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The five-membered 1,3,4-oxadiazole heterocyclic ring has received considerable attention because of its unique bio-isosteric properties and an unusually wide spectrum of biological activities. After a century since 1,3,4-oxadiazole was discovered, its uncommon potential attracted medicinal chemist's attention, leading to the discovery of a few presently accessible drugs containing 1,3,4-oxadiazole units, and a large number of patents have been granted on research related to 1,3,4-oxadiazole. It is worth noting that interest in 1,3,4-oxadiazoles' biological applications has doubled in the last few years. Herein, this review presents a comprehensive overview of the recent achievements in the synthesis of 1,3,4-oxadiazole-based compounds and highlights the major advances in their biological applications in the last 10 years, as well as brief remarks on prospects for further development. We hope that researchers across the scientific streams will benefit from the presented review articles for designing their work related to 1,3,4-oxadiazoles., (© 2024 John Wiley & Sons Ltd.)

Amyloid aggregation results from the self‐assembly of identical aggregation‐prone sequences into cross‐beta‐sheet structures. The process is best known for its association with a wide range of human pathologies but also as a functional mechanism in all kingdoms of life. Less well elucidated is the role of heterotypic interactions between amyloids and other proteins and macromolecules and how this contributes to disease. We here review current data with a focus on neurodegenerative amyloid‐associated diseases. Evidence indicates that heterotypic interactions occur in a wide range of amyloid processes and that these interactions modify fundamental aspects of amyloid aggregation including seeding, aggregation rates and toxicity. More work is required to understand the mechanistic origin of these interactions, but current understanding suggests that both supersaturation and sequence‐specific binding can contribute to heterotypic amyloid interactions. Further unravelling these mechanisms may help to answer outstanding questions in the field including the selective vulnerability of cells types and tissues and the stereotypical spreading patterns of amyloids in disease. [ABSTRACT FROM AUTHOR]

The objective of this study was to synthesize and coat a biocompatible polyvinylpyrrolidone polymer with pendent functional groups capable of forming triazole functionality onto surface of polyvinylchloride (PVC) and evaluate the modified surface. The coated surfaces were assessed with cell adhesion, bacterial adhesion and bacterial viability. Mouse fibroblast (NIH‐3 T3) cells and three bacteria species were used to assess surface adhesion and antibacterial activity. Results showed that the coated surface not only exhibited significantly reduced cell adhesion with a 65–85% decrease to 3 T3 fibroblast but also showed significantly reduced bacterial attachment with 52–76%, 45–66%, and 45–69% decrease to Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa, respectively, as compared to original PVC. Furthermore, the polymer‐coated PVC surface exhibited a significant antibacterial function by inhibiting bacterial growth with reduction of 77–90%, 55–87%, and 55–92% to S. aureus, E. coli, and P. aeruginosa, respectively, as compared to original PVC. These results indicate that covalent polymer attachment enhanced antibacterial and antifouling properties to the PVC surface. [ABSTRACT FROM AUTHOR]

Aging is a biological process which accounts for the deterioration of effective physiological functions. The malfunctioning of vital organ systems leads to the onset of neurodegenerative, cardiovascular, and immunomodulatory diseases in the elder population. Age‐dependent mitochondrial dysfunctions trigger the production of reactive oxygen species, which serve as a major contributing factor for the onset of age‐associated diseases. The increasing burden of age‐related pathologies explicates the relevance of identifying novel therapeutic agents with enhanced potency and bioavailability. Key information on the biological mechanisms of significant age‐related diseases aids in understanding relevant druggable targets essential for the initiation and progression of the disease. This review provides detailed insights into the druggable targets of key anti‐aging properties of therapeutic agents such as anti‐oxidant, immunomodulation, cardioprotection, anti‐melanogenic, and anti‐elastase properties. This information aids in the development of novel therapeutic agents/ supplements with enhanced efficacy. [ABSTRACT FROM AUTHOR]

Salmonella is a facultative intracellular pathogen that invades epithelial cells of the intestine using the SPI‐1 Type 3 secretion System (T3SS). Insertion of the SPI‐1 T3SS translocon is facilitated by acylation of the translocator SipB, which involves a protein–protein interaction with the acyl carrier protein IacP. Using nuclear magnetic resonance and biological tests, we identified the residues of IacP that are involved in the interaction with SipB. Our results suggest that the 4′‐phosphopantetheine group that functionalizes IacP participates in the interaction. Its solvent exposition may rely on two residues highly conserved in acyl carrier proteins associated with T3SS. This study is the first to address the specificity of acyl carrier proteins associated with T3SS. [ABSTRACT FROM AUTHOR]

