scholarly journals New Nystatin-Related Antifungal Polyene Macrolides with Altered Polyol Region Generated via Biosynthetic Engineering of Streptomyces noursei

2011 ◽  
Vol 77 (18) ◽  
pp. 6636-6643 ◽  
Author(s):  
Trygve Brautaset ◽  
Håvard Sletta ◽  
Kristin F. Degnes ◽  
Olga N. Sekurova ◽  
Ingrid Bakke ◽  
...  
Keyword(s):  
Polyketide Synthase ◽  
Fungal Infections ◽  
Therapeutic Index ◽  
Hydroxyl Group ◽  
Hydroxyl Groups ◽  
Marginal Effect ◽  
P450 Monooxygenase ◽  
Polyene Macrolides ◽  
Biosynthetic Engineering

ABSTRACTPolyene macrolide antibiotics, including nystatin and amphotericin B, possess fungicidal activity and are being used as antifungal agents to treat both superficial and invasive fungal infections. Due to their toxicity, however, their clinical applications are relatively limited, and new-generation polyene macrolides with an improved therapeutic index are highly desirable. We subjected the polyol region of the heptaene nystatin analogue S44HP to biosynthetic engineering designed to remove and introduce hydroxyl groups in the C-9-C-10 region. This modification strategy involved inactivation of the P450 monooxygenase NysL and the dehydratase domain in module 15 (DH15) of the nystatin polyketide synthase. Subsequently, these modifications were combined with replacement of the exocyclic C-16 carboxyl with the methyl group through inactivation of the P450 monooxygenase NysN. Four new polyene macrolides with up to three chemical modifications were generated, produced at relatively high yields (up to 0.51 g/liter), purified, structurally characterized, and subjected toin vitroassays for antifungal and hemolytic activities. Introduction of a C-9 hydroxyl by DH15 inactivation also blocked NysL-catalyzed C-10 hydroxylation, and these modifications caused a drastic decrease in both antifungal and hemolytic activities of the resulting analogues. In contrast, single removal of the C-10 hydroxyl group by NysL inactivation had only a marginal effect on these activities. Results from the extended antifungal assays strongly suggested that the 9-hydroxy-10-deoxy S44HP analogues became fungistatic rather than fungicidal antibiotics.

scholarly journals Enhancement of Antioxidant and Hydrophobic Properties of Alginate via Aromatic Derivatization: Preparation, Characterization, and Evaluation

Polymers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 2575
Author(s):  
Smaher M. Elbayomi ◽  
Haili Wang ◽  
Tamer M. Tamer ◽  
Yezi You
Keyword(s):  
Radical Scavenging Activity ◽  
Radical Scavenging ◽  
Hydroxyl Group ◽  
Hydroxyl Groups ◽  
Gravimetric Analysis ◽  
Scanning Calorimetry ◽  
Benzoyl Group ◽  
Antioxidant Evaluation ◽  
Thermo Stability

The preparation of bioactive polymeric molecules requires the attention of scientists as it has a potential function in biomedical applications. In the current study, functional substitution of alginate with a benzoyl group was prepared via coupling its hydroxyl group with benzoyl chloride. Fourier transform infrared spectroscopy indicated the characteristic peaks of aromatic C=C in alginate derivative at 1431 cm−1. HNMR analysis demonstrated the aromatic protons at 7.5 ppm assigned to benzoyl groups attached to alginate hydroxyl groups. Wetting analysis showed a decrease in hydrophilicity in the new alginate derivative. Differential scanning calorimetry and thermal gravimetric analysis showed that the designed aromatic alginate derivative demonstrated higher thermo-stability than alginates. The aromatic alginate derivative displayed high anti-inflammatory properties compared to alginate. Finally, the in vitro antioxidant evaluation of the aromatic alginate derivative showed a significant increase in free radical scavenging activity compared to neat alginate against DPPH (2,2-diphenyll-picrylhydrazyl) and ABTS free radicals. The obtained results proposed that the new alginate derivative could be employed for gene and drug delivery applications.

