scholarly journals Chemical and enzymic studies on the characterization of intermediates during the removal of the 14α-methyl group in cholesterol biosynthesis. The use of 32-functionalized lanostane derivatives

1978 ◽  
Vol 169 (3) ◽  
pp. 449-463 ◽  
Author(s):  
M Akhtar ◽  
K Alexander ◽  
R B Boar ◽  
J F McGhie ◽  
D H R Barton
Keyword(s):  
Formic Acid ◽  
Cholesterol Biosynthesis ◽  
Aldehyde Group ◽  
Type I ◽  
Compound I ◽  
Major Pathway ◽  
Methyl Group ◽  
Experimental Approaches ◽  
C 32 ◽  
Compound Ii

By using cell-free preparations of rat liver it was shown that the removal of the 14alpha-methyl group (C-32) of steroids containing either a delta7(8) or a delta8(9) double bond is attended exclusively by the formation of the corresponding 7,14- and 8,14-dienes respectively (structures of types III and VIII). Cumulative evidence from a variety of experimental approaches had led to the deduction that delta8(14)-steroids are not involved as intermediates on the major pathway of cholesterol biosynthesis. The metabolism of [32-3H]lanost-7-ene-3beta,32-diol (structure of type I) results in the formation of radioactive formic acid, no labelled formaldehyde being formed. By using appropriately labelled species of the compound (I) it was found that the release of formic acid and the formation of 4,4-dimethylcholesta-7,14-dien-3beta-ol (strurcture of type III) were closely linked processes, and that in the conversion of compound (I) into compound (III), 3-beta-hydroxylanost-7-en-32-al (II) is an obligatory intermediate. Both the conversion of lanost-7-ene-3beta,32-diol (I) into 3beta-hydroxylanost-7-en-32-al (II) and the further metabolism of the latter (II) to 4,4-dimethylcholesta-7,14-dien-3beta-ol (III) exhibited a requirement for NADPH and O2. This suggests that the oxidation of the 32-hydroxy group of compound (I) to the aldehyde group of compound (II) does not occur by the conventional alcohol dehydrogenase type of reaction, but may proceed by a novel mechanism involving the intermediacy of a gem-diol. A detailed overall pathway for the 14alpha-demethylation in cholesterol biosynthesis is considered, and proposals about the mechanism of individual steps in the pathway are made.

scholarly journals Studies on the mechanism of lanosterol 14 α-demethylation. A requirement for two distinct types of mixed-function-oxidase systems

1979 ◽  
Vol 183 (2) ◽  
pp. 309-315 ◽  
Author(s):  
F G Gibbons ◽  
C R Pullinger ◽  
K A Mitropoulos
Keyword(s):  
Carbon Monoxide ◽  
Formic Acid ◽  
Enzyme System ◽  
Mixed Function Oxidase ◽  
Initial Oxidation ◽  
Radioactive Label ◽  
Methyl Group ◽  
C 32 ◽  
Compound Ii ◽  
Cytochrome P 450

Carbon monoxide inhibited the removal of C-32 of dihydrolanosterol (I), but not of its metabolites 5 alpha-lanost-8-ene-3 beta,32-diol (II) and 3 beta-hydroxy-5 alpha-lanost-8-en-32-al (III). It appears therefore that cytochrome P-450 is a component of the enzyme system required to initiate oxidation of the 14 alpha-methyl group, but not of that responsible for the subsequent oxidation steps required for elimination of C-32 as formic acid. Non-radioactive compounds (II) and (III), when added to cell-free systems actively converting dihydrolanosterol into cholesterol, inhibited 14 alpha-demethylation measured by the rate of formation of labelled cholesterol from dihydro[1,7,15,22,26,30-14C]lanosterol or of labelled formic acid from dihydro[32-14C]lanosterol. However, neither compound (II) nor compound (III) accumulated radioactive label under these conditions. These observations could be attributed partly to inhibition of the initial oxidation of the 14 alpha-methyl group by compounds (II) and (III).