A new series of 1‐(5‐(benzylsulfinyl)‐3‐methyl‐1,3,4‐thiadiazol‐2(3H)‐ylidene)‐thiourea/urea derivatives (1a–j) were designed and synthesized. For the first time, (i) a new process was developed for N‐methylation of 1,3,4‐thiadiazole moiety using dimethyl carbonate an environmentally benign reagent in presence of N,N,N′,N′‐tetramethylethylenediamine and (ii) the sulfide was selectively oxidized to sulfoxide in higher yield by using chlorine (g) in aqueous acetic acid media under mild reaction condition. The synthesized compounds (1a–j) were investigated for their antimicrobial activities. The tested compounds (1a–j) were exhibited moderate to excellent antibacterial activities against both Gram‐positive and Gram‐negative bacterial strains. The same compounds exhibited good antifungal activities against selected fungal strains. Particularly, the compounds 1b, 1d, 1h, and 1i were proved to be promising leads exhibiting both antibacterial and antifungal activities compared with standard drugs, ciprofloxacin, and fluconazole. The presence of 1,3,4‐thiadiazole moiety has a significant role in the display of antimicrobial activity. In addition, the presence of both sulfinyl and thiourea or urea functionalities has enhanced the activity as per obtained antimicrobial activity data. [ABSTRACT FROM AUTHOR]

Surfaces with antibacterial and hydrophilic properties are very attractive to cardiovascular applications. The objective of this study was to synthesize and immobilize a novel antibacterial and hydrophilic polymer onto surface of polyvinylchloride via an effective and mild surface coating technique. The surface coated with a terpolymer constructed with N‐vinylpyrrolidone, 3,4‐dichloro‐5‐hydroxy‐2(5H)‐furanone derivative, and succinimide residue was evaluated with cell adhesion, bacterial adhesion, and bacterial viability. 3T3 mouse fibroblast cells and two bacteria species were used to evaluate surface adhesion and antibacterial activity. Results showed that the polymer‐modified polyvinylchloride surface exhibited not only significantly decreased 3T3 fibroblast cell adhesion with a 66% to 87% reduction but also significantly decreased bacterial adhesion with 69% to 87% and 52% to 74% reduction of Pseudomonas aeruginosa and Staphylococcus aureus attachment, respectively, as compared with original polyvinylchloride. Furthermore, the modified polyvinylchloride surfaces exhibited significant antibacterial functions by inhibiting bacterial growth (75%‐84% and 78–94% inhibition of P aeruginosa and S aureus, respectively, as compared to original polyvinylchloride) and killing bacteria. These results demonstrate that covalent polymer attachment conferred antifouling and antibacterial properties to the polyvinylchloride surface. [ABSTRACT FROM AUTHOR]

Novel hybrid molecules were synthesized through the amalgamation of quinoxaline residue with 1,3,4‐oxadiazole molecule. The purity of obtained 1,3,4‐oxadiazoles derivatives containing quinoxaline residue (total 11) was confirmed through thin‐layer chromatography, combustion analysis, and melting point, whereas their structures were confirmed by infrared spectroscopy, nuclear magnetic resonance, and mass spectroscopy. In animal studies, the derivatives 4‐(5‐(4‐(3‐methylquinoxalin‐2‐yl)phenyl)‐1,3,4‐oxadiazol‐2‐yl)benzenamine and 2‐(5‐(4‐(3‐methylquinoxalin‐2‐yl)phenyl)‐1,3,4‐oxadiazol‐2‐yl)benzenamine showed excellent analgesic and anti‐inflammatory activities, respectively, as compared with other derivatives. In order to rationalize the biological results of the derivatives, molecular docking studies were performed using Argus lab. The compounds exhibited good docking scores between −12.987 and −9.92 kcal/mol against cyclooxygenase‐II (5IKQ) protein fragment. [ABSTRACT FROM AUTHOR]

A novel series of phenyl substituted azetidine containing 1, 2, 4‐triazole derivatives 7(a–j) were synthesized and characterized by IR, 1HNMR, 13CNMR, and mass spectroscopy. Synthesized 1, 2, 4‐triazole derivatives were subsequently assayed in vitro to investigate their antibacterial activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli using broth dilution method. Compounds 7c, 7d, and 7e exhibited potent inhibitory activities as compared to standard cefotaxime. Further, fluorescence spectral studies were also carried out to ascertain the antibacterial potential of compound 7c against two bacterial strains, that is, P. aeruginosa and S. aureus. In docking studies, all the compounds exhibited good docking scores between −12.04 and −11.36 kcal/mol and indicated that compounds could act through inhibition of bacterial DNA gyrase (PDB ID 3U2D). Among all, 7c has shown the maximum docking score and found in agreement to in vitro studies. In conclusion, synthesized 1, 2, 4‐triazole derivatives holds substantial caliber to be categorized as antibacterial agents. [ABSTRACT FROM AUTHOR]