scholarly journals Chemical and biochemical studies on 18-hydroxyoestrone

1974 ◽  
Vol 137 (2) ◽  
pp. 263-272 ◽  
Author(s):  
John K. Findlay ◽  
Lothar Siekmann ◽  
Heinz Breuer
Keyword(s):  
Mass Spectra ◽  
Strong Acid ◽  
Hydroxyl Group ◽  
Hydroxyl Groups ◽  
No Formation ◽  
Polar Metabolites ◽  
Characteristic Fragmentation ◽  
Liquid Chromatographic

1. 18-Hydroxyoestrone was reduced by NaBH4 in methanol, giving 18-hydroxyoestradiol-17α and 18-hydroxyoestradiol-17β in the ratio 3:7. 2. Treatment of 18-hydroxyoestrone with a strong alkali yielded 18-noroestrone; however, the 18-hydroxyoestradiols did not undergo transformation to their respective 18-nor derivatives. 3. All the 18-hydroxylated oestrogens were stable under acid conditions. They formed Kober chromogens: the chromogenicity of 18-hydroxyoestrone was only one-third that of the 18-hydroxyoestradiols and oestriol. 4. Paper-, thin-layer- and gas–liquid-chromatographic systems for the characterization of these compounds are described. 5. An examination of the mass spectra revealed peaks characteristic of the substituted carbon atoms. Definite assignment of the 17α- and 17β-hydroxyl groups of the epimeric 18-hydroxyoestrogens was possible by characteristic fragmentation of the free steroids. Further, the configuration of 18-hydroxyoestradiol-17β was confirmed by the formation of the dimethylsildioxy derivative of the 3-methylether of the steroid. 6. Both rat and rabbit liver slices reduced 18-hydroxyoestrone to 18-hydroxyoestradiol-17β and some other labile, polar metabolites with properties similar to 2-hydroxylated oestrogens. No formation of 18-hydroxyoestradiol-17α in vitro was observed. 7. The results are discussed with respect to the possible influence of the 18-hydroxyl group on reactions at C-17, as well as the reactions of 18-hydroxylated oestrogens with strong acid (Kober reactions) and alkali.

scholarly journals Complete Reconstitution and Deorphanization of the 3 MDa NOCAP (NOCardiosis-Associated Polyketide) Synthase

2020 ◽  
Author(s):  
Kai P. Yuet ◽  
Corey W. Liu ◽  
Stephen R. Lynch ◽  
James Kuo ◽  
Wesley Michaels ◽  
...  
Keyword(s):  
Structure Elucidation ◽  
Assembly Line ◽  
Polyketide Synthase ◽  
Spectroscopic Analysis ◽  
Hydroxyl Group ◽  
E Coli ◽  
Life Threatening ◽  
Tailoring Enzymes ◽  
Protein Components

ABSTRACTSeveral Nocardia strains associated with nocardiosis, a potentially life-threatening disease, house a nonamodular assembly-line polyketide synthase (PKS) that presumably synthesizes an unknown natural product. Here, we report the discovery and structure elucidation of the NOCAP (NOCardiosis-Associated Polyketide) aglycone by first fully reconstituting the NOCAP synthase in vitro from purified protein components followed by heterologous expression in E. coli and spectroscopic analysis of the purified products. The NOCAP aglycone has an unprecedented structure comprised of a substituted resorcylaldehyde headgroup linked to a 15-carbon tail that harbors two conjugated all-trans trienes separated by a stereogenic hydroxyl group. This report is the first example of reconstituting a trans-acyltransferase assembly-line PKS either in vitro or in E. coli, and of using these approaches to “deorphanize” a complete assembly-line PKS identified via genomic sequencing. With the NOCAP aglycone in hand, the stage is set for understanding how this PKS and associated tailoring enzymes confer an advantage to their native hosts during human Nocardia infections.

scholarly journals Bioapplications of Bacterial Cellulose Polymers Conjugated with Resveratrol for Epithelial Defect Regeneration

Polymers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 1048 ◽  
Author(s):  
En Meng ◽  
Chin-Li Chen ◽  
Chuan-Chieh Liu ◽  
Cheng-Che Liu ◽  
Shu-Jen Chang ◽  
...  
Keyword(s):  
Mechanical Strength ◽  
Bacterial Cellulose ◽  
Wound Repair ◽  
Cell Attachment ◽  
Skin Irritation ◽  
Hydroxyl Group ◽  
Hydroxyl Groups ◽  
Skin Substitutes ◽  
Epithelial Regeneration

