| 1. |
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5-HT1A targeting PARCEST agent DO3AM-MPP with potential for receptor imaging : Synthesis, physico-chemical and MR studies
- 2021
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Ingår i: Bioorganic chemistry. - : Elsevier. - 0045-2068. ; 106
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Tidskriftsartikel (refereegranskat)abstract
- Contrast enhancement in MRI using magnetization or saturation transfer techniques promises better sensitivity, and faster acquisition compared to T-1 or T-2 contrast. This work reports the synthesis and evaluation of 5-HT1A targeted PARACEST MRI contrast agent using 1,4,7,10-tetraazacycloDOdecane-4,7,10-triacetAMide (DO3AM) as the bifunctional chelator, and 5-HT1A-antagonist methoxyphenyl piperazine (MPP) as a targeting unit. The multistep synthesis led to the MPP conjugated DO3AM with 60% yield. CEST-related physicochemical parameters were evaluated after loading DO3AM-MPP with paramagnetic MRI active lanthanides: Gadolinium (Gd-DO3AM-MPP) and Europium (Eu-DO3AM-MPP). Luminescence lifetime measurements with Eu-DO3AM-MPP and computational DFT studies using Gd-DO3AM-MPP revealed the coordination of one water molecule (q = 1.43) with metal-water distance (r(M)-H2O) of 2.7 angstrom and water residence time (tau(m)) of 0.23 ms. The dissociation constant of K-d 62 +/- 0.02 pM as evaluated from fluorescence quenching of 5-HT1A (protein) and docking score of -4.81 in theoretical evaluation reflect the binding potential of the complex Gd-DO3AM-MPP with the receptor 5-HT1A. Insights of the docked pose reflect the importance of NH2 (amide) and aromatic ring in Gd-DO3AM-MPP while interacting with Ser 374 and Phe 370 in the antagonist binding pocket of 5-HT1A. Gd-DO3AM-MPP shows longitudinal relaxivity 5.85 mM(-1)s(-1) with a water residence lifetime of 0.93 ms in hippocampal homogenate containing 5-HT1A. The potentiometric titration of DO3AM-MPP showed strong selectivity for Gd3+ over physiological metal ions such as Zn2+ and Cu2+. The in vitro and in vivo studies confirmed the minimal cytotoxicity and presential binding of Gd-DO3AM-MPP with 5-HT1A receptor in the hippocampus region of the mice. Summarizing, the complex Gd-DO3AM-MPP can have a potential for CEST imaging of 5-HT1A receptors.
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| 2. |
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| 3. |
- Arshad, Nasima, et al.
(författare)
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Synthesis, X-ray, Hirshfeld surface analysis, exploration of DNA binding, urease enzyme inhibition and anticancer activities of novel adamantane-naphthyl thiourea conjugate
- 2021
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Ingår i: Bioorganic chemistry (Print). - : Elsevier. - 0045-2068. ; 109
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Tidskriftsartikel (refereegranskat)abstract
- 1-(adamantane-1-carbonyl-3-(1-naphthyl)) thiourea (C22H24N2OS (4), was synthesized by the reaction of freshly prepared adamantane-1-carbonyl chloride from corresponding acid (3) with ammonium thiocyanate in 1:1 M ratio in dry acetone to afford the adamantane-1-carbonyl isothiocyanate (2) in situ followed by treatment with 1-naphthyl amine (3). The structure was established by elemental analyses, FTIR, H-1, C-13 NMR and mass spectroscopy. The molecular and crystal structure were determined by single crystal X-ray analysis. It belongs to triclinic system P - 1 space group with a = 6.7832(5) angstrom, b = 11.1810(8) angstrom, c = 13.6660(10) angstrom, alpha = 105.941(6)degrees, beta = 103.730(6)degrees, gamma = 104.562(6)degrees, Z = 2, V = 910.82(11) angstrom(3). The naphthyl group is almost planar. In the crystal structure, intermolecular C-H center dot center dot center dot O hydrogen bonds link the molecules into centrosymmetric dimers, enclosing R-2(2)(14) ring motifs, while the intramolecular N-H center dot center dot center dot O hydrogen bonds enclose S(6) ring motifs, in which they may be effective in the stabilization of the structure. The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the crystal packing are from H center dot center dot center dot H (59.3%), H center dot center dot center dot C/C center dot center dot center dot H (19.8%) and H center dot center dot center dot S/S center dot center dot center dot H (10.1%) interactions. Hydrogen bonding and van der Waals interactions are the dominant interactions in the crystal packing. DFT, molecular docking and urease inhibition studies revealed stability and electron withdrawing nature of 4 as compared to DNA base pairs and residues of urease. The DNA binding results from docking, UV-visible spectroscopy, and viscosity studies indicated significant binding of 4 with the DNA via intercalation and groove binding. Further investigation of the compound was done on hepatocellular carcinoma; Huh-7 cell line as well as normal human embryonic kidney; Hek-293 cell line. The compound showed significant cytotoxic activity against Huh-7 cells in comparison to normal Hek-293 cells indicating selective cytotoxicity towards cancer cells.