An overview is given of the significance of the oxazole and isoxazole scaffolds in crop protection chemistry. The main herbicidally, fungicidally, and insecticidally active oxazole and isoxazole classes are presented, together with their synthesis routes, modes of action, and biological efficacies. In addition, the role of oxazoles and isoxazoles as lead structure or as intermediate in the synthesis of other agrochemicals is reported. Also, partially and fully saturated oxazole and isoxazole derivatives such as oxazolines, isoxazolines, oxazolidines, and isoxazolidines, oxygenated derivatives such as oxazolones and isoxazolones as well as annulated derivatives, such as benzoxazoles and benzisoxazoles, are covered. [ABSTRACT FROM AUTHOR]

Sixteen Schiff bases of quinazolin-4-one-linked 1,3,4-oxadiazoles were synthesized by reaction with different aromatic aldehydes. Purity of newly synthesized derivatives was confirmed through thin-layer chromatography, combustion analysis, and melting point. The structure of the derivatives was confirmed by determining infrared spectroscopy, nuclear magnetic resonance, and mass spectroscopy. All the synthesized derivatives were evaluated for their analgesic and anti-inflammatory activities in mice and rats, respectively. In animal studies, the derivative ( E)-3-(5-(4-(4-methoxybenzylideneamino)phenyl)-1,3,4-oxadiazol-2-yl)-2-phenylquinazolin-4(3 H)-one showed more potent analgesic activity and the derivative ( Z)-3-(5-(2-(2-hydroxybenzylideneamino)phenyl)-1,3,4-oxadiazol-2-yl)-2-phenylquinazolin-4(3 H)-one showed more potent anti-inflammatory activity as compared with other derivatives. The results of the present study indicate that reactions of 3-(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-phenylquinazolin-4(3 H)-one and 3-(5-(2-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-phenylquinazolin-4(3 H)-one with different aromatic aldehydes produce Schiff bases of quinazolin-4-one-linked 1,3,4-oxadiazoles with potent analgesic and anti-inflammatory activities. [ABSTRACT FROM AUTHOR]

Several new heterocyclic compounds such as 7-substituted pyrazolo[1,5- a]pyrimidine ( 5a-e) derivatives have been synthesized by the reactions of the versatile unreported sodium 3-(4-methyl-2-(4-methylphenylsulfonamido)thiazol-5-yl)-3-oxoprop-1-en-1-olate (2) with amino heterocyclic ( 3a-e) derivatives. Reaction of (2) with hydrazonyl halide ( 7a-d) and hydroximoyl chloride ( 11a,b) derivatives followed by reaction with hydrazine hydrate afforded pyrazolo[3,4- d]pyridazine and isoxazolo[3,4- d]pyridazine derivatives, respectively incorporating a thiazole moiety have been described. All newly synthesized compounds were elucidated by considering the data of both elemental and spectral analysis. [ABSTRACT FROM AUTHOR]

A synthesis of novel three-, four-, and sixfold branched 4-phenylthiazolylhydrazones, 4-pyrazolylthiazolyl hydrazones, and thiadiazoles which are linked to a benzene core via phenoxymethyl spacers was reported. The synthetic methodology includes initially formation of poly(aldehyde thiosemicarbazones) 9, 14, and 15 by acid catalyzed condensation of thiosemicarbazide ( 8) with the appropriate poly(aldehydes) 3, 5, and 7, respectively. Subsequent reaction of 9, 14, and 15 with each of 2-bromo-1-phenylethanone ( 10a) and 2-bromo-1-( 4-chlorophenyl)ethanone ( 10b) in refluxing ethanol in the presence of few drops of TEA afforded 11, 16, and 18, respectively, in good yields. On the other hand, the synthesis of the novel poly(4,5-dihydro-1,3,4-thiadiazolyl) derivatives 20, 21a, 21b, and 22 was performed by of 9b, 14a, 14b, and 15a, respectively, in refluxing . [ABSTRACT FROM AUTHOR]

N-{( E)-(dimethylamino)methylidenearbamothioyl}-4-toluenesulfonamide ( 2) was obtained by reaction of N-carbamothioyl-4-toluenesulfonamide ( 1) with dimethylformamide dimethylacetal or alternatively by the reaction of 1-(dimethylamino)methylidenethiourea with tosyl chloride. Compound 2 was reacted with substituted anilines to yield anilinomethylidine derivatives 3a, 3b, 3c, 3d, 3e, 3f, 3g. Treatment of 3a, 3b, 3c, 3d, 3e, 3f, 3g with phenacyl bromide gave triazepines 4a, 4b, 4c, 4d, 4e, 4f, 4g and imidazoles 5a, 5b, 5c, 5d, 5e, 5f, 5g. of compound 3e afforded ester derivative 6, which was subjected to react with hydrazine to yield hydrazide derivative 7. Oxadiazole 8 was obtained by reaction of 7 with CS2/KOH. Compound 3e was treated with o-aminophenol or o-aminothiophenol to give benzazoles 9a, 9b. N-(Diaminomethylidene)-4-toluenesulfonamide ( 10) reacted with enaminones to yield pyrimidines 11, 12, 13, respectively. The structures of the compounds were elucidated by elemental and spectral analyses. Some selected compounds were screened for their in vitro antifungal activity. In general, the newly synthesized compounds showed good antifungal activity. [ABSTRACT FROM AUTHOR]