Chemistry of the S=O bond. 13. Structures of isomers 1 (I) and 2 (II) of 4-methyl-1,3,2-dioxathiane 2-oxide and 1,3,2-dioxathiepane 2-oxide (III) at 256, 240 and 228 K

1996 ◽  
Vol 52 (3) ◽  
pp. 505-508 ◽  
Author(s):  
D.G. Hellier ◽  
P. Luger ◽  
J. Buschmann
Keyword(s):  
Single Crystals ◽  
Low Temperatures ◽  
Chair Conformation ◽  
Equatorial Position ◽  
X Ray Diffraction ◽  
Compound I ◽  
Methyl Group ◽  
X Ray ◽  
Compound Ii ◽  
Axis Passing

The structures of the two isomers of 4-methyl-1,3,2-dioxathiane 2-oxide, C4H8SO3 (I, II), and 1,3,2-dioxathiepane 2-oxide, C4H8SO3 (III), have been determined by X-ray diffraction methods for single crystals that were grown in this case at low temperatures from the normally liquid compounds. Compound (I): orthorhombic, P212121, Mr = 136.17, a = 7.204 (6), b = 13.670 (11), c = 6.041 (6) Å, V = 594.91 Å3, Z= 4, Dx = 1.520 Mg m−3, Mo Kα (λ = 0.71068 Å), μ = 4.49 cm−1, F(000) = 288, T = 256 K, R = 0.042 for 778 unique reflections. Compound (II): orthorhombic, P212121, Mr = 136.17, a = 18.238 (6), b = 10.265 (3), c = 6.616 (2) Å, V = 1238.60 Å3, Z= 8, Dx = 1.460 Mg m−3, Mo Kα (λ = 0.71068 Å), μ = 4.31 cm−1, F(000) = 576, T = 240 K, R = 0.032 for 1597 unique reflections. Compound (III): monoclinic, P21/n, Mr = 136.17, a = 6.060 (3), b = 11.185 (8), c = 9.186 (4) Å, β = 101.32 (4)°, V = 610.52 Å3, Z = 4, Dx = 1.481 Mg m−3, Mo Kα (λ = 0.71068 Å), μ = 4.38 cm−1, F(000) = 288, T = 228 K, R = 0.037 for 1161 unique reflections. Compound (I) adopts a chair structure, which has a methyl group in an equatorial position and an axially oriented S=O group. Compound (II) is similar, except that the S=O group is equatorially oriented. Compound (III) adopts a twist-chair conformation with a local approximate endocyclic twofold axis passing through S(1) and the middle of the opposite bond, C(4)—C(5).

scholarly journals Mechanistic studies on C-19 demethylation in oestrogen biosynthesis

1982 ◽  
Vol 201 (3) ◽  
pp. 569-580 ◽  
Author(s):  
Muhammad Akhtar ◽  
Michael R. Calder ◽  
David L. Corina ◽  
J. Neville Wright
Keyword(s):  
Formic Acid ◽  
Bond Cleavage ◽  
Mechanistic Studies ◽  
Hydroxy Compound ◽  
Microsomal Preparation ◽  
Methyl Group ◽  
Cleavage Step ◽  
Compound Ii ◽  
Cumulative Evidence ◽  
Oxygen Atoms

