Additional Hydroxy Group Research Articles

Octanuclear Zinc Clusters in Microporous Organic Polymers: Network-Enhanced Reductive CO2 Fixation to Formamides at Room Temperature.

A building block containing eight zincs and eight iodo groups (8Zn) is obtained by the Zn complexation of a salen ligand bearing two additional hydroxy groups. Through the Sonogashira-Hagihara coupling of 8Zn with 1,3,5,7-tetra(4-ethynylphenyl) adamantane, microporous organic polymers bearing octanuclear zinc clusters (MOP-8Zn) are prepared, exhibiting a high surface area of 562 m2g-1, microporosity, and a particulate morphology with an average diameter of 249nm. The MOP-8Zn exhibits significantly enhanced catalytic performance, compared to molecular counterparts, in the reductive carbon dioxide fixation to formamides, possibly due to the cooperative adsorption and confinement effect of networks on substrates.

Evaluation of the binding efficacy of flavonol derivatives on estrogen receptors (ER) with respect to ring B hydroxylation

RationaleFlavonols are a class of flavonoids, consist of two aromatic rings (A and B) connected by a three-carbon bridge, forming a closed pyran ring (C) with a hydroxyl group at position 3. Galangin is a form of flavonols formed with additional hydroxyl groups at ring A positions 5 and 7. The hydroxylation at ring B of galangin may result in resonance and delocalization of electrons and the formation of different derivatives like kaempferol, quercetin, and myricetin. Most of these flavonols have a similarity to 17β-estradiol, the steroid sex hormone which bound to estrogen receptors (ER), a class of nuclear transcription factors involved in the regulation of many complex pathophysiological processes including breast cancer genesis and progression. Various studies have reported that most of the flavonols are antiestrogenic and show anticancer potential, but the mechanisms may be varied like estrogenic, anti-estrogenic, non-estrogenic, and biphasic activities and their mechanisms of action have not been systematically evaluated. AimThe goal of this study is to ascertain the possible interactions of flavonol derivatives to ER with respect to ring B hydroxylation and the unsaturation degree of the C2′=C3′ bond. MethodsThe variations in structure, frontier molecular orbital, molecular electrostatic potential maps, Mullikan charge population of derivatives was determined by Density functional theory (DFT) calculations at B3LYP/6-311G (d,p) level on model molecular systems. A deep insight into these interactions with ER was described by molecular docking studies. Results and discussionResults shows that the flavonol was found more affinity to ERβ and the efficacy was increased with respect to the OH group on ring B. The hydroxyl group at position 3 and 5 in ring A and C are not found much relevant. The site of ERβ is more hydrophilic while binding ligand and the electropositive and electronegative area of the molecule was increased and reaches a maximum for quercetin with the 3 OH group; after that, it found to diminish. Moreover, the reduced cavity size of ERβ and the replacement of LEU384 with polar HIE475 and MET336 increased the polarity and hydrophilicity of the cavity and led to more electrostatic interaction with ligands. ERα is found to be hydrophobic and the polar interaction between the ligands and ERα is less due to open confirmation of the cavity and bulk empty space. The results also emphasize that myricetin and quercetin require less energy to activate while accounting for the values of Gibbs free energy, the electronic configuration of frontier molecular orbitals, and entropy. ConclusionThe hydroxylation on ring B has a significant importance in the chemical reactivity as well as estrogenic activity of flavonol.

Interfacial adsorption mechanism of hydroxycinnamic acids on iron surfaces: A computational perspective toward eco-friendly corrosion mitigation strategies

Corrosion remains a critical global concern with substantial financial and infrastructural implications. Herein, an in-depth computational exploration of four hydroxycinnamic acids-(HCAs), namely p-coumaric acid-(CMA), caffeic acid-(CFA), ferulic acid-(FRA), and sinapic acid-(SPA) was conducted. Using SCC-DFTB, MD simulation, and quantum chemical calculations, structural and electronic properties of biomolecules and their interactions with iron surfaces were probed. The SCC-DFTB simulations revealed a pronounced tendency of HCAs to form coordination bonds with iron atoms, facilitated by significant hybridization between the orbitals of HCAs and the unoccupied d-orbitals of iron, as evidenced from the projected density of states analysis. Interestingly, SPA, enhanced by its methoxy groups, displayed the highest negative interaction energy (-2.874 eV), followed by FRA (-2.108 eV), CFA (-1.527 eV), and CMA (-1.058 eV). Consistently, MD simulations validated these findings, demonstrating similar adsorption trends for HCAs under aqueous and vacuum conditions. Further quantum chemical analysis, focusing on global and local reactivity descriptors, provided additional insights into the reactivity, stability, and potential interaction sites of the HCAs. It affirmed that additional hydroxy and methoxy functional groups strongly influenced the reactivity of SPA, FRA, and CFA compared to CMA. These insights highlight potential pathways for addressing material corrosion from an atomic and molecular standpoint.

4‐Hydroxy Enigmol, a 1‐Deoxyphytosphingolipid that Exhibit Good Activity against Prostate and Colon Cancer

AbstractIn the present work, 4‐hydroxy enigmol (1), an analogue of enigmol which is a known orally bioavailable 1‐deoxysphingolipid, effective against multiple cancer cell lines, has been synthesized with an additional hydroxy group for improved anti‐cancer activity. The additional group in compound (1) is likely to show enhanced activity due to improved cell permeability and hydrophilicity. The key steps involved are stereoselective cross metathesis reaction and OsO4/NMO mediated dihydroxylation. Further, analogues of 4‐hydroxy enigmol (1) with varying chain lengths (2, 3) have also been synthesized using the same synthetic strategy for varying hydrophobicity as an additional structural feature. To support the genesis in the design of compound (1–3), the pharmacokinetic studies and docking analysis has been done for calculating the polar surface area, binding affinity and hydrophobicity/hydrophilicity. The preliminary in‐vitro cytotoxicity on cancer cell lines displayed promising activity against the PC‐3 cell lines and HCT‐116 cell lines.

Stereoselective Synthesis and Antiproliferative Activities of Tetrafunctional Diterpene Steviol Derivatives.

A new family of diterpene-type aminotriol derivatives has been synthesised from stevioside in a stereoselective manner. The key intermediate spiro-epoxide was prepared through the methyl ester of the allilyc diol derived from steviol. The oxirane ring was opened with primary and secondary amines, providing a versatile library of aminotriols. The corresponding primary aminotriol was formed by palladium-catalysed hydrogenation, and an N,O-heterocyclic compound was synthesised in a regioselective reaction. All new compounds were characterised by 1D- and 2D-NMR techniques and HRMS measurements. In our in vitro investigations, we found that the aromatic N-substituted derivatives exhibited high inhibition of cell growth on human cancer cell lines (HeLa, SiHa, A2780, MCF-7 and MDA-MB-231). The antiproliferative activities were assayed by the MTT method. Furthermore, the introduction of an additional hydroxy group slightly increased the biological activity. The drug-likeness of the compounds was assessed by in silico and experimental physicochemical characterisations, completed by kinetic aqueous solubility and in vitro intestinal-specific parallel artificial membrane permeability assay (PAMPA-GI) measurements.

Role of reactive oxygen species in regulating 27-hydroxycholesterol-induced apoptosis of hematopoietic progenitor cells and myeloid cell lines