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| 4. |
- Bohlin, Christina, et al.
(författare)
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Oxidation of the erythro and threo forms of the phenolic lignin model compound 1-(4-hydroxy-3-methoxyphenyl)-2-(2-methoxyphenoxy)-1,3-propanediol by laccases and model oxidants
- 2009
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Ingår i: Bioorganic chemistry (Print). - : Elsevier. - 0045-2068 .- 1090-2120. ; 37:5, s. 143-148
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Tidskriftsartikel (refereegranskat)abstract
- Mixtures of equal amounts of the erythro and threo forms of the phenolic arylglycerol β-aryl ether 1-(4-hydroxy-3-methoxyphenyl)-2-(2-methoxyphenoxy)-1,3-propanediol were oxidized (i) with laccases from Trametes versicolor, Agaricus bisporus, Myceliophthora thermophila and Rhus vernicifera, (ii) with laccase-mediator systems consisting of T. versicolor laccase and ABTS or HBT, and (iii) with various model oxidants including cerium(IV) ammonium nitrate (CAN), lignin peroxidase, Fenton’s reagent, and lead(IV) tetraacetate (LTA). All the laccases exhibited a similar preferential degradation of the threo form. The mediator ABTS counteracted the threo preference of laccase, but the mediator HBT did not affect it. The outer-sphere model oxidants CAN and lignin peroxidase showed a preferential degradation of the threo form. LTA and Fenton’s reagent did not exhibit any stereo-preference. The results suggest that laccases of different origin, primary structure, and redox potential behave as typical outer-sphere oxidants in their interaction with the diastereomers of the arylglycerol β-aryl ether
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| 5. |
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| 6. |
- Bouzian, Younos, et al.
(författare)
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Design and evaluation of novel inhibitors for the treatment of clear cell renal cell carcinoma
- 2024
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Ingår i: Bioorganic chemistry. - : Elsevier BV. - 0045-2068. ; 151
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Tidskriftsartikel (refereegranskat)abstract
- The efficacy of conventional chemotherapies in treating clear cell renal cell carcinoma (ccRCC) is often limited due to its high molecular diversity, generally low response rates to standard treatments, and prevalent drug resistance. Recent advancements in the molecular understanding of ccRCC, alongside the discovery of novel therapeutic agents targeting specific proteins, have significantly altered the treatment landscape for ccRCC. Here, we synthesized 27 new compounds that are derivatives of TG-101209 to modulate BUB1B (BUB1 mitotic checkpoint serine/threonine kinase B). BUB1B has been recently identified as a drug target for the development of effective ccRCC treatment based on global transcriptomics profiling of ccRCC tumours and gene co-expression network analysis. We characterized the molecular structures of these 27 compounds by 1H and 13C NMR and Mass spectrometry. We evaluated the effect of these 27 compounds by analysing the modulation of the BUB1B expression. Our primary objective was to design and assess the efficacy of these new compounds in reducing the viability of Caki-1 cells, a ccRCC cell line. We performed the computational docking studies by the Schrödinger Maestro software and demonstrated that three of these compounds (13a, 5i, and 5j) effectively downregulated BUB1B expression and eventually triggered necrosis and apoptosis in the Caki-1 cell line based on the structure–activity relationship (SAR) analysis. The IC50 values for compounds 13a, 5i, and 5j were calculated as 2.047 µM, 10.046 µM, and 6.985 µM, respectively, indicating their potent inhibitory effects on cell viability. Our study suggests that these compounds targeting BUB1B could offer a more effective and promising approach for ccRCC treatment compared to the conventionally used tyrosine kinase inhibitors. Our study underscores the potential of leveraging targeted therapies against specific molecular pathways in ccRCC may open new avenues for the development of effective treatment strategies against ccRCC.
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| 7. |
- Chang, Chiao-Nien, et al.
(författare)
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The Design, Structure–Activity, and Kinetic Studies of 3-Benzyl-5-oxa-1,2,3,4-Tetrahydro-2H-chromeno-(3,4-c)pyridin-8-yl Sulfamates as Steroid Sulfatase Inhibitors
- 2022
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Ingår i: Bioorganic chemistry. - : Elsevier BV. - 0045-2068.