A synthesis of novel bis(triazolothiadiazines) 11, 12, 13, 14, bis(quinoxalines) 16 and 17, bis(thiadiazoles) 24 and 25, and bis(oxadiazole) 31, which are linked to the thieno[2,3- b]thiophene core via phenoxymethyl group, was reported. Thus, reaction of the bis( α-bromoketones) 6 and 7 with the corresponding 4-amino-3-mercapto-1,2,4-triazole derivatives 8, 9, 10 in ethanol-DMF mixture in the presence of a few drops of triethylamine as a catalyst under reflux afforded the novel bis(5,6-dihydro- s-triazolo[3,4- b]thiadiazines) 11, 12, 13, 14 in 60-72% yields. The bis(quinoxalines) 16 and 17 were also synthesized as a sole product in high yields by the reaction of 6 and 7 with o-phenylenediamine 15 in refluxing acetonitrile in the presence of piperidine as a catalyst. of the bis(aldehyde thiosemicarbazones) 20 and 21 with afforded the corresponding bis(4,5-dihydro-1,3,4-thiadiazolyl) derivatives 24 and 25 in good yield. Bis(5-phenyl-2,3-dihydro-1,3,4-oxadiazole) derivative 31 could be obtained in 67% yield by of the appropriate bis( N-phenylhydrazone) 29 in refluxing for 3 h. [ABSTRACT FROM AUTHOR]

Novel enantiopure 1,2,4-trizole-3-thiones containing a benzensulfonamide moiety were synthesized via multistep reaction sequence starting with D-phenylalanine methyl ester and L-phenylalanine ethyl ester as a source of chirality. The chemical structures of all compounds were characterized by elemental analysis, UV, IR, 1H NMR, 13C NMR, 2D NMR (HETCOR), and mass spectral data. All compounds were tested in vitro antiviral activity against a broad variety of DNA and RNA viruses and in vitro cytostatic activity against murine leukemia (L1210), human T-lymphocyte (CEM) and human cervix carcinoma (HeLa) cell lines. Although enantiopure 1,2,4-triazole-3-thione analogs in ( R) configuration emerged as promising anti-influenza A H1N1 subtype in Madin Darby canine kidney cell cultures (MDCK), their enantiomers exhibited no activity. Especially compounds 18a, 21a, 22a, 23a, and 24a (EC50: 6.5, 6.1, 2.4, 1.6, 1.7 μM, respectively) had excellent activity against influenza A H1N1 subtype compared to the reference drug ribavirin (EC50: 8.0 μM). Several compounds have been found to inhibit proliferation of L1210, CEM and HeLa cell cultures with IC50 in the 12-53 μM range. Compound 5a and 27a in ( R) configuration were the most active compounds (IC50: 12-22 μM for 5a and IC50: 19-23 μM for 27a). Chirality 28:495-513, 2016. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

ABSTRACT Glutathione (GSH) structure-guided tripeptide analogues were designed and synthesized by solid phase technology, purified (≥95%) by RP and/or GF column chromatography, to identify those that, compared with GSH, exhibited similar or higher binding and catalytic efficiency toward the MDR-involved human GSTP1-1 isoenzyme, and could discriminate between the allozymic expression products of the polymorphic human GSTP1 gene locus, designated as hGSTP1*A (Ile104/Ala113), hGSTP1*B (Val104/Ala113), and hGSTP1*C (Val104/Val113). The analogues bear single amino acid alterations as well as alterations in more than one position. Some analogues showed remarkable allozyme selectivity, binding catalytically to A ( I, II, IV, XII), to C ( V and XVI), to A and C ( III, VII, XIV) or to all three allozymes ( XV). A heterocyclic substituent at positions 1 or 2 of GSH favors inhibition of A, whereas a small hydrophobic/hydrophilic amide substituent at position 2 (Cys) favors inhibition of B and C. Heterocyclic substituents at position 1, only, produce catalytic analogues for A, whereas less bulky and more flexible hydrophobic/hydrophilic substituents, at positions 1 or 3, lead to effective substrates with C. When such substituents were introduced simultaneously at positions 1 and 3, the analogues produced have no catalytic potential but showed appreciable inhibitory effects, instead, with all allozymes. It is anticipated that when GSH analogues with selective inhibitory or catalytic binding, were conjugated to allozyme-selective inhibitors of hGSTP1-1, the derived leads would be useful for the designing of novel chimeric inhibitors against the MDR-involved hGSTP1-1 allozymes. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 330-344, 2016. [ABSTRACT FROM AUTHOR]