Excellent wound dressing is essential for effective wound repair and regeneration. However, natural polymeric skin substitutes often lack mechanical strength and hydrophilicity. One way to overcome this limitation is to use biodegradable polymers with high mechanical strength and low skin-irritation induction in wet environments. Bacterial cellulose (BC) is an attractive polymer for medical applications; unlike synthetic polymers, it is biodegradable and renewable and has a strong affinity for materials containing hydroxyl groups. Therefore, we conjugated it with resveratrol (RSV), which has a 4′-hydroxyl group and exhibits good biocompatibility and no cytotoxicity. We synthesized BC scaffolds with immobilized RSV and characterized the resulting BC/RSV scaffold with scanning electron microscopy and Fourier-transform infrared spectroscopy. We found that RSV was released from the BC in vitro after ~10 min, and immunofluorescence staining showed that BC was highly biocompatible and regenerated epithelia. Additionally, Masson’s trichrome staining showed that the scaffolds preserved the normal collagen-bundling pattern and induced re-epithelialization in defective rat epidermis. These results indicated that RSV-conjugated BC created a biocompatible environment for stem cell attachment and growth and promoted epithelial regeneration during wound healing.

scholarly journals Metabolism of apigenin and related compounds in the rat. Metabolite formation in vivo and by the intestinal microflora in vitro

1972 ◽  
Vol 128 (4) ◽  
pp. 901-911 ◽  
Author(s):  
L. A. Griffiths ◽  
G. E. Smith
Keyword(s):  
Oral Administration ◽  
Intestinal Microflora ◽  
Biochanin A ◽  
Hydroxyl Group ◽  
Hydroxyl Groups ◽  
Flavonoid Compounds ◽  
Ring Fission ◽  
Micro Organisms

1. The metabolism of a group of flavonoid compounds related in structure to apigenin (4′,5,7-trihydroxyflavone) and including apigenin, apiin, naringin, phlorrhizin, acacetin, kaempferol, robinin, chrysin, tectochrysin and 4′,7-dihydroxyflavone, was studied both in vivo after oral administration to the rat, and in vitro in cultures of micro-organisms derived from the intestine of the rat. 2. The rat intestinal microflora is capable of effecting degradation of flavonoid compounds to metabolites observed in the urine after oral administration of the specific flavonoid. 3. All compounds possessing free 5- and 7-hydroxyl groups in the A ring and a free 4′-hydroxyl group in the B ring gave rise to ring-fission products, which included 4′-hydroxyphenylacyl derivatives. 4. On anaerobic incubation in a thioglycollate medium, intestinal micro-organisms can effect flavonoid-ring fission, cleavage of glycosidic bonds and the reduction of double bonds in the side chains of certain metabolites. 5. Two flavonoids (chrysin and tectochrysin) undergo hydroxylation in the 4′-position in vivo but not during incubation with the intestinal microflora in vitro. 6. Observations on the metabolism of other compounds substituted in the 4′-position, e.g. epiafzelechin, pelargonin and the isoflavones, genistein, biochanin A, daidzein and formononetin, by the intestinal microflora of the rat are also reported.

scholarly journals Phenolic Hydroxyl Groups in the Lignin Polymer Affect the Formation of Lignin Nanoparticles

Nanomaterials ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 1790
Author(s):  
Jae Hoon Lee ◽  
Tae Min Kim ◽  
In-Gyu Choi ◽  
Joon Weon Choi
Keyword(s):  
Solvent Extraction ◽  
Colloidal Stability ◽  
Molecular Size ◽  
Phenolic Hydroxyl ◽  
Hydroxyl Group ◽  
Hydroxyl Groups ◽  
Nanoprecipitation Method ◽  
Phenolic Hydroxyl Groups ◽  
Soda Lignin

