Serum concentrations of 3, 3'-diiodothyronine, 3', 5'-diiodothyronine, and 3, 5-diiodothyronine in altered thyroid states

To investigate the thyroid hormone metabolism in altered states of thyroid function, serum concentrations of 3, 3'-diiodothyronine (3, 3'-T2), 3', 5'-T2 and 3, 5-T2 as well as T4, T3 and rT3 were determined by specific radioimmunoassays in 17 hyperthyroid and 10 hypothyroid patients, before and during the treatment. Serum T4, T3, rT3, 3, 3'-T2 and 3', 5'-T2 concentrations were all higher in the hyperthyroid patients than in age-matched controls and decreased to the normal ranges within 3 to 4 months following treatment with antithyroid drugs. In the hypothyroid patients, these iodothyronine concentrations were lower than in age-matched controls and returned to the normal ranges after 2 to 3 months treatment with T4. In contrast, serum 3, 5-T2 concentrations in hyperthyroid patients (mean +/- SE : 4.0 +/- 0.5 ng/dl) were not significantly different from those in controls (3.9 +/ 0.4 ng/dl), although they tended to decrease in 3 of 6 patients after the antithyroid drug therapy. Serum 3, 5-T2 levels in the hypothyroid patients (3.8 +/- 0.6 ng/dl) were also within the normal range and showed no significant change following the T4 replacement therapy. However, serum 3, 5-T2 as well as 3, 3'T2 concentrations rose significantly with a marked rise in serum T3 following T3 administration, 75 micrograms/day for 7 days, in Graves' patients in euthyroid state.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synthesis of 2'-O-deuteriomethyl ribonucleosides Gm-d3, Am-d3, Um-d3 and Cm-d3.

The synthesis of 2'-O-deuteriomethyl ribonucleosides by iodomethane-d3 (99.5 + atom % D) deuteriomethylation of 3',5'-O-tetra(isopropyldisiloxane)-diyl nucleosides, followed by deprotection, is described.     

Monodeiodination of thyroxine to 3, 5, 3'-triiodothyronine and to 3, 3', 5'-triiodothyronine in isolated dog renal cortical tubuli

Monodeiodination of T4 to T3 and rT3 in the intact cells of dog renal tubuli and glomeruli was investigated. The tubuli and glomeruli were obtained by a sieve method. T4 (2 micrograms/ml) was incubated in Tris-HCl buffer, pH 7.5, with renal cells (180 micrograms protein/ml) and 5 mM DTT for 1 h at 37 degrees C and the T3 and rT3 generated during incubation were measured by specific radioimmunoassays. In order of decreasing activity, dog renal cortical tubuli, cortical homogenate, glomeruli and medullary tubuli were capable of converting T4 to T3. Net rT3 production from T4 in cortical tubuli was also greater than that in cortical homogenate. The conversion of T4 to T3 and also to rT3 in cortical tubuli was enzymatic in nature, since the reactions showed dependence on time and protein concentration; instability to heating; temperature and pH optimum. The production of T3 and rT3 from T4 was maximum at pH 6.5 and at pH 9.5, respectively, indicating that two different enzymic systems, a 5- and a 5'-monodeiodinase, might be involved in the deiodination of the tyrosyl and the phenolic ring of T4 in dog kidney.     

Cell density and amino acid transport in 3T3, SV3T3, and SV3T3 revertant cells

The transport of selected neutral and cationic amino acids has been studied in Balb/c 3T3, SV3T3, and SV3T3 revertant cell lines. After properly timed preincubations to control the size of internal amino acid pools, the activity of systems A, ASC, L, and Ly⁺ has been discriminated by measurements of amino acid uptake (initial entry rate) in the presence and absence of sodium and of transportspecific model substrates. L-Proline, 2-aminoisobutyric acid, and glycine were primarily taken up by system A; L-alanine and L-serine by system ASC; L-phenylalanine by system L; and L-lysine by system Ly⁺ in SV3T3 cells. L-Proline and L-serine were also preferential substrates of systems A and ASC, respectively, in 3T3 and SV3T3 revertant cells. Transport activity of the Na⁺-dependent systems A and ASC decreased markedly with the increase of cell density, whereas the activity of the Na⁺-independent systems L and Ly⁺remained substantially unchanged. The density-dependent change in activity of system A occurred through a mechanism affecting transport maximum (V_max) rather than substrate concentration for half-maximal velocity (K_m). Transport activity of systems A and ASC was severalfold higher in transformed SV3T3 cells than in 3T3 parental cells at all the culture densities that could be compared. In SV3T3 revertant cells, transport activity by these systems remained substantially similar to that observed in transformed SV3T3 cells. The results presented here add cell density as a regulatory factor of the activity of systems A and ASC, and show that this control mechanism of amino acid transport is maintained in SV40 virus-transformed 3T3 cells that have lost density-dependent inhibition of growth, as well as in SV3T3 revertant cells that have resumed it.     

Syntheses, crystal structures, and hydrogen bonding patterns of 3'-C-methylenecarboxylic-3'-deoxythymidine and 3'-C-methyleneamidilylic-3'-deoxythymidine

Thymidine derivatives containing carboxylic acid and amide groups have been synthesized and the hydrogen-bonding patterns of 3'-C-methylenecarboxylic-3'-deoxythymidine 6 and 3'-C-methyleneamidilylic-3'-deoxythymidine 9 have been characterized by using X-ray crystallography.     

Serum TSH, T4, T3, FT4, FT3, rT3, and TBG in youngsters with non-ketotic insulin-dependent diabetes mellitus

Several parameters of thyroid function were studied in 112 non-ketoacidotic youngsters with insulin-dependent diabetes mellitus (IDDM). Levels of thyroxine (T4), reverse triiodothyronine (rT3), thyroxine-binding globulin (TBG) and T3 were lower than in controls, whereas FT4, and FT3 were normal. T4 levels in IDDM patients were positively related to T3, rT3 and TBG, and inversely related to haemoglobin A1 (HbA1). However, only 4 patients showed biochemical hypothyroidism (T4 less than 5 micrograms/100 ml), whereas their FT4, FT3 and thyroid-stimulating hormone (TSH) levels were normal. Concurrent variations of T3 and rT3 levels were found in IDDM patients; thus, their T3/rT3 ratios were stable or higher than in controls, indicating that peripheral deiodination of T4 is preferentially oriented to production of rT3 only during ketoacidosis. Although changes in thyroid function may reflect the degree of metabolic control of diabetes in a large population, the clinical usefulness of serum thyroid hormone measurements in an individual case still appears to be limited.     

New Karplus equations for 2JHH, 3JHH, 2JCH, 3JCH, 3JCOCH, 3JCSCH, and 3JCCCH in some aldohexopyranoside derivatives as determined using NMR spectroscopy and density functional theory calculations

The (1)H-(13)C coupling constants of methyl alpha- and beta-pyranosides of D-glucose and D-galactose have been measured by one-dimensional and two-dimensional (1)H-(13)C heteronuclear zero and double quantum, phase sensitive J-HMBC spectra to determine a complete set of coupling constants ((1)J(CH), (2)J(CH), (3)J(CH), (2)J(HH), and (3)J(HH)) within the exocyclic hydroxymethyl group (CH(2)OH) for each compound. In parallel with these experimental studies, structure, energy, and potential energy surfaces of the hydroxymethyl group for these compounds were determined employing quantum mechanical calculations at the B3LYP level using the 6-311++G( * *) basis set. Values of the vicinal coupling constants involving (1)H and (13)C in the C5-C6 (omega) and C6-O6 (theta) torsion angles in the aldohexopyranoside model compounds were calculated with water as the solvent using the PCM method. To test the relationship between (3)J(CXCH) (X=C, O, S) and torsion angle C1-X (phi) around the anomeric center, the conformations of 24 derivatives of glucose and galactose, which represent sequences of atoms at the anomeric center of C-glycosides (C-C bond), O-glycosides (C-O bond), thioglycosides (C-S bond), glycosylamines (C-N bond), and glycosyl halides (C-halogen (F/Cl) bond) have been calculated. Nonlinear regression analysis of the coupling constants (1)J(C1,H1), (2)J(C5,H6R), (2)J(C5,H6S), (2)J(C6,H5), (3)J(C4,H6R), (3)J(C4,H6S), (2)J(H6R,H5), and (3)J(H5,H6R) as well as (3)J(CXCH) (X=C, O, S) on the dihedral angles omega, theta, and phi have yielded new Karplus equations. Good agreement between calculated and experimentally measured coupling constants revealed that the DFT method was able to accurately predict J-couplings in aqueous solutions.     

3-chloro-1, 3, 5-pregnatriene derivatives with glucocorticoid activity

Novel synthetic glucocorticoid analogues were tested for receptor binding and glucocorticoid activity. They were of unusual structure, insofar as they had a 3-chloro rather than a 3-oxo function. 3-Chloro analogues of fluorinated glucocorticoids formed extremely stable complexes with the rat liver glucocorticoid receptor. 3-Chloro derivative of fluocinolone acetonide also had $\text{in vivo}$ glucocorticoid activity. It induced tyrosine aminotransferase in the liver and repressed thymidine kinase in the thymus very effectively. It is concluded that 3-chloro analogues may retain glucocorticoid activity as well as the ability to bind to the glucocorticoid receptor protein.     

Syntheses of 3-fluoro-, 3-epi-3-fluoro-, and 3,3-difluoro-3-de(methoxy)sporaricin A

3-Fluoro- (4), 3-epi-3-fluoro- (3), and 3,3-difluoro-3-de(methoxy)sporaricin A (5) have been prepared by reaction of diethylaminosulfur trifluoride with the corresponding precursors: 1,2′,6′-tris(N-benzyloxycarbonyl)-4-N, 5-O-carbonyl-3-de(O-methyl)sporaricin B (6), its 3-epi-3-hydroxy isomer (10), and the 3-oxo derivative (9). The structures of 3,4, and 5 were determined by ¹H-, ¹³C-, and ¹⁹F-n.m.r. spectroscopy.     

Nomenklatorischer Kurzbericht, 3

Dieser dritte »Nomenklatorische Kurzbericht« informiert über die Anfang 1985 erschienene dritte Auflage des »International Code of Zoological Nomenclature« sowie über neue gutachtliche Entscheidungen (»Opinions«) der Nomenklatur-Kommission aus den Jahren 1980-1984 (Bulletin of Zoological Nomenclature, Band 37-41). Ältere derartige Entscheidungen, soweit sie fossile Taxa betreffen, sind im »Nomenklatorischen Kurzbericht, 1« (Paläont. Z.,46 (3/4): 251-255, 1972) und im »Nomenklatorischen Kurzbericht, 2« (Paläont. Z.,54 (3/4): 343-349, 1980) zusammengestellt.     

Synthesis and biological evaluation of 2',3'-didehydro-2',3'-dideoxy-9-deazaguanosine, a monophosphate prodrug and two analogues, 2',3'-dideoxy-9-deazaguanosine and 2',3'-didehydro-2',3'-dideoxy-9-deazainosine

2',3'-Didehydro-2',3'-dideoxy-9-deazaguanosine (1), its monophosphate prodrug (2), and two analogues, 2',3'-dideoxy-9-deazaguanosine (3) and 2',3'-didehydro-2',3'-dideoxy-9-deazainosine (4), have been synthesized from benzoylated 9-deazaguanosine (5). Basic hydrolysis of 5, selective protection of the 2-amino and 5'-hydroxy functions with isobutyryl and silyl groups, respectively, followed by reaction with thiocarbonyldiimidazole gave the cyclic thiocarbonate, which, upon reaction with triethyl phosphite, followed by deprotection, afforded 1. Treatment of 1 with phenyl methoxyalaninylphosphochloridate and N-methylimidazole gave 2. Catalytic hydrogenation of 1 gave 3. Hydrodediazoniation of 1 with tert-butyl nitrite and tris(trimethylsilyl)silane gave 4. Compounds 1-4 were found to be inactive against the human immunodeficiency virus and exhibited minimal to no cytotoxic activity against the L1210 leukemia, CCRF-CEM lymphoblastic leukemia, and B16F10 melanoma in vitro.     

Interaction of the 5'-phosphates of the anti-HIV agents, 3'-azido-3'-deoxythymidine and 3'-azido-2',3'-dideoxyuridine, with thymidylate synthase

A study has been made of the interaction of 3'-azido-3'-deoxythymidine 5'-phosphate (AZTMP) and 3'-azido-2',3'-dideoxy-uridine 5'-phosphate (AZdUMP) with thymidylate synthase. With the enzyme from L1210 cells and the tapeworm Hymenolepis diminuta, AZTMP was a weak inhibitor competitive with respect to dUMP (Ki = 6.3 mM and 0.5 mM); hence cytotoxicity of AZT, in cells in which accumulation of AZTMP is not high, is not due to inhibition of cellular thymidylate synthase. AZdUMP, with the L1210 enzyme, was a weak substrate (competition with dUMP described by apparent Ki = 4.7 mM), excluding conversion of AZdUMP to AZTMP as a source of toxicity of 3'-azido-2',3'-dideoxyuridine. An efficient procedure is described for enzymatic phosphorylation on a preparative scale of dideoxynucleosides.