ABSTRACT Pmel17 is the major component of functional amyloid fibrils that have an important role during pigment deposition. Pmel17 polymerization is promoted within the mildly acidic conditions of melanosomes, organelles located in pigment-specific cells. A repeat domain (RPT domain) of Pmel17, rich in glutamic acid residues has been extensively associated with the formation of the fibrous matrix. Here, we examine the RPT domain of human Pmel17 in order to provide information on this mechanism. Specifically, we have identified an aggregation-prone peptide segment (405VSIVVLSGT413), close to the C-terminal part of the RPT domain. Experimental results utilizing electron microscopy, X-ray fiber diffraction, Congo red staining and ATR FT-IR spectroscopy indicate that this peptide segment self-assembles forming fibrils with evident amyloidogenic properties. Conclusively, our results demonstrate that the 405VSIVVLSGT413 peptide segment possibly has an essential role in RPT domain fibrillogenesis. © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 133-139, 2016. [ABSTRACT FROM AUTHOR]

ABSTRACT CD2 and CD58 are two important costimulatory molecules involved in generating the signal II required for normal immune signaling. However, this interaction can be targeted to be of benefit in cases of abnormal immune signaling seen in autoimmune diseases. Our objective in this study was to design a peptidomimetic (compound 7) based on a β-strand structure of the adhesion domain of CD2 protein to inhibit CD2-CD58 protein-protein interaction and its effect on immunomodulation in the collagen-induced arthritis (CIA) model. The ability of compound 7 to bind to CD58 protein was assessed using flow cytometry. The effect of compound 7 on modulating the immune response was evaluated in an autoimmune disease using CIA in mice. The stability of compound 7 was evaluated in mouse serum using mass spectrometry. Antibody (Ab) binding inhibition studies suggested that compound 7 binds to CD58 protein. Compound 7 was successful in modulating immune responses when administered in the CIA mouse model along with reducing anti-collagen Ab levels and decreasing the level of interferon gamma (IFN-γ) relative to control treatments. Compound 7 was found to be nonimmunogenic and stable in mouse serum up to 48 h. Results suggest that compound 7 can serve as a lead compound for immunomodulation, and could be a therapeutic agent for the autoimmune disease rheumatoid arthritis (RA). © 2015 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 104: 733-742, 2015. [ABSTRACT FROM AUTHOR]

The selectivity of certain benzophenones and their carbonyl N-analogues was investigated towards the human GSTP1-1 allozymes A, B and C involved in MDR. The allozymes were purified from extracts derived from E. coli harbouring the plasmids pEXP5- CT/ TOPO- TA- hGSTP1*A, pOXO4- hGSTP1*B or pOXO4- hGSTP1*C. Compound screening with each allozyme activity indicated three compounds with appreciable inhibitory potencies, 12 and 13 with P1-1A 62% and 67%, 11 and 12 with P1-1C 51% and 70%, whereas that of 15 fell behind with P1-1B (41%). These findings were confirmed by IC50 values (74-125 μ m). Enzyme inhibition kinetics, aided by molecular modelling and docking, revealed that there is competition with the substrate CDNB for the same binding site on the allozyme ( Ki(13/A) = 63.6 ± 3.0 μ m, Ki(15/B) = 198.6 ± 14.3 μ m, and Ki(11/C) = 16.5 ± 2.7 μ m). These data were brought into context by an in silico structural comparative analysis of the targeted proteins. Although the screened compounds showed moderate inhibitory potency against hGSTP1-1, remarkably, some of them demonstrated absolute isoenzyme and/or allozyme selectivity. [ABSTRACT FROM AUTHOR]

A new series of 4-(4-substitutedbenzylideneamino)-5-((1-methyl-1 H-tetrazol-5-ylthio)methyl)-4 H-1,2,4-triazole-3-thiol derivatives ( 5a, 5b, 5c, 5d, 5e, 5f, 5g, 5h, 5i, 5j, 5k) are prepared using 4-amino-5-((1-methyl-1 H-tetrazol-5-ylthio)methyl-4 H-1,2,4-triazole-3-thiol ( 4), as an compound. The structures of all the newly synthesized products are established supported by their spectral 1H NMR, 13C NMR, FTIR, electrospray ionization (mass), and analytical data. All the compounds are screened for their insecticidal activity against Plodia interpunctella, and six compounds exhibited significant activity. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinase-2 ( MMP-2) shares structural similarities with the angiotensin-converting enzyme ( ACE). ACE inhibitors have been described to inhibit MMP-2, but this inhibitory potential was not shown using a highly purified MMP-2. This study aimed to investigate the inhibitory potential of captopril and lisinopril regarding MMP-2 activity. The first objective was to test the potential of captopril to change the pH of the buffer solution. The second objective was to test the direct inhibitory effect of captopril and lisinopril on plasma MMP-2 and on recombinant human MMP-2 (rh MMP-2). The in vitro activity assays included gelatin zymography and a fluorimetric assay. Captopril solubilization significantly decreased the pH of the 50 mM Tris buffer solution at the following concentrations: 2 mM ( p < 0.05), 4 mM and 8 mM ( p < 0.01), while only the 8 mM lisinopril induced a drop in pH ( p < 0.05). Thus, only 200 mM buffer solutions were used. Zymography results of plasma MMP-2 and rh MMP-2 showed that inhibition only happened at captopril concentrations ≥ 4 and 1 mM, respectively ( p < 0.05), while only the higher concentration of lisinopril (8 mM) inhibited plasma MMP-2 ( p < 0.05). In the fluorimetric assay, captopril led to significant inhibition of the rhMMP-2 activity at concentrations ≥2 mM ( p < 0.01), whereas aminophenylmercuric acetate-activated rh MMP-2 was inhibited by 0.5 mM captopril ( p < 0.01). The captopril and lisinopril concentrations found to inhibit MMP-2 are 3 orders of magnitude higher than those present in vivo after drug administration. We also discuss possible pitfalls for gelatinase inhibitory assays (besides the obvious pH problem already cited). In conclusion, this study's data show that captopril and lisinopril did not inhibit MMP-2 directly at the concentrations reached in vivo. [ABSTRACT FROM AUTHOR]

Lamprey gonadotropin-releasing hormone type III (lGnRH-III) is an isoform of GnRH isolated from the sea lamprey (Petromyzon marinus) with negligible endocrine activity in mammalian systems. Data concerning the superior direct anticancer activity of lGnRH-III have been published, raising questions on the structure-activity relationship. We synthesized 21 lGnRH-III analogs with rational amino acid substitutions and studied their effect on PC3 and LNCaP prostate cancer cell proliferation. Our results question the importance of the acidic charge of Asp6 for the antiproliferative activity and indicate the significance of the stereochemistry of Trp in positions 3 and 7. Furthermore, conjugation of an acetyl-group to the side chain of Lys8 or side chain cyclization of amino acids 1-8 increased the antiproliferative activity of lGnRH-III demonstrating that the proposed salt bridge between Asp6 and Lys8 is not crucial. Conformational studies of lGnRH-III were performed through NMR spectroscopy, and the solution structure of GnRH-I was solved. In solution, lGnRH-III adopts an extended backbone conformation in contrast to the well-defined β-turn conformation of GnRH-I. © 2012 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 98: 525-534, 2012. [ABSTRACT FROM AUTHOR]

No abstract is available for this article. [ABSTRACT FROM AUTHOR]

The thiophene-derived amido bis-nitrogen mustard N2, N2, N5, N5-tetrakis(2-chloroethyl)-3,4-dimethylthiophene-2,5-dicarboxamide was designed and synthesized via five-step reactions from commercially available 2-chloroacetonitrile. This target compound was confirmed by 1H NMR, 13C NMR, MS, IR spectra and elemental analyses, and its structure was further characterized by X-ray single-crystal analysis. The biological activities for the title compound and some intermediates were evaluated in vitro for their antibacterial, antifungal and cytotoxic activities. The preliminary results showed that the title compound could inhibit efficiently the growth of the tested microorganisms including drug-resistant bacteria MRSA to some extent. Moreover, the target compound was found to be effective against prostatic carcinoma cell line (PC-3), breast carcinoma cell line (MCF-7), colon carcinoma (LoVo) and lung cancer (A549). Especially, it gave selective antitumor efficacy against prostatic carcinoma cell line (PC-3) at a low dose. [ABSTRACT FROM AUTHOR]

The hydroxamic acid moiety is an effective metal-binding warhead for a variety of metalloenzyme targets of interest in drug-discovery. For the zinc-containing histone deacetylase enzymes in particular, this chemical group has been widely incorporated and studied in the clinic. An alternative chemical functionality for binding zinc is the α-aminocarbonyl motif, which has been shown to bind to histone deacetylase enzymes. The current article explores the minimal binding site theoretical approach combined with structural knowledge to explore the ideal chemical substitution pattern of the α-aminocarbonyl motif within HDAC8. The metal-binding strength of the group is predicted to be highly tunable to chemical substitution at the carbonyl and the α-amino carbon. A fixed receptor model approach with a dispersion-corrected density functional, clearly discerned the effect of different substituents at both these positions using either a flexible or partially fixed ligand optimized in the presence of a fixed receptor model of the HDAC8 binding site. An electron donating substituent such as methyl at the Cα in combination with NMe2 substitution at the carbonyl position, similar to observed crystal structures, result in the optimal energetic profile for binding the zinc atom in the HDAC8 enzyme. [ABSTRACT FROM AUTHOR]

To explore the anticancer effect associated with the piperidine framework, several (substituted phenyl) {4-[3-(piperidin-4-yl)propyl]piperidin-1-yl} methanone derivatives 3( a- i) were synthesized. Variation in the functional group at N-terminal of the piperidine led to a set of compounds bearing amide moiety. Their chemical structures were confirmed by 1H NMR, IR and mass spectra analysis. Among these, compounds 3a, 3d and 3e were endowed with antiproliferative activity. The most active compound among this series was 3a with nitro and fluoro substitution on the phenyl ring of aryl carboxamide moiety, which inhibited the growth of human leukemia cells (K562 and Reh) at low concentration. Comparison with other derivative ( 3h) results shown by LDH assay, cell cycle analysis and DNA fragmentation suggested that 3a is more potent to induce apoptosis. [ABSTRACT FROM AUTHOR]

The article investigates how changes in angiotensin II (AngII) structure affect binding and cleavage by angiotensin converting enzyme 2 (ACE2). It discusses the generation of a series of C3 β-amino acid AngII analogs and the assessment of their secondary structure, ACE2 inhibition and proteolytic stability. The results showed the ability of β-substitution to dramatically alter the structure of AngII and changes in structure correlated with ACE2 inhibition and/or substrate cleavage.