Mechanistic aspects of the biosynthesis of oestrogen have been studied with a microsomal preparation from full-term human placenta. The overall transformation, termed the aromatization process, involves three steps using O2 and NADPH, in which the C-19 methyl group of an androgen is oxidised to formic acid with concomitant production of the aromatic ring of oestrogen: [Formula: see text] To study the mechanism of this process in terms of the involvement of the oxygen atoms, a number of labelled precursors were synthesized. Notable amongst these were 19-hydroxy-4-androstene-3,17-dione (II) and 19-oxo-4-androstene-3,17-dione (IV) in which the C-19 was labelled with2H in addition to18O. In order to follow the fate of the labelled atoms at C-19 of (II) and (IV) during the aromatization, the formic acid released from C-19 was benzylated and analysed by mass spectrometry. Experimental procedures were devised to minimize the exchange of oxygen atoms in substrates and product with oxygens of the medium. In the conversion of the 19-[18O] compounds of types (II) and (IV) into 3-hydroxy-1,3,5-(10)-oestratriene-17-one (V, oestrone), it was found that the formic acid from C-19 retained the original substrate oxygen. When the equivalent16O substrates were aromatized under18O2, the formic acid from both substrates contained one atom of18O. It is argued that in the conversion of the 19-hydroxy compound (II) into the 19-oxo compound (IV), the C-19 oxygen of the former remains intact and that one atom of oxygen from O2 is incorporated into formic acid during the conversion of the 19-oxo compound (IV) into oestrogen. This conclusion was further substantiated by demonstrating that in the aromatization of 4-androstene-3,17-dione (I), both the oxygen atoms in the formic acid originated from molecular oxygen. 10β-Hydroxy-4-oestrene-3,17-dione formate, a possible intermediate in the aromatization, was synthesized and shown not to be converted into oestrogen. In the light of the cumulative evidence available to date, stereochemical aspects of the conversion of the 19-hydroxy compound (II) into the 19-oxo compound (IV), and mechanistic features of the C-10–C-19 bond cleavage step during the conversion of the 19-oxo compound (IV) into oestrogen are discussed.

scholarly journals The crystal structures of three 3-methyl-1H-1,2,4-triazole-5-thiones, including a second polymorph of 4-[(E)-(5-bromo-2-hydroxybenzylidene)amino]-3-methyl-1H-1,2,4-triazole-5(4H)-thione and a redetermination of 4-amino-3-methyl-1H-1,2,4-triazole-5(4H)-thione

2015 ◽  
Vol 71 (9) ◽  
pp. 1003-1009 ◽  
Author(s):  
Padmanabha S. Manjula ◽  
Balladka K. Sarojini ◽  
Hemmige S. Yathirajan ◽  
Mehmet Akkurt ◽  
Cem Cüneyt Ersanlı ◽  
...  
Keyword(s):  
Hydrogen Bond ◽  
Hydrogen Bonds ◽  
Crystal Structures ◽  
Dihedral Angle ◽  
Compound I ◽  
Methyl Group ◽  
Space Group ◽  
Improved Model ◽  
Compound Ii

The structures of three 3-methyl-1H-1,2,4-triazole-5-thione derivatives are reported. The structure of 4-amino-3-methyl-1H-1,2,4-triazole-5(4H)-thione, C3H6N4S, (I), has been redetermined with an improved model for the H atoms: the non-H atoms of (I) all lie on mirror planes in space groupPbcm, and the H atoms of the methyl group are disordered over two sets of reflection-related atomic sites having occupancy 0.5: two independent N—H...S hydrogen bonds link the molecules of compound (I) into complex sheets. The non-H atoms in the molecules of 4-[(E)-(3,4-dimethoxybenzylidene)amino]-3-methyl-1H-1,2,4-triazol-5(4H)-thione, C12H14N4O2S, (II), despite lying in general positions are close to planar, with a dihedral angle between the two rings of 6.31 (10)°: the molecules of compound (II) are linked by a three-centre N—H...(O)2hydrogen bond into aC(10)C(11)[R12(5)] chain of rings. A second polymorph of 4-[(E)-(5-bromo-2-hydroxy-5-bromobenzylidene)amino]-3-methyl-1H-1,2,4-triazole-5(4H)-thione, C10H9BrN4OS, (III), has been identified; the non-H atoms are nearly co-planar with a dihedral angle between the two rings of 1.9 (4)°. There is an intramolecular O—H...N hydrogen bond and the molecules are linked by N—H...S hydrogen bonds, forming centrosymmetricR22(8) dimers. Comparisons are made with some related structures.

New Amine and Aromatic Substituted Analogues of Phencyclidine: Synthesis and Determination of Acute and Chronic Pain Activities

2019 ◽  
Vol 22 (8) ◽  
pp. 570-576
Author(s):  
Maryam Shokrollahi ◽  
Marjaneh Samadizadeh ◽  
Mohsen Khalili ◽  
Seyed A. Sobhanian ◽  
Abbas Ahmadi
Keyword(s):  
Nmda Receptors ◽  
Phenyl Ring ◽  
Piperidine Ring ◽  
Methyl Group ◽  
Physiological Properties ◽  
Antinociceptive Effects ◽  
The Central Nervous System ◽  
Analgesic Activities ◽  
Compound Ii ◽  
New Compounds

Background: Phencyclidine (PCP, I) is a synthetic drug with remarkable physiological properties. PCP and its analogues exert many pharmacological activities and interact with some neurotransmitter systems in the central nervous system like particular affinity for PCP sites in NMDA receptors or dopamine uptake blocking or even both. Aim and Objective: The following research, methyl group with electron-donating and dipole moment characters was added in different positions of phenyl ring along with the substitution of benzylamine (with many pharmacological effects) instead of piperidine ring of I to produce new compounds (II-V) of this family with more analgesic activities. Materials and Methods: Analgesic activities of these new compounds were measured by tail immersion and formalin tests for acute and chronic pains, respectively. Also, the outcomes were compared with control and PCP (10 mg/kg) groups. Results: The results indicate that compounds III, IV, and V have more acute and chronic antinociceptive effects than PCP and compound II which may be concerned with more antagonizing activities of these new painkillers for the blockage of dopamine reuptake as well as high affinity for NMDA receptors PCP binding site. Conclusion: It can be concluded that the benzylamine derivative of phencyclidine with a methyl group on the benzyl position on phenyl ring (V) is a more appropriate candidate to reduce acute and chronic (thermal and chemical) pains compared to other substituted phenyl analogs (II-IV) and PCP.

scholarly journals Interplay between Oxo and Fluoro in Vanadium Oxyfluorides for Centrosymmetric and Non-Centrosymmetric Structure Formation

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 603
Author(s):  
Prashanth Sandineni ◽  
Hooman Yaghoobnejad Asl ◽  
Weiguo Zhang ◽  
P. Shiv Halasyamani ◽  
Kartik Ghosh ◽  
...  
Keyword(s):  
Second Harmonic ◽  
Metastable Phase ◽  
Compound I ◽  
Hydrothermal Route ◽  
Prolonged Heating ◽  
Space Group ◽  
Lithium Vanadium Oxide ◽  
Compound Ii ◽  
Unambiguous Assignment ◽  
Centrosymmetric Structure

Herein, we report the syntheses of two lithium-vanadium oxide-fluoride compounds crystallized from the same reaction mixture through a time variation experiment. A low temperature hydrothermal route employing a viscous paste of V2O5, oxalic acid, LiF, and HF allowed the crystallization of one metastable phase initially, Li2VO0.55(H2O)0.45F5⋅2H2O (I), which on prolonged heating transforms to a chemically similar yet structurally different phase, Li3VOF5 (II). Compound I crystallizes in centrosymmetric space group, I2/a with a = 6.052(3), b = 7.928(4), c = 12.461(6) Å, and β = 103.99(2)°, while compound II crystallizes in a non-centrosymmetric (NCS) space group, Pna21 with a = 5.1173(2), b = 8.612(3), c = 9.346(3) Å. Synthesis of NCS crystals are highly sought after in solid-state chemistry for their second-harmonic-generation (SHG) response and compound II exhibits SHG activity albeit non-phase-matchable. In this article, we also describe their magnetic properties which helped in unambiguous assignment of mixed valency of V (+4/+5) for Li2VO0.55(H2O)0.45F5⋅2H2O (I) and +4 valency of V for Li3VOF5 (II).

scholarly journals Crystal structures of {[Cu(Lpn)2][Fe(CN)5(NO)]·H2O}nand {[Cu(Lpn)2]3[Cr(CN)6]2·5H2O}n[where Lpn = (R)-propane-1,2-diamine]: two heterometallic chiral cyanide-bridged coordination polymers

2015 ◽  
Vol 71 (4) ◽  
pp. 392-397
Author(s):  
Olha Sereda ◽  
Helen Stoeckli-Evans
Keyword(s):  
Hydrogen Bonds ◽  
Coordination Polymers ◽  
Three Dimensional ◽  
Water Molecules ◽  
Two Dimensional ◽  
Asymmetric Unit ◽  
Compound I ◽  
Distorted Octahedral ◽  
Coordination Spheres ◽  
Compound Ii