Alkaline soda lignin (AL) was sequentially fractionated into six fractions of different molecular size by means of solvent extraction and their phenolic hydroxyl groups were chemoselectively methylated to determine their effect on nanoparticle formation of lignin polymers. The effect of the lignin structure on the physical properties of nanoparticles was also clarified in this study. Nanoparticles were obtained from neat alkaline soda lignin (ALNP), solvent-extracted fractions (FALNPs, i.d. 414–1214 nm), and methylated lignins (MALNPs, i.d. 516–721 nm) via the nanoprecipitation method. Specifically, the size properties of MALNPs showed a high negative correlation (R2 = 0.95) with the phenolic hydroxyl group amount. This indicates that the phenolic hydroxyl groups in lignin could be influenced on the nucleation or condensation during the nanoprecipitation process. Lignin nanoparticles exhibited high colloidal stability, and most of them also showed good in vitro cell viability. This study presents a possible way to control nanoparticle size by blocking specific functional groups and decreasing the interaction between hydroxyl groups of lignin.

scholarly journals Carrier effects on biological activity of amphotericin B.

1996 ◽  
Vol 9 (4) ◽  
pp. 512-531 ◽  
Author(s):  
J Brajtburg ◽  
J Bolard
Keyword(s):  
Amphotericin B ◽  
Mammalian Cells ◽  
Fungal Infections ◽  
Therapeutic Index ◽  
Fungal Cell ◽  
Drug Of Choice ◽  
Higher Doses ◽  
Lipid Formulations

Amphotericin B (AmB), the drug of choice for the treatment of most systemic fungal infections, is marketed under the trademark Fungizone, as an AmB-deoxycholate complex suitable for intravenous administration. The association between AmB and deoxycholate is relatively weak; therefore, dissociation occurs in the blood. The drug itself interacts with both mammalian and fungal cell membranes to damage cells, but the greater susceptibility of fungal cells to its effects forms the basis for its clinical usefulness. The ability of the drug to form stable complexes with lipids has allowed the development of new formulations of AmB based on this property. Several lipid-based formulations of the drug which are more selective in damaging fungal or parasitic cells than mammalian cells and some of which also have a better therapeutic index than Fungizone have been developed. In vitro investigations have led to the conclusion that the increase in selectivity observed is due to the selective transfer of AmB from lipid complexes to fungal cells or to the higher thermodynamic stability of lipid formulations. Association with lipids modulates AmB binding to lipoproteins in vivo, thus influencing tissue distribution and toxicity. For example, lipid complexes of AmB can be internalized by macrophages, and the macrophages then serve as a reservoir for the drug. Furthermore, stable AmB-lipid complexes are much less toxic to the host than Fungizone and can therefore be administered in higher doses. Experimentally, the efficacy of AmB-lipid formulations compared with Fungizone depends on the animal model used. Improved therapeutic indices for AmB-lipid formations have been demonstrated in clinical trials, but the definitive trials leading to the selection of an optimal formulation and therapeutic regimen have not been done.

scholarly journals Tailoring the component of protein corona via simple chemistry

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Xiang Lu ◽  
Peipei Xu ◽  
Hong-Ming Ding ◽  
You-Sheng Yu ◽  
Da Huo ◽  
...  
Keyword(s):  
Surface Properties ◽  
Blood Circulation ◽  
Molecular Simulations ◽  
Protein Corona ◽  
Hydroxyl Group ◽  
Hydroxyl Groups ◽  
Surface Hydroxyl ◽  
Surface Hydroxyl Groups ◽  
In Vitro Measurements

Abstract Control over the protein corona of nanomaterials allows them to function better. Here, by taking graphene/gold as examples, we comprehensively assessed the association of surface properties with the protein corona. As revealed by in vitro measurements and computations, the interaction between graphene/gold and HSA/IgE was inversely correlated with the hydroxyl group availability, whereas the interaction between that and ApoE was comparatively less relevant. Molecular simulations revealed that the number and the distribution of surface hydroxyl groups could regulate the manner in which nanomaterials interact with proteins. Moreover, we validated that ApoE pre-adsorption before injection enhances the blood circulation of nanomaterials relative to their pristine and IgE-coated counterparts. This benefit can be attributed to the invulnerability of the complementary system provided by ApoE, whose encasement does not increase cytotoxicity. Overall, this study offers a robust yet simple way to create protein corona enriched in dysopsonins to realize better delivery efficacy.

scholarly journals Regulation of the Bacillus subtilis Divergent yetL and yetM Genes by a Transcriptional Repressor, YetL, in Response to Flavonoids