The anthrax toxin of the bacterium Bacillus anthracis consists of three distinct proteins, one of which is the anthrax lethal factor (LF). LF is a gluzincin Zn-dependent, highly specific metalloprotease with a molecular mass of ∼90 kDa that cleaves most isoforms of the family of mitogen-activated protein kinase kinases (MEKs/MKKs) close to their amino termini, resulting in the inhibition of one or more signaling pathways. Previous studies on the crystal structures of uncomplexed LF and LF complexed with the substrate MEK2 or a MKK-based synthetic peptide provided structure-activity correlations and the basis for the rational design of efficient inhibitors. However, in the crystallographic structures, the substrate peptide was not properly oriented in the active site because of the absence of the catalytic zinc atom. In the current study, docking and molecular dynamics calculations were employed to examine the LF-MEK/MKK interaction along the catalytic channel up to a distance of 20 Å from the zinc atom. This residue-specific view of the enzyme-substrate interaction provides valuable information about: (i) the substrate selectivity of LF and its inactivation of MEKs/MKKs (an issue highly important not only to anthrax infection but also to the pathogenesis of cancer), and (ii) the discovery of new, previously unexploited, hot-spots of the LF catalytic channel that are important in the enzyme/substrate binding and interaction. [ABSTRACT FROM AUTHOR]

Angiotensin-converting enzyme (ACE) is a key molecule of the renin-angiotensin-aldosterone system which is responsible for the control of blood pressure. For over 30 years it has become the target for fighting off hypertension. Many inhibitors of the enzyme have been synthesized and used widely in medicine despite the lack of ACE structure. The last 5 years the crystal structure of ACE separate domains has been revealed, but in order to understand how the enzyme works it is necessary to study its structure in solution. We present here the cloning, overexpression in Escherichia coli, purification and structural study of the Ala959 to Ser1066 region (ACE_C) that corresponds to the C-catalytic domain of human somatic angiotensin-I-converting enzyme. ACE_C was purified under denatured conditions and the yield was 6 mg/l of culture. Circular dichroism (CD) spectroscopy indicated that 1,1,1-trifluoroethanol (TFE) is necessary for the correct folding of the protein fragment. The described procedure can be used for the production of an isotopically labelled ACE959-1066 protein fragment in order to study its structure in solution by NMR spectroscopy. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A novel liposomal formulation was developed for the encapsulation of the oligopeptide leuprolide (GlpHisTrpSerTyr- D-LeuLeuArgProNHEt), a potent analogue of gonadotropin releasing hormone used in the treatment of advanced prostate cancer, endometriosis and precocious puberty. Leuprolide was synthesized using solid phase methodology on a {3-[(ethyl-Fmoc-amino)-methyl]-1-indol-1-yl}-acetyl AM resin and Fmoc/ tBu chemistry. The new liposomal formulation, called 'liposomes in liposomes' is composed of egg phosphatidylcholine:dipalmitoylphosphatidylglycerol in a molar ratio of 98.91:1.09 (internal liposomes) and egg phosphatidylcholine:dipalmitoylphosphatidylglycerol:cholesterol in a molar ratio of 68.71:0.76:30.53 (external liposomes). It offers high encapsulation efficiency (73.8% for leuprolide); it can provide new delivery characteristics and it may have possible advantages in future applications regarding the encapsulation and delivery of bioactive peptides to target tissues. Furthermore, the physicochemical characteristics (size distribution and ζ-potential) of the liposomal formulations and the thermal effects on leuprolide in model lipidic bilayers composed of dipalmitoylphosphatidylcholine were studied using differential scanning calorimetry. Finally, the dynamic effects of leuprolide in an egg phosphatidylcholine/cholesterol system were examined using solid state 13C MAS NMR spectroscopy. Copyright © 2005 European Peptide Society and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Analogues of GnRH have been widely used in oncology and gynaecology to induce reversible chemical castration. In addition to the classic hypophysiotropic action of GnRH, it has been shown that many malignant cells, such as breast cancer cells, secrete GnRH and express the GnRH receptor/s. In order to study the effect of modifications in position 3 and 6 of GnRH on both pituitary binding affinity and breast cancer cell proliferation, we synthesized eight new GnRH analogues. All GnRH analogues lacked the carboxy–terminal Gly10–amide of GnRH and an ethylamide residue was added to Pro9. Gly6 was substituted by α,α-dialkyl amino acids (Aib: α-aminoisobutyric acid, Deg: diethylglycine) and Trp3 by D–Trp, D- and L-1,2,3,4,-tetrahydro-isoquinoline-3-carboxylic acid (Tic). During competition binding experiments in mouse anterior pituitary αT3-1 cells, [Aib6, desGly10]GnRH-NHEt bound to the GnRH receptor with IC50 values comparable to those of parent hormone in contrast to the analogues substituted at position 3. However, [L-Tic3,Deg6, desGly10]GnRH-NHEt had high pituitary binding affinity. With the exception of GnRH and [Aib6, desGly10]GnRH-NHEt, all GnRH analogues significantly inhibited the proliferation of human breast cancer cells (MCF-7); higher inhibitory effect was observed for analogues modified at position 3. Results show differential impact of the modifications on the binding affinity to the GnRH receptor in mouse pituitary cells and on the inhibition of human breast cancer cell proliferation and provide insight into structure-activity relationship of GnRH in different biological systems. [ABSTRACT FROM AUTHOR]

