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PubMed1981

Interaction of A-nor, A, 19-dinor, and A-homo-5 alpha-androstane derivatives with the androgen receptor and the epididymal androgen-binding protein.

The equilibrium affinity constant for rat prostate androgen receptor and epididymal androgen binding protein (ABP) has been determined for thirty-four potential progestogens. Three A-nor-, four A,19-dinor-, and one A-homo-5 alpha-androstane derivative bind to the androgen receptor (KD less than 0.5 muM). Five of these compounds also bind to ABP with an affinity of the same order of magnitude. "Anordrin" (compound 24) and "Dinordrins" (compounds 10, 14, 15, 16, 17), which are potential female contraceptives, do not bind with high affinity to the androgen receptor or to ABP. The following modifications in A-nor derivatives favour binding to the receptor as compared to ABP: 19-nor substitution (compound 1), C-18 methyl homologation (compound 5), 2 alpha-ethinylation (compound 22). One 2 alpha-allenyl A-nor derivative (compound 25) and one A-homo derivative (compound 34) bind almost exclusively to ABP. The interaction with either binding protein is decreased by oxidation or esterification of the hydroxyl group at C-17, and by addition of a 17 alpha-ethinyl group. The latter modifications are likely to increase the specificity of androstane derivatives for receptors other than androgen binding proteins, such as the progesterone receptor.

Androgen-Binding Protein↗
PubMed1983

D-homoandrostanes. 4. The incubation of some D-homo-5 alpha-androstanes with Rhizopus nigricans.

Nine dioxygenated D-homoandrostanes were incubated with Rhizopus nigricans to investigate the effect of D-ring modification on microbiological hydroxylation. Structure determination of the products by NMR spectroscopy, and in certain cases independent synthesis of their oxidised products, showed that in contrast to 5 alpha-androstanes the majority of the compounds were hydroxylated in the "reverse" mode, and only D-homo-5 alpha-androstane-3,17-dione was hydroxylated in the "normal" mode to any extent. Stereospecific ring D-hydroxylation at C(17 alpha) was observed for both D-homo-5 alpha-androstane-3,6- and 3,7-diones.

Androstanes↗
PubMedDate not supplied

An efficient procedure for the regiospecific preparation of D-homo-steroid derivatives.

alpha-Diazo-beta-hydroxy esters 3, obtained by condensation of ketones 1 with ethyl diazo(lithio)acetate 2, are efficiently converted into the corresponding beta-ketoesters 4 by exposure to dirhodium (II) tetraacetate. Application of this two-step sequence to 3 beta-acetoxy-5-androstene-17-one 5b and to 3-acetoxy estrone 10b afforded regiospecifically and in very high overall yield the corresponding ethyl 17a-oxo-D-homo-steroid-17-carboxylates 7a,b and 12a,b, which were decarboalkoxylated to give, respectively, 3 beta-hydroxy-D-homo-5-androstene-17a-one 8 and D-homoestrone 13.

Chemical Phenomena↗
PubMedDate not supplied

Recognition of D-homoannulation by proton and carbon NMR spectra.

One-and two dimensional proton and carbon NMR spectra of the D-homoannulated rearrangement product of triamcinolone (9 alpha-fluoro-11 beta,16 alpha,17 alpha, 21-tetrahydroxy-pregna-1,4-diene-3,20-dione) establish its structure as that of 9 alpha-fluoro-11 beta,16 alpha,17 alpha-trihydroxy-17 beta-hydroxy-methyl-D-homoandrosta-1,4-diene-3,17 alpha-dione. These methods accord ready recognition of D-homoannulation of C21-17-hydroxy-20-ketosteroids.

Androstenols↗
PubMed1997

Evidence that 85 kDa phospholipase A2 is not linked to CoA-independent transacylase-mediated production of platelet-activating factor in human monocytes.