Oxysterols are oxygenated derivatives of cholesterol that contain an additional hydroxy, epoxide, or ketone group in the sterol nucleus and/or a hydroxyl group in the side chain of the cholesterol molecule. 27-Hydroxycholesterol (27HC) is a side-chain oxysterol that is oxygenated at the 27th carbon atom of cholesterol. The oxysterol (27HC) is produced via oxidation by sterol 27-hydroxylase (CYP27A1) and metabolized via oxysterol 7a-hydroxylase (CYP7B1) for bile acid synthesis in the liver. A previous study has demonstrated that treatment with the alternative Estrogen receptor alpha (ERα) ligand 27HC induces ERα-dependent hematopoietic stem cell (HSC) mobilization. In addition, Cyp27a1-deficient mice demonstrate significantly reduced 27HC levels and HSC mobilization. Here, we report that exogenous 27HC treatment leads to a substantial reduction in the hematopoietic stem and progenitor cell (HSPC) population owing to significantly increased reactive oxygen species (ROS) levels and apoptosis in the bone marrow (BM). However, 27HC does not influence the population of mature hematopoietic cells in the BM. Furthermore, exogenous 27HC treatment suppresses cell growth and promotes ROS production and apoptosis in leukemic cells. Moreover, acute myeloid leukemia (AML) patients with high CYP7B1 expression (expected to have inhibition of 27HC) had significantly shorter survival than those with low CYP7B1 expression (expected to have an elevation of 27HC). Single-cell RNA-sequencing (scRNA seq) analysis revealed that the expression of CYP7B1 was significantly increased in AML patients. Thus, our study suggests that 27HC may serve as a potent agent for regulating pools of HSPCs and may have an application as a novel therapeutic target for hematological malignancies. Collectively, pharmacological inhibition of CYP7B1 (expected to have an elevation of 27HC) would potentially have fewer long-term hematological side effects, particularly when used in combination with chemotherapy or radiation for the treatment of leukemia patients.

Excited state deactivation mechanisms in Shikonin rationalized from its naphthoquinone parent structures.

Shikonin, a naphthoquinone dye, is a molecule of colour of natural origin, whose peculiar properties have not yet been fully rationalized. Its core structure consists of a di-hydroxy-naphthoquinone with an additional non-aromatic hydroxy group. From a comprehensive study involving fast spectroscopic techniques (fs-TA and fs-UC) and TDDFT electronic structure calculations on shikonin (Shk) and its derivatives 5-hydroxy-1,4-naphthoquinone (5HNQ), 5,8-diacetoxy-1,4-naphthoquinone (DiAc), 5,8-dihidroxy-1,4-naphthoquinone (DHNQ) and acetylshikonin, AcShk, it is shown that intramolecular excited state proton transfer (ESIPT) is present and is determinant in the deactivation of the hydroxy containing molecules. This is mirrored by the dominance of the internal conversion deactivation channel. In Shk, the non-aromatic hydroxy group determines the preferred conformer in both the ground- and excited-state, as reflected in the doubling of the fluorescence quantum yield value of this molecule relative to DHNQ. From fs-UC, a kinetic isotopic effect of 1.7 was obtained for DHNQ.

The Cerebrospinal Fluid Profile of Cholesterol Metabolites in Parkinson's Disease and Their Association With Disease State and Clinical Features.

Disordered cholesterol metabolism is linked to neurodegeneration. In this study we investigated the profile of cholesterol metabolites found in the cerebrospinal fluid (CSF) of Parkinson’s disease (PD) patients. When adjustments were made for confounding variables of age and sex, 7α,(25R)26-dihydroxycholesterol and a second oxysterol 7α,x,y-trihydroxycholest-4-en-3-one (7α,x,y-triHCO), whose exact structure is unknown, were found to be significantly elevated in PD CSF. The likely location of the additional hydroxy groups on the second oxysterol are on the sterol side-chain. We found that CSF 7α-hydroxycholesterol levels correlated positively with depression in PD patients, while two presumptively identified cholestenoic acids correlated negatively with depression.

Synthesis of acyclic and cyclic phosphonates based on substituted 2-hydroxybenzylic alcohols

A convenient synthesis of benzylic phosphonates and 2,3-dihydrobenzo[d][1,2]oxaphosphole 2-oxides substituted at the aromatic ring, as well as their precursors, 2-hydroxybenzylic alcohols, from the derivatives of salicylic aldehyde, salicylic acid, and 2-hydroxyacetophenone bearing an additional hydroxy or methoxy group at the para position of the aromatic ring was developed. For the first time, the possibility of selective demethylation of the methoxy group positioned ortho to the methylene phosphonate fragment with retention of the methoxy group at the para position was shown.