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Tidskriftsartikel (refereegranskat)abstract
- Steroid sulfatase inhibitors block the local production of estrogenic steroids and are attractive agents for the treatment of estrogen-dependent cancers. Inspiration of coumarin-based inhibitors, we synthesized thirty-two 5-oxa-1,2,3,4-tetrahydro-2H-chromeno-(3,4-c)pyridin-8-yl sulfamates, focusing on the substitution derivatives on the adjacent phenyl ring and evaluated their abilities to block STS from human placenta and MCF-7 cells. SAR analysis revealed that the incorporation of chlorine at either meta and/or para position of the adjacent phenyl ring of the tricyclic skeleton enhanced STS inhibition. Di-substitutions at the adjacent phenyl ring were superior to mono and tri-substitutions. Further kinetic analysis of these compounds revealed that chloride-bearing compounds, such as 19m, 19v, and 19w, had KI of 0.02 to 0.11 nM and kinact/KI ratios of 8.8-17.5 nM-1min-1, a parameter indicated for the efficiency of irreversible inhibition. We also used the docking model to illustrate the difference in STS inhibitory potency of compounds. Finally, the safety and anti-cancer activity of selected compounds 19m, 19v, and 19w were also studied, showing the results of low cytotoxicity on NHDF cell line and being more potent than irosustat on ZR-75-1 cell, which was a hormone-dependent cancer cell line with high STS expression.
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| 8. |
- Channar, Pervaiz Ali, et al.
(författare)
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Synthesis of aryl pyrazole via Suzuki coupling reaction, in vitro mushroom tyrosinase enzyme inhibition assay and in silico comparative molecular docking analysis with Kojic acid
- 2018
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Ingår i: Bioorganic chemistry (Print). - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0045-2068. ; 79, s. 293-300
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Tidskriftsartikel (refereegranskat)abstract
- Aryl pyrazoles are well recognized class of heterocyclic compounds found in several commercially available drugs. Owing to their significance in medicinal chemistry, in this current account we have synthesized a series of suitably substituted aryl pyrazole by employing Suzuki cross-coupling reaction. All compounds were evaluated for inhibition of mushroom tyrosinase enzyme both in vitro and in silico. Compound 3f (IC50 = 1.568 +/- 0.01 mu M) showed relatively better potential compared to reference kojic acid (IC50 = 16.051 +/- 1.27 mu M). A comparative docking studies showed that compound 3f have maximum binding affinity against mushroom tyrosinase (PDBID: 2Y9X) with binding energy value (-6.90 kcal/mol) as compared to Kojic acid. The 4-methoxy group in compound 3f shows 100% interaction with Cu. Compound 3f displayed hydrogen binding interaction with His61 and His94 at distance of 1.71 and 1.74 angstrom which might be responsible for higher activity compared to Kojic acid.
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| 9. |
- Chiu, Pei-Fang, et al.
(författare)
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Design, structure–activity relationships, and enzyme kinetic studies of tricyclic and tetracyclic coumarin–based sulfamates as steroid sulfatase inhibitors
- 2023
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Ingår i: Bioorganic chemistry. - : Elsevier BV. - 0045-2068. ; 138, s. 106581-106581
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Tidskriftsartikel (refereegranskat)abstract
- Inhibition of steroid sulfatase (STS) decreases estrogen production and thus, suppresses tumor proliferation. Inspired by irosustat, the first STS inhibitor in clinical trials, we explored twenty-one tricyclic and tetra-heterocyclic coumarin–based derivatives. Their STS enzyme kinetic parameters, docking models, and cytotoxicity toward breast cancer and normal cells were evaluated. Tricyclic derivative 9e and tetracyclic derivative 10c were the most promising irreversible inhibitors developed in this study, with KI of 0.05 and 0.4 nM, and kinact/KI ratios of 28.6 and 19.1 nM−1min−1 on human placenta STS, respectively.
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| 10. |
- Deplano, Alessandro, et al.
