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.

Rhodium(I)-Catalysed Aryl C–H Carboxylation of 2-Arylanilines with CO2

2019 ◽  
Author(s):  
yuzhen gao ◽  
Zhihua Cai ◽  
Shangda Li ◽  
Gang Li
Keyword(s):  
General Type ◽  
Bond Cleavage ◽  
Bond Formation ◽  
Direct Conversion ◽  
Activation Process ◽  
Amino Group ◽  
Mechanistic Studies ◽  
Organometallic Reagent ◽  
Cleavage Step ◽  
Neutral Conditions

<b>An unprecedented amino-group assisted C–H carboxylation of 2-arylanilines with CO<sub>2</sub> under redox-neutral conditions using a Rhodium(I)-catalyst has been developed. This reaction was promoted by a phosphine ligand with <i>t</i>-BuOK as the base and did not require the use of an extra strong organometallic reagent. Notably, this protocol may involve an oxidative addition in the C–H bond cleavage step and is distinct from previous Rh(I) or Rh(II)-catalysed methods for C–H carboxylation with </b><b>CO<sub>2</sub> </b><b>mechanistically. It enabled an efficient direct conversion of a broad range of 2-(hetero)arylanilines including electron-deficient heteroarenes to various phenanthridinones, which could be further transformed to other synthetically useful compounds readily. Preliminary mechanistic studies were carried out and possible intermediates of the reaction were evaluated, which revealed that the Rh(I)-catalyst is essential for the C–H activation process, providing a promising general type of method for utilization of </b><b>CO<sub>2</sub></b><b> for C–C bond formation.</b><br>

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).

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.

Rhodium(I)-Catalysed Aryl C–H Carboxylation of 2-Arylanilines with CO2

2019 ◽  
Author(s):  
yuzhen gao ◽  
Zhihua Cai ◽  
Shangda Li ◽  
Gang Li
Keyword(s):  
General Type ◽  
Bond Cleavage ◽  
Bond Formation ◽  
Direct Conversion ◽  
Activation Process ◽  
Amino Group ◽  
Mechanistic Studies ◽  
Organometallic Reagent ◽  
Cleavage Step ◽  
Neutral Conditions

<b>An unprecedented amino-group assisted C–H carboxylation of 2-arylanilines with CO<sub>2</sub> under redox-neutral conditions using a Rhodium(I)-catalyst has been developed. This reaction was promoted by a phosphine ligand with <i>t</i>-BuOK as the base and did not require the use of an extra strong organometallic reagent. Notably, this protocol may involve an oxidative addition in the C–H bond cleavage step and is distinct from previous Rh(I) or Rh(II)-catalysed methods for C–H carboxylation with </b><b>CO<sub>2</sub> </b><b>mechanistically. It enabled an efficient direct conversion of a broad range of 2-(hetero)arylanilines including electron-deficient heteroarenes to various phenanthridinones, which could be further transformed to other synthetically useful compounds readily. Preliminary mechanistic studies were carried out and possible intermediates of the reaction were evaluated, which revealed that the Rh(I)-catalyst is essential for the C–H activation process, providing a promising general type of method for utilization of </b><b>CO<sub>2</sub></b><b> for C–C bond formation.</b><br>

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 Crystallization and preliminary X-ray characterization of the 2,4′-dihydroxyacetophenone dioxygenase fromAlcaligenessp. 4HAP

2014 ◽  
Vol 70 (6) ◽  
pp. 823-826 ◽  
Author(s):  
G. Beaven ◽  
A. Bowyer ◽  
P. Erskine ◽  
S. P. Wood ◽  
A. McCoy ◽  
...  
Keyword(s):  
Synchrotron Radiation ◽  
Formic Acid ◽  
Molecular Oxygen ◽  
Aromatic Ring ◽  
Bond Cleavage ◽  
Its Sequence ◽  
Hydroxybenzoic Acid ◽  
X Ray

The enzyme 2,4′-dihydroxyacetophenone dioxygenase (or DAD) catalyses the conversion of 2,4′-dihydroxyacetophenone to 4-hydroxybenzoic acid and formic acid with the incorporation of molecular oxygen. Whilst the vast majority of dioxygenases cleave within the aromatic ring of the substrate, DAD is very unusual in that it is involved in C—C bond cleavage in a substituent of the aromatic ring. There is evidence that the enzyme is a homotetramer of 20.3 kDa subunits each containing nonhaem iron and its sequence suggests that it belongs to the cupin family of dioxygenases. By the use of limited chymotrypsinolysis, the DAD enzyme fromAlcaligenessp. 4HAP has been crystallized in a form that diffracts synchrotron radiation to a resolution of 2.2 Å.

Electrocatalysis of formic acid on palladium and platinum surfaces: from fundamental mechanisms to fuel cell applications

2014 ◽  
Vol 16 (38) ◽  
pp. 20360-20376 ◽  
Author(s):  
Kun Jiang ◽  
Han-Xuan Zhang ◽  
Shouzhong Zou ◽  
Wen-Bin Cai
Keyword(s):  
Fuel Cell ◽  
Formic Acid ◽  
Recent Progress ◽  
Formic Acid Oxidation ◽  
Acid Oxidation ◽  
Mechanistic Studies ◽  
Practical Applications ◽  
Platinum Surfaces ◽  
Formic Acid Fuel Cells ◽  
Oxidation Synthesis

A brief overview is presented on recent progress in mechanistic studies of formic acid oxidation, synthesis of novel Pd- and Pt-based nanocatalysts and their practical applications in direct formic acid fuel cells.

scholarly journals Controlling Non-Native B12 Reactivity and Catalysis in the Transcription Factor CarH

2021 ◽  
Author(s):  
Xinhang Yang ◽  
Benjamin H. R. Gerroll ◽  
Yuhua Jiang ◽  
Amardeep Kumar ◽  
Yasmine S. Zubi ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Vitamin B12 ◽  
Transcription Regulation ◽  
Bond Cleavage ◽  
Oxidative Addition ◽  
Mechanistic Studies ◽  
Organic Transformations ◽  
Carbon Bond ◽  
Wide Range ◽  
Hydride Elimination

Vitamin B12 derivatives catalyze a wide range of organic transformations, but B12-dependent enzymes are underutilized in biocatalysis relative to other metalloenzymes. In this study, we engineered a variant of the transcription factor CarH, called CarH*, that catalyzes styrene C-H alkylation with improved yield and selectivity relative to B12 itself. While the native function of CarH involves transcription regulation via AdoCbl Co(III)-carbon bond cleavage and β-hydride elimination to generate 4’,5’-didehydroadenosine, CarH*-catalyzed styrene alkylation proceeds via non-native oxidative addition and olefin addition coupled with a native-like β-hydride elimination. Mechanistic studies on this reaction echo findings from earlier studies on AdoCbl homolysis under strong cage conditions to suggest that CarH* can enable non-native radical chemistry with improved selectivity relative to B12 itself. These findings lay the groundwork for the development of B12-dependent enzymes as catalysts for a wide range of non-native transformations.

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