The title compounds,catena-poly[[[bis[(R)-propane-1,2-diamine-κ2N,N′]copper(II)]-μ-cyanido-κ2N:C-[tris(cyanido-κC)(nitroso-κN)iron(III)]-μ-cyanido-κ2C:N] monohydrate], {[Cu(Lpn)2][Fe(CN)5(NO)]·H2O}n, (I), and poly[[hexa-μ-cyanido-κ12C:N-hexacyanido-κ6C-hexakis[(R)-propane-1,2-diamine-κ2N,N′]dichromium(III)tricopper(II)] pentahydrate], {[Cu(Lpn)2]3[Cr(CN)6]2·5H2O}n, (II) [where Lpn = (R)-propane-1,2-diamine, C3H10N2], are new chiral cyanide-bridged bimetallic coordination polymers. The asymmetric unit of compound (I) is composed of two independent cation–anion units of {[Cu(Lpn)2][Fe(CN)5)(NO)]} and two water molecules. The FeIIIatoms have distorted octahedral geometries, while the CuIIatoms can be considered to be pentacoordinate. In the crystal, however, the units align to form zigzag cyanide-bridged chains propagating along [101]. Hence, the CuIIatoms have distorted octahedral coordination spheres with extremely long semicoordination Cu—N(cyanido) bridging bonds. The chains are linked by O—H...N and N—H...N hydrogen bonds, forming two-dimensional networks parallel to (010), and the networks are linkedviaN—H...O and N—H...N hydrogen bonds, forming a three-dimensional framework. Compound (II) is a two-dimensional cyanide-bridged coordination polymer. The asymmetric unit is composed of two chiral {[Cu(Lpn)2][Cr(CN)6]}−anions bridged by a chiral [Cu(Lpn)2]2+cation and five water molecules of crystallization. Both the CrIIIatoms and the central CuIIatom have distorted octahedral geometries. The coordination spheres of the outer CuIIatoms of the asymmetric unit can be considered to be pentacoordinate. In the crystal, these units are bridged by long semicoordination Cu—N(cyanide) bridging bonds forming a two-dimensional network, hence these CuIIatoms now have distorted octahedral geometries. The networks, which lie parallel to (10-1), are linkedviaO—H...O, O—H...N, N—H...O and N—H...N hydrogen bonds involving all five non-coordinating water molecules, the cyanide N atoms and the NH2groups of the Lpn ligands, forming a three-dimensional framework.

scholarly journals Human parainfluenza virus type 1 regulates cholesterol biosynthesis and establishes quiescent infection in human airway cells

2021 ◽  
Vol 17 (9) ◽  
pp. e1009908
Author(s):  
Yuki Kurebayashi ◽  
Shringkhala Bajimaya ◽  
Masahiro Watanabe ◽  
Nicholas Lim ◽  
Michael Lutz ◽  
...  
Keyword(s):  
Virus Type ◽  
Cholesterol Biosynthesis ◽  
Parainfluenza Virus ◽  
Type I ◽  
Human Airway ◽  
Virion Release ◽  
Infected Cells ◽  
Human Parainfluenza Virus ◽  
Airway Cells

Human parainfluenza virus type 1 (hPIV1) and 3 (hPIV3) cause seasonal epidemics, but little is known about their interaction with human airway cells. In this study, we determined cytopathology, replication, and progeny virion release from human airway cells during long-term infection in vitro. Both viruses readily established persistent infection without causing significant cytopathic effects. However, assembly and release of hPIV1 rapidly declined in sharp contrast to hPIV3 due to impaired viral ribonucleocapsid (vRNP) trafficking and virus assembly. Transcriptomic analysis revealed that both viruses induced similar levels of type I and III IFNs. However, hPIV1 induced specific ISGs stronger than hPIV3, such as MX2, which bound to hPIV1 vRNPs in infected cells. In addition, hPIV1 but not hPIV3 suppressed genes involved in lipid biogenesis and hPIV1 infection resulted in ubiquitination and degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, a rate limiting enzyme in cholesterol biosynthesis. Consequently, formation of cholesterol-rich lipid rafts was impaired in hPIV1 infected cells. These results indicate that hPIV1 is capable of regulating cholesterol biogenesis, which likely together with ISGs contributes to establishment of a quiescent infection.