Presents an author index for the issue of the "FEBS Journal."

NSC290205 (A) is an hybrid synthetic antineoplastic ester that is a combination of ad-lactam derivative of androsterone and an alkylating derivative ofN,N-bis(2-chloroethyl)aniline. We tested NSC290205 for synergistic antileukaemic activity with adriamycin (ADR), (i)in vitroagainst the human lymphoid leukaemia cell lines: CCRF-CEM, MOLT-4, and RPMI-8226, (ii)in vivoagainst P388 lymphocytic and L1210 lymphoid murine leukaemias (at incipient and advanced phase). Our results indicated significant cytostatic and cytotoxic synergy of NSC290205 and ADRin vitro. We further examined these resultsin vivoby replacing cyclophosphamide in the standard CHOP (cyclophosphamide, hydroxydaunomycin, Oncovin, prednisone) regimen with NSC290205 (AHOP) and comparing the efficiency of these two regimensin vivo. Although treatment of P388 and L1210 with cyclophosphamide or NSC290205 alone yielded equivalent results, AHOP produced a clear benefit for survival compared with CHOP against advanced leukaemias, confirming thein vitroobservations [higher percentage increase in median lifespan of treated animals over the untreated (control): 188% and 239% in L1210, 308% and 353% in P388,P < 0·01, for CHOP and AHOP respectively]. AHOP also proved to be more genotoxic and cytostatic than CHOP, inducing higher sister chromatid exchange levels and cell division delays on P388 cellsin vivo. NSC290205 showed superior antineoplastic potential against lymphoid leukaemia and significant synergy with ADR, producing an excellent therapeutic outcome. [ABSTRACT FROM AUTHOR]

A new human/rat CRH analogue has been synthesized using the Fmoc/tBu solid-phase synthetic protocol. The sequence of the new peptide differs from the original in two positions, 12 and 15, at which the native amino acids l-phenylalanine 12 and l-leucine 15 have been replaced by the nonprotein amino acids d-phenylalanine and α-aminoisobutyric acid (Aib), respectively. The high resolution three-dimensional solution structure of [d-Phe12, Aib15]CRH has been determined by 688 distance constraints (656 meaningful NOE and 32 H-bonds distance limits) and 21 angle constraints. A family of 40 energy-minimized conformers was obtained with average rmsd of 0.39 ± 0.16 Å and 0.99 ± 0.13 Å for backbone and heavy atoms, respectively, and distance penalty functions of 0.42 ± 0.03 Å2 . The NMR data acquired in a solvent system of water/trifluoroethanol (34%/66%, v/v) revealed that this 41-polypeptide adopts an almost linear helical structure in solution with helical content which reaches an 84% of the residues. Structural analysis confirmed the existence of two helical peptide fragments. The first was comprised of residues Ile6–Arg16 and the second of residues Glu20–Ile40, forming an angle of 34.2°. The structural differences with respect to the native peptide have been identified in the region d-Phe12–Glu20 where double substitution at positions 12 and 15 seems to perturb the elements of the native 35-residue helix. These structural rearrangements promote non-native intramolecular interactions in the region of the molecule between either the hydrophobic side-chains of d-Phe12, Aib15 and Leu18, or the charged groups of the residue pairs Arg16–Glu20 and His13–Glu17 being responsible for changes in hormonal functionality. This CRH analogue currently exhibits lack of any activity. [ABSTRACT FROM AUTHOR]

The article presents the cover page of the periodical and the list of the editors including David Selwood, Dimitris Agrafiotis and Harren Jhoti.

Presents an index of authors who contributed research articles to the December 15, 2002, issue of the 'European Journal of Biochemistry' periodical. Author names; Pages where the authors' research articles on biochemistry can be located.