Structural bases of IMiD selectivity that emerges by 5-hydroxythalidomide

Thalidomide and its derivatives exert not only therapeutic effects as immunomodulatory drugs (IMiDs) but also adverse effects such as teratogenicity, which are due in part to different C2H2 zinc-finger (ZF) transcription factors, IKZF1 (or IKZF3) and SALL4, respectively. Here, we report the structural bases for the SALL4-specific proteasomal degradation induced by 5-hydroxythalidomide, a primary thalidomide metabolite generated by the enzymatic activity of cytochrome P450 isozymes, through the interaction with cereblon (CRBN). The crystal structure of the metabolite-mediated human SALL4-CRBN complex and mutagenesis studies elucidate the complex formation enhanced by the interaction between CRBN and an additional hydroxy group of (S)-5-hydroxythalidomide and the variation in the second residue of β-hairpin structure that underlies the C2H2 ZF-type neo-morphic substrate (neosubstrate) selectivity of 5-hydroxythalidomide. These findings deepen our understanding of the pharmaceutical action of IMiDs and provide structural evidence that the glue-type E3 ligase modulators cause altered neosubstrate specificities through their metabolism.

In vitro C132-dealkoxycarbonylations of zinc chlorophyll a derivatives including C132-substitutes by a BciC enzyme

Chlorosomes in the green photosynthetic bacteria are the largest and most efficient light-harvesting antenna systems of all phototrophs. The core part of chlorosomes consists of bacteriochlorophyll c, d, e, or f molecules. In their biosynthetic pathway, a BciC enzyme catalyzes the removal of the C132-methoxycarbonyl group of chlorophyllide a. In this study, in vitro C132-dealkoxycarbonylations of zinc chlorophyll a derivatives bearing a methyl-, ethyl- or propyl-esterifying group and its methyl ester analogs with additional alkyl and hydroxy groups at the C132-position were examined using the BciC enzyme. The BciC-catalyzed reaction activity for the C132-methoxycarbonylated substrate was comparable to that for the ethoxycarbonylated compound; however, depropoxycarbonylation did not proceed. The BciC enzymatic demethoxycarbonylation of zinc methyl C132-alkylated pheophorbides a was gradually suppressed with the elongation of the alkyl chain and finally became inactive for the propyl substrate. The reaction of the C132-hydroxylated substrate (allomer) was accelerated compared to that of the C132-methyl analog possessing a similar steric size, and gave the corresponding C132-oxo product via further air-oxidation. All of the abovementioned enzymatic reactions occurred for one of the C132-epimers with the same configuration as in chlorophyllide a. The above substrate specificities and product distributions indicated the stereochemistry and size of the BciC enzymatic active site (pocket).

Effect of additional hydroxy group on self-aggregation of synthetic zinc bacteriochlorophyll-c analogs

Zinc methyl 3-hydroxymethyl-pyropheophorbides-a possessing a hydroxymethyl or 2-hydroxyethyl group at the 20-position were prepared by chemical modification of naturally occurring chlorophyll-a. The synthetic bacterio-chlorophyll-c analog bearing the 201-hydroxy group self-aggregated in an aqueous Triton X-100 micellar solution to give large oligomers with red-shifted and broadened electronic absorption bands, which was similar to the chlorophyllous J-aggregates in the main light-harvesting antennas of green photosynthetic bacteria. By contrast, the other 202-hydroxylated analog did not aggregate under the same conditions to remain its monomeric species. The red shift in the longest wavelength (Qy) band by the self-aggregation of the former analog was greater than that of the corresponding 201-methyl substitute with a similar size (CH3 ≈ OH). These results could be ascribable to the less sterically demanding and more electron-withdrawing 20-hydroxymethyl group, compared with more interacting 2-hydroxyethyl and more electron-donating ethyl groups at the 20-position.