2009 ◽  
Vol 191 (11) ◽  
pp. 3685-3697 ◽  
Author(s):  
Kazutake Hirooka ◽  
Yusuke Danjo ◽  
Yuki Hanano ◽  
Satoshi Kunikane ◽  
Hiroshi Matsuoka ◽  
...  
Keyword(s):  
Bacillus Subtilis ◽  
Hydroxyl Group ◽  
Hydroxyl Groups ◽  
Promoter Regions ◽  
Gene Encoding ◽  
Gel Retardation ◽  
Dnase I Footprinting ◽  
Shine Dalgarno Sequence

ABSTRACT DNA microarray analysis revealed that transcription of the Bacillus subtilis yetM gene encoding a putative flavin adenine dinucleotide-dependent monooxygenase was triggered by certain flavonoids during culture and was derepressed by disruption of the yetL gene in the opposite orientation situated immediately upstream of yetM, which encodes a putative MarR family transcriptional regulator. In vitro analyses, including DNase I footprinting and gel retardation analysis, indicated that YetL binds specifically to corresponding single sites in the divergent yetL and yetM promoter regions, with higher affinity to the yetM region; the former region overlaps the Shine-Dalgarno sequence of yetL, and the latter region contains a perfect 18-bp palindromic sequence (TAGTTAGGCGCCTAACTA). In vitro gel retardation and in vivo lacZ fusion analyses indicated that some flavonoids (kaempferol, apigenin, and luteolin) effectively inhibit YetL binding to the yetM cis sequence, but quercetin, galangin, and chrysin do not inhibit this binding, implying that the 4-hydroxyl group on the B-ring of the flavone structure is indispensable for this inhibition and that the coexistence of the 3-hydroxyl groups on the B- and C-rings does not allow antagonism of YetL.

scholarly journals ANTI-COAGULANT PROPERTIES OF FLAVONOID COMPOUNDS: POTENTIAL STRUCTURE-FUNCTIONAL RELATIONSHIP

2021 ◽  
pp. 9-12
Author(s):  
PHISIT POUYFUNG ◽  
SURIYAN SUKATI
Keyword(s):  
Fruits And Vegetables ◽  
Hydroxyl Group ◽  
Hydroxyl Groups ◽  
Flavonoid Compounds ◽  
Naturally Occurring ◽  
Prolonged Aptt ◽  
Potential Structure ◽  
Risk Patients ◽  
Vegetables And Fruits

Objective: Flavonoids, naturally-occurring compounds in fruits and vegetables, possess anti-coagulant property. However, a very few studies wereattempted to understand how flavonoid structure influences its anti-coagulation property, such as clotting time. In this study, we investigatedstructurally similar flavonoid compounds which differ in the number of hydroxyl groups and compared their anti-coagulation properties.Methods: We selected and evaluated five flavonoid compounds, that is, chrysin, apigenin, luteolin, kaempferol, and quercetin, for their anti-coagulantproperties using in vitro prothrombin time (PT) assays and activated partial thromboplastin time (APTT) assay.Results: Our findings suggested that quercetin, kaempferol, and luteolin showed a significant anti-coagulant effect on APTT (p<0.05) in a dosedependentmanner. The dose of 500 μM quercetin showed potent prolong APTT with 37.43±1.60 s, followed by 500 μM of kaempferol and luteolin(34.63±1.29 s and 4.83±1.56 s, respectively). Furthermore, a combination of 500 μM of quercetin with 0.25 U/ml of heparin demonstrated prolongAPTT (52.16±5.18 s) when compared with individual effects of either 0.25 U/ml heparin (33.4±0.50 s) or 500 μM quercetin (37.43±1.62 s) alone.Conclusion: Our results demonstrated that numbers of the hydroxyl group on flavonoid compounds influence anti-coagulation properties. Inaddition, the prolonged APTT assay results suggested that quercetin, kaempferol, and luteolin could affect factors VIII, IX, XI, and XII of intrinsicpathway. Moreover, the synergistic effect of quercetin further enhances the heparin anti-coagulation effect. Based on our findings, we recommendthat the consumption of vegetables and fruits rich in quercetin, luteolin, and kaempferol could help prevent thrombotic stroke in high-risk patients.

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