Platelet-activating factor (PAF) production is carefully controlled in inflammatory cells. The specific removal of arachidonate (AA) from 1-O-alkyl-2-arachidonoyl-sn-glycero-3-phosphocholine (GPC), thought to be mediated by CoA-independent transacylase (CoA-IT), is required to generate the PAF precursor 1-O-alkyl-2-lyso-GPC in human neutrophils. Exposure of A23187-stimulated human monocytes to the CoA-IT inhibitors SK&F 98625 and SK&F 45905 inhibited PAF formation (IC50s of 10 and 12 microM, respectively), indicating that these cells also need CoA-IT activity for PAF production. Because CoA-IT activity transfers arachidonate to a 2-lyso phospholipid substrate, its activity is obligated to an sn-2 acyl hydrolase to form the 2-lyso phospholipid substrate. SB 203347, an inhibitor of 14 kDa phospholipase A2 (PLA2), and AACOCF3, an inhibitor of 85 kDa PLA2, both inhibited AA release from A23187-stimulated human monocytes. However, AACOCF3 had no effect on A23187-induced PAF formation at concentrations as high as 3 microM. Further, depletion of 85 kDa PLA2 using antisense (SB 7111, 1 microM) had no effect on PAF production, indicating a lack of a role of 85 kDa PLA2 in PAF biosynthesis. Both SB 203347 and the 14 kDa PLA2 inhibitor scalaradial blocked PAF synthesis in monocytes (IC50s of 2 and 0.5 microM, respectively), suggesting a key role of 14 kDa PLA2 in this process. Further, A23187-stimulated monocytes produced two forms of PAF: 80% 1-O-alkyl-2-acetyl-GPC and 20% 1-acyl-2-acetyl-GPC, which were both equally inhibited by SB 203347. In contrast, inhibition of CoA-IT using SK&F 45905 (20 microM) had a greater effect on the production of 1-O-alkyl (-80%) than of 1-acyl (-14%) acetylated material. Finally, treatment of U937 cell membranes with exogenous human recombinant (rh) type II 14 kDa PLA2, but not rh 85 kDa PLA2, induced PAF production. Elimination of membrane CoA-IT activity by heat treatment impaired the ability of 14 kDa PLA2 to induce PAF formation. Taken together, these results suggest that a 14 kDa PLA2-like activity, and not 85 kDa PLA2, is coupled to monocyte CoA-IT-induced PAF production.

Acyltransferases↗
PubMed1975

Cholesterol oxidase. Further studies of substrate specificity in relation to the analytical characterisation of steroids.

The substrate specificity of cholesterol oxidase has been further examined with respect to the size and shape of the steroid 17beta-side-chain and oxygenation of the nucleus. The relatively unreactive 17-keto-delta5-3beta-hydroxysteroids were converted to satisfactory substrates by formation of the isopentyl- or benzyloximes. The results obtained have been used to illustrate further uses of the enzyme in the gas-phase analytical characterisation and selective oxidation steroids. Oxidations were studied by kinetic experiments, gas-liquid chromatography-mass spectrometry.

17-Ketosteroids↗
PubMed2003

Synthesis, X-ray crystal structures and biological activity of 16-amino-17-substituted-D-homo steroid derivatives.

D-Homo derivatives in the androstane and estrane series, 12-19, were synthesized by a fragmentation-cyclization reaction of 16-oximino-17-hydroxy-17-substituted derivatives 3-9, or by cyclization of the corresponding D-seco derivatives 20-26. The structures were confirmed by X-ray analysis of compounds 12 and 16. Preliminary assessment of inhibitory effects of D-homo derivatives from androstane series towards aromatase, 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD), 17 alpha-hydroxylase/C17-20 lyase (P450c17) and 17 beta-HSD indicated much lower inhibitory potential compared to previously tested activity of another type of D-modified steroids, namely D-seco derivatives. Also, assessment of potential antiestrogenic activity of derivatives from estrane series showed absence of such an activity.

