellinic acid. Treatment with methanolic magnesium methoxide solution gave aromatic compounds derivable from different cyclization modes of the poly- β-keto chain. Among the compounds isolated were two representative of the naturally-occurring curvulinic acid and the 5,7-dihydroxychromones respectively. Structural assignments were made largely on the basis of the characteristic spectral properties of the compounds. / Science, Faculty of / Chemistry, Department of / Graduate

This thesis reports the results of studies on steroid metabolism in a subject with an adrenocortical carcinoma and hypoglycemia, in the testes obtained from a subject with virilizing male pseudohermaphroditism and in the testes of the normal rat. Incubations of cell-free homogenates of an adrenocortical carcinoma from a 51 year old female with severe hypoglycemia were performed using ³H-pregnenolone and ¹⁴C-progesterone as substrates. Transformation of ³H-pregnenolone to progesterone, dehydroepiandrosterone and androstenedione was observed; no metabolites of ¹⁴C-progesterone were detected. The excretion rate in urine of 3α ,17,21-trihydroxy-5β -pregnan-20-one, a metabolite of cortexolone, was elevated which suggests that a defect in 11β -hydroxylase activity was present. The excretion rates in urine of total 17-ketosteroids, 17-hydroxycorticoids and 17-ketogenic steroids were elevated; the excretion rates of testosterone, dehydroepiandrosterone, pregnandiol, pregnanetriol and free cortisol were not elevated. The etiology of the hypoglycemia that may accompany some adrenocortical tumors remains unknown. It was not possible to relate the results of the investigations of steroid metabolism reported herein to the hypoglycemia that was present. Steroid biosynthesis in vitro was investigated in testes obtained during puberty from a 14 year old subject with virilizing male pseudohermaphroditism. Cell-free homogenates of gonadal tissue efficiently metabolized ³H-pregnenolone, ¹⁴C-progesterone and ¹⁴C-androstenedione to testosterone; formation of estrone and estradiol-17β was not detected. 16α-Htdroxyprogesterone was formed from both ³H-pregnenolone and ¹⁴C-progesterone. The results are similar to those of others who have investigated the steroidogenic capacity of gonadal tissue in patients with male pseudohermaphroditism and feminization at puberty. A defect in the formation of progesterone from pregnenolone has been suggested to explain the results of a previous study in which the gonadal tissue obtained from a patient with virilizing male pseudohermaphroditism was incubated with ³H-pregnenolone as substrate. In the investigations reported herein, transformations of ³H-pregnenolone to testosterone and androstenedione occurred both via 17-hydroxypregnenolone and dehydroepiandrosterone and via progesterone and 17-hydroxyprogesterone. The failure of patients with virilizing male pseudohermaphroditism to masculinize during embryonic development contrasts with the virilization that occurs during puberty. A biochemical abnormality may exert a transient effect during embryonic development. Alternatively, the sensitivity to androgenic hormones may be subnormal in certain tissues and normal in other tissues of patients with virilizing male pseudohermaphroditism. The biosynthesis of testosterone from progesterone and pregnenolone was investigated in the rat testis. Time studies were performed using cell-free homogenates and ³H-progesterone and ¹⁴C-17-hydroxyprogesterone in combination as substrates. It was demonstrated that the side-chain cleavage of 17-hydroxyprogesterone is the rate-limiting reaction in the biosynthesis of testosterone from progesterone and the evidence suggested that 17-hydroxyprogesterone was present as a bound intermediate (at least in part). The progesterone 17-hydroxylase and the 17-hydroxyprogesterone side- chain cleavage enzyme of the rat testis can be solubilized by treatment of lyophilized microsomes with Triton N-101. Both enzymes displayed maximal activity at pH 6.8 and at 37°. Progesterone rather than pregnenolone is the preferred substrate for the 17α-hydroxylase. Either NADH or NADPH can serve as the reductant for active 17-hydroxylation of progesterone and for side-chain cleavage of 17-hydroxyprogesterone. The soluble fraction contains NADPH dehydrogenase, non-heme iron protein and cytochrome P-450. The presence of these compounds in association with the 17α-hydroxylase and the side-chain cleavage enzyme activities suggests that these reactions are catalyzed by elaborate enzymatic systems analogous to those required for 11β-hydroxylation and cholesterol side-chain cleavage in adrenal mitochondria / Medicine, Faculty of / Biochemistry and Molecular Biology, Department of / Graduate

The cortex of vertebrate adrenal glands secretes two major groups of hormones--glucocorticoids and mineralocorticoids. Glucocorticoids, which have an oxygen atom at carbon number 11, increase the rate of gluconeogenesis and increase the mobilization of lipids in mammals (Turner and Bagnara 1971). At the same time there is a decrease in protein synthesis. This latter effect may be homologous to a decrease in fibroblast growth in culture in the presence of certain corticosteroids (Ruhmann and Berliner 1965). The main function of mineralocorticoids, on the other hand, is to retain sodium ions. They have little or no gluconeogenic activity. Interestingly, however, these hormones also have been found to depress growth of mouse fibroblasts (Berliner and Ruhmann 1966). Although glucocorticoids and mineralocorticoids function through the mediation of DNA-dependent synthesis of RNA (Pan, Chin and Pai 1971) and several enzyme systems have been implicated in bringing about these responses (Talanti and Hopsu 1961, Fallon and Byrne 1967, and Turner and Bagnara 1971), the precise mechanism of action is still not well understood.

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