Membrane properties of hydroxycholesterols related to the brain cholesterol metabolism.

Compared to cholesterol, hydroxycholesterols contain an additional hydroxy group in the alkyl chain and are able to efficiently cross the brain–blood barrier. Therefore, they are responsible for the sterol transfer between brain and circulation. The current study compares the membrane properties of several hydroxycholesterols with those of cholesterol using 2H NMR spectroscopy, a membrane permeability assay, and fluorescence microscopy experiments. It is shown that hydroxycholesterols do not exert the unique impact on membrane properties characteristic for cholesterol with regard to the influence on lipid chain order, membrane permeability and formation of lateral domains.

Pleospdione, A Tricyclic Natural Product with Dense Oxygenation at the A-Ring: Total Synthesis and Incongruity of the Originally Assigned Structure and its C3-Epimer

Abstract Previously we developed a promising synthetic approach to complex polycyclic natural products, including aromatic polyketides derived from the type-II polyketide biosynthesis. The approach consists of three key steps; (1) cycloaddition or cyclocondensation of nitrile oxide for assembling the carbon skeleton having an isoxazole as a 1,3-diketone equivalent, (2) benzoin cyclization for stereoselective ring fusion with an angular hydroxy group, and (3) oxidation of isoxazolium salt for installing an additional angular hydroxy group in stereoselective manner. As a synthetic exercise to highlight the utility of this approach, the first total syntheses of the proposed structure of pleospdione (1) and its C3-epimer (3-epi-1) have been achieved. The synthesis has proved the efficiency of the strategy as an entry into polyketide-derived complex architectures. At the same time, it was revealed that neither 1 nor 3-epi-1 represent the true structure of the natural product by incongruity of the NMR spectra.

Role of polyol moiety of amphotericin B in ion channel formation and sterol selectivity in bilayer membrane

Amphotericin B (AmB) is a polyene macrolide antibiotic widely used to treat mycotic infections. In this paper, we focus on the role of the polyol moiety of AmB in sterol selectivity using 7-oxo-AmB, 7α-OH-AmB, and 7β-OH-AmB. The 7-OH analogs were prepared from 7-oxo-AmB. Their K+ flux activity in liposomes showed that introduction of an additional ketone or hydroxy group on the polyol moiety reduces the original activity. Conformational analyses of these derivatives indicated that intramolecular hydrogen-bonding network possibly influenced the conformational rigidity of the macrolactone ring, and stabilized the active conformation in the membrane. Additionally, the flexible polyol leads to destabilization of the whole macrolactone ring conformation, resulting in a loss of sterol selectivity.

Spirangien Derivatives from the Myxobacterium Sorangium cellulosum: Isolation, Structure Elucidation, and Biological Activity

AbstractIn addition to spirangiens A (1) and B (2), 11 new spirangiens have been isolated from the myxobacterium Sorangium cellulosum (strain So ce90). Spirangiens A and B consist of a polyketide backbone with a spiroketal core, 13 stereocenters, and a conjugated pentaene chromophore with a terminal carboxylic acid. The structures of the derivatives were elucidated on the basis of NMR and MS data. The stereochemistry was determined by 1D and 2D NMR experiments as well as by biosynthetic studies. Four derivatives 6–9 differ in the cis/trans double‐bond geometry of the pentaene chromophore side‐chain and four of them (4–6 and 10) are characterized by the absence of methoxy groups. Derivative 13 does not exhibit the spiroketal core due to reduction of the acetalic carbonyl group. In addition, 11 and 12 exhibit the opposite configuration at C‐20 compared with the known spirangiens A and B. Derivative 3 contains an additional hydroxy group at the end of the side‐chain. All the new spirangien derivatives, as well as spirangiens A and B, were tested in cytotoxicity assays against two different cell lines and showed strong cytotoxic activity. Even though spirangien A was identified as the most cytotoxic compound, other derivatives, such as 3, 4, 6, and 10, showed significantly higher activity against the KB‐3‐1 cell line than against the nontransformed cells (L‐929).

Accumulation of novel glycolipids and ornithine lipids in Mesorhizobium loti under phosphate deprivation.

Glycolipids are found mainly in photosynthetic organisms (plants, algae, and cyanobacteria), Gram-positive bacteria, and a few other bacterial phyla. They serve as membrane lipids and play a role under phosphate deprivation as surrogates for phospholipids. Mesorhizobium loti accumulates different di- and triglycosyl diacylglycerols, synthesized by the processive glycosyltransferase Pgt-Ml, and two so far unknown glycolipids, which were identified in this study by mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy as O-methyl-digalactosyl diacylglycerol (Me-DGD) and glucuronosyl diacylglycerol (GlcAD). Me-DGD is a novel glycolipid, whose synthesis depends on Pgt-Ml activity and the involvement of an unknown methyltransferase, while GlcAD is formed by a novel glycosyltransferase encoded by the open reading frame (ORF) mlr2668, using UDP-glucuronic acid as a sugar donor. Deletion mutants lacking GlcAD are not impaired in growth. Our data suggest that the different glycolipids in Mesorhizobium can mutually replace each other. This may be an adaptation mechanism to enhance the competitiveness in natural environments. A further nonphospholipid in Mesorhizobium was identified as a hydroxylated form of an ornithine lipid with the additional hydroxy group linked to the amide-bound fatty acid, introduced by the hydroxylase OlsD. The presence of this lipid has not been reported for rhizobia yet. The hydroxy group is placed on the C-2 position of the acyl chain as determined by NMR spectroscopy. Furthermore, the isolated ornithine lipids contained up to 80 to 90% d-configured ornithine, a stereoform so far undescribed in bacteria.

Microbial transformations of halolactones with p-menthane system

Biologically active piperitone-derived racemic iodo-, bromo- and chlorolactones (1-3) were transformed with the use of microbial enzymatic systems. Four strains of filamentous fungi Absidia glauca AM254, Absidia cylindrospora AM336, Mortierella vinaceae AM149 and Nigrospora oryzae AM8 transformed halolactones (1-3) to four new halohydroxylactones (4-7). In all biotransformations the hydroxy group was incorporated in inactivated methine carbon atom at isopropyl substituent. In N. oryzae AM8 culture the bromolactone with additional hydroxy group in α-position, relative to CO bond in γ-lactone ring, was also formed as a product. The structures of new compounds were established on the basis of spectral data.

Structural characteristics that determine the inhibitory role of phenolic compounds on 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) formation

In an attempt to understand the structural characteristics of phenolic compounds that favour the inhibition of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) formation, this study analyzes the role of twenty-five phenolic compounds on the PhIP produced in phenylalanine/creatinine/oxidised lipid reaction mixtures. The results showed that phenols having two hydroxy groups at meta positions of the aromatic ring were the most efficient inhibitors. The presence of alkyl or carboxylic groups as additional substituents in the aromatic ring slightly reduced the inhibitory effect. On the other hand, the introduction of additional hydroxy and amino groups mostly cancelled the inhibitory effect, which was also mostly absent in ortho and para dihydroxy derivatives. In complex phenols, the presence of several rings with opposite effects produced a reduced inhibitory effect. All these results suggest that it is possible to predict if a phenolic derivative will inhibit the formation of PhIP, or not, based on its structure.

Synthesis of Hydroxylated Analogues of α‐Galactosyl Ceramide (KRN7000) with Varying Stereochemistry

AbstractThe synthesis of analogues of α‐galactosyl ceramide (KRN7000) with an additional hydroxy group in the phytosphingosine chains and with varying stereochemistry is described. Careful selection of glucose, galactose, mannose, and talose hexopyranoses allowed us to control the stereochemistry of some of the hydroxy groups in the sphingosine chain to give some interesting hydroxylated KRN7000 analogues.