17-Hydroxysteroid Dehydrogenases↗
PubMed1997

Phospholipase A2 has a role in proliferation but not in differentiation of HL-60 cells.

The role of phospholipase A2 (PLA2) and its metabolite arachidonic acid (AA) in the proliferation and differentiation of HL-60 cells was investigated. Addition of either 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) or retinoic acid (RA) to HL-60 cells for 2 h inhibited PMA-stimulated PLA2 activity measured by [3H]AA release. The inhibitor of PLA2 activity, p-bromophenacyl bromide (BPB), significantly inhibited the proliferation of HL-60 cells and of fibroblast L929 and Swiss 3T3 cells in a dose-dependent manner. The effect of BPB on proliferation is probably through its inhibitory effect on PLA2 activity, since the same doses of BPB which inhibited proliferation also inhibited PLA2 activity determined by [3H]AA release. The importance of PLA2 activity for cell growth was further supported by the effect of two other PLA2 inhibitors, AACOCF3 and scalaradial, which inhibited HL-60 proliferation in a dose-dependent manner. BPB, AACOCF3 and scalaradial significantly increased the doubling time to 32.4 h, 34.0 h and 31.8 h, respectively, compared with 24.6 h in the control. The inhibitory effect of BPB on HL-60 proliferation was reversed by addition of exogenous free AA to HL-60 cells, indicating the importance of this metabolite for the proliferation process. This reversible effect is specific for AA since it was not achieved by other fatty acids like linolenic acid (LA) or oleic acid (OA). Addition of free AA to HL-60 cells did not induce differentiation, as expected. Although BPB, AACOCF3, or scalaradial inhibited proliferation, they did not induce differentiation nor affect the differentiation induced by 1,25(OH)2D3 or RA. These results implicate that PLA2 activity has no regulatory role in differentiation of HL-60 cells. The differential effect of PLA2 inhibitors on proliferation and differentiation of HL-60 cells suggests that these two processes function under different regulatory mechanisms.

3T3 Cells↗
PubMed1998

Interfacial recognition by bee venom phospholipase A2: insights into nonelectrostatic molecular determinants by charge reversal mutagenesis.

The basis for tight binding of bee venom phospholipase A2 (bvPLA2) to anionic versus zwitterionic phospholipid interfaces is explored by charge reversal mutagenesis of basic residues (lysines/arginines to glutamates) on the putative membrane binding surface. Single-site mutants and, surprisingly, multisite mutants (2-5 of the 6 basic residues mutated) are fully functional on anionic vesicles. Mutants bind tightly to anionic vesicles, and active-site substrate and Ca2+ binding are not impaired. Multisite mutants undergo intervesicle exchange slightly faster than wild type, especially in the presence of salt. It is estimated that electrostatic contribution to interfacial binding is modest, perhaps 2-3 kcal/mol of the estimated 15 kcal/mol. Elution properties of bvPLA2 from HPLC columns containing solid phases of tightly packed monolayers of phosphocholine amphiphiles suggest that ionic effects provide a modest portion of the interfacial binding energy and that this contribution decreases as the number of cationic residues mutated is increased. These results are consistent with the observation that Gila monster venom PLA2 (Pa2), which is homologous to bvPLA2, has high activity on anionic vesicles despite the fact that it has only a single basic residue on its putative interfacial recognition face. Results with bvPLA2 mutants show that manoalogue and 12-epi-scalaradial inactivate bvPLA2 by modification of K94. Also, deletion of the large beta-loop (residues 99-118) is without consequence for interfacial binding and catalysis of bvPLA2. All together, the preferential binding of bvPLA2 to anionic vesicles versus phosphatidylcholine vesicles is mainly due to factors other than electrostatics. Therefore hydrogen-bonding and hydrophobic interactions must provide a major portion of the interfacial binding energy, and this is consistent with recent spectroscopic studies.

Animals↗