scholarly journals Crosstalk Between Autophagy and the cGAS–STING Signaling Pathway in Type I Interferon Production

2021 ◽  
Vol 9 ◽  
Author(s):  
Kunli Zhang ◽  
Sutian Wang ◽  
Hongchao Gou ◽  
Jianfeng Zhang ◽  
Chunling Li
Keyword(s):  
Signaling Pathway ◽  
Adenosine Monophosphate ◽  
Degradation Process ◽  
Guanosine Monophosphate ◽  
Type I Interferons ◽  
Research Progress ◽  
Type I ◽  
Type I Ifn ◽  
Major Pathway ◽  
Sting Pathway

Innate immunity is the front-line defense against infectious microorganisms, including viruses and bacteria. Type I interferons are pleiotropic cytokines that perform antiviral, antiproliferative, and immunomodulatory functions in cells. The cGAS–STING pathway, comprising the main DNA sensor cyclic guanosine monophosphate/adenosine monophosphate synthase (cGAS) and stimulator of IFN genes (STING), is a major pathway that mediates immune reactions and is involved in the strong induction of type I IFN production, which can fight against microbial infections. Autophagy is an evolutionarily conserved degradation process that is required to maintain host health and facilitate capture and elimination of invading pathogens by the immune system. Mounting evidence indicates that autophagy plays an important role in cGAS–STING signaling pathway-mediated type I IFN production. This review briefly summarizes the research progress on how autophagy regulates the cGAS–STING pathway, regulating type I IFN production, with a particular focus on the crosstalk between autophagy and cGAS–STING signaling during infection by pathogenic microorganisms.

Zolmitriptan oxalate and zolmitriptan camphorsulfonate: the first structural study of salt complexes of the antimigraine drug zolmitriptan

2013 ◽  
Vol 69 (10) ◽  
pp. 1186-1191
Author(s):  
Balasubramanian Sridhar ◽  
Krishnan Ravikumar ◽  
Venkatasubramanian Hariharakrishnan
Keyword(s):  
Structural Study ◽  
Three Dimensional ◽  
Helical Chain ◽  
Side Chain ◽  
Indole Ring ◽  
Asymmetric Unit ◽  
Compound I ◽  
Space Group ◽  
Compound Ii ◽  
Ring Motif

Zolmitriptan hydrogen oxalate [(S)-dimethyl(2-{5-[(2-oxo-1,3-oxazolidin-4-yl)methyl]-1H-indol-3-yl}ethyl)azanium hydrogen oxalate], C16H22N3O2+·C2HO4−, (I), and zolmitriptan camphorsulfonate [(S)-dimethyl(2-{5-[(2-oxo-1,3-oxazolidin-4-yl)methyl]-1H-indol-3-yl}ethyl)azanium (S,R)-{2-hydroxy-7,7-dimethylbicyclo[2.2.1]heptan-1-yl}methanesulfonate], C16H22N3O2+·C10H15O4S−, (II), are the first reported salt complexes of the antimigraine drug zolmitriptan. Compound (I) crystallizes in the space groupP21with two molecules of protonated zolmitriptan and two oxalate monoanions in the asymmetric unit, while compound (II) crystallizes in the space groupP212121with one protonated zolmitriptan molecule and one camphorsulfonate anion in the asymmetric unit. The orientations of the ethylamine side chain and the oxazolidinone ring with respect to the indole ring of the zolmitriptan cation are different for (I) and (II). In (I), they are oriented in opposite directions and the molecule adopts a step-like appearance, while in (II) the corresponding side chains are folded in the same direction, giving the molecule a cup-like appearance. The zolmitriptan molecules of (I) form anR22(8) dimer, while in (II) they form a helical chain with aC(11) motif. The oxalate monoanions of (I) interact with the zolmitriptan cations and extend the dimer into a three-dimensional hydrogen-bonded network. In (II), the camphorsulfonate anion forms anR22(15) ring motif with the zolmitriptan cation.

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