(författare)
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The fatty acid amide hydrolase and cyclooxygenase-inhibitory properties of novel amide derivatives of carprofen
- 2020
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Ingår i: Bioorganic chemistry (Print). - : Elsevier. - 0045-2068. ; 101
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Tidskriftsartikel (refereegranskat)abstract
- In experimental animals, inhibition of fatty acid amide hydrolase (FAAH) reduces the gastrointestinal damage produced by non-steroidal anti-inflammatory agents that act by inhibition of cyclooxygenase (COX). This suggests that compounds able to inhibit both enzymes may be potentially useful therapeutic agents. In the present study, we have investigated eight novel amide analogues of carprofen, ketoprofen and fenoprofen as potential FAAH/COX dual action inhibitors. Carpro-AM1 (2-(6-Chloro-9H-carbazol-2-yl)-N-(3-methylpyridin-2-yl)propenamide) and Carpro-AM6 (2-(6-Chloro-9H-carbazol-2-yl)-N-(3-chloropyridin-2-yl)propenamide) were found to be fully re-versible inhibitors of the hydrolysis of 0.5 mu M [H-3]anandamide in rat brain homogenates with IC50 values of 94 and 23 nM, respectively, i.e. 2-3 orders of magnitude more potent than carprofen in this respect. Both compounds inhibited the cyclooxygenation of arachidonic acid by ovine COX-1, and were more potent inhibitors of human recombinant COX-2 when 2-arachidonoylglycerol was used as substrate than when arachidonic acid was used. It is concluded that Carpro-AM1 and Carpro-AM6 are dual-acting FAAH/substrate-selective COX inhibitors.
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| 11. |
- Fraczyk, Tomasz, et al.
(författare)
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Phosphorylation of thymidylate synthase from various sources by human protein kinase CK2 and its catalytic subunits
- 2010
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Ingår i: Bioorganic chemistry (Print). - : Elsevier BV. - 0045-2068. ; 38:3, s. 124-131
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Tidskriftsartikel (refereegranskat)abstract
- Thymidylate synthase (TS) was found to be a substrate for both catalytic subunits of human CK2, with phosphorylation by CK2alpha and CK2alpha' characterized by similar K(m) values, 4.6microM and 4.2microM, respectively, but different efficiencies, the apparent turnover number with CK2alpha being 10-fold higher. With both catalytic subunits, phosphorylation of human TS, like calmodulin and BID, was strongly inhibited in the presence of the regulatory subunit CK2beta, the holoenzyme being activated by polylysine. Phosphorylation of recombinant human, rat, mouse and Trichinella spiralis TSs proteins was compared, with the human enzyme being apparently a much better substrate than the others. Following hydrolysis and TLC, phosphoserine was detected in human and rat, and phosphotyrosine in T. spiralis, TS, used as substrates for CK2alpha. MALDI-TOF MS analysis led to identification of phosphorylated Ser(124) in human TS, within a sequence LGFS(124)TREEGD, atypical for a CK2 substrate recognition site. The phosphorylation site is located in a region considered important for the catalytic mechanism or regulation of human TS, corresponding to the loop 107-128. Following phosphorylation by CK2alpha, resulting in incorporation of 0.4mol of phosphate per mol of dimeric TS, human TS exhibits unaltered K(m) values for dUMP and N(5,10)-methylenetetrahydrofolate, but a 50% lower turnover number, pointing to a strong influence of Ser(124) phosphorylation on its catalytic efficiency.
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| 12. |
- Iqbal, Shazia, et al.
(författare)
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Design and synthesis of novel JNK inhibitors targeting liver pyruvate kinase for the treatment of non-alcoholic fatty liver disease and hepatocellular carcinoma
- 2024
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Ingår i: Bioorganic chemistry. - : Elsevier BV. - 0045-2068. ; 147
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Tidskriftsartikel (refereegranskat)abstract
- Non-alcoholic fatty liver disease (NAFLD) comprises a broad range of liver disease including hepatocellular carcinoma (HCC) with is no FDA-approved drug. Liver pyruvate kinase (PKL) is a major regulator of metabolic flux and ATP generation in liver presenting a potential target for the treatment of NAFLD. Based on our recent finding of JNK-5A's effectiveness in inhibiting PKLR expression through a drug repositioning pipeline, this study aims to improve its efficacy further. We synthesized a series of JNK-5A analogues with targeted modifications, guided by molecular docking studies. These compounds were evaluated for their activities on PKL expression, cell viability, triacylglyceride (TAG) levels, and the expressions of steatosis-related proteins in the human HepG2 cell line. Subsequently, the efficacy of these compounds was assessed in reducing TAG level and toxicity. Compounds 40 (SET-151) and 41 (SET-152) proved to be the most efficient in reducing TAG levels (11.51 ± 0.90 % and 10.77 ± 0.67 %) and demonstrated lower toxicity (61.60 ± 5.00 % and 43.87 ± 1.42 %) in HepG2 cells. Additionally, all synthesized compounds were evaluated for their anti-cancer properties revealing that compound 74 (SET-171) exhibited the highest toxicity in cell viability with IC50 values of 8.82 µM and 2.97 µM in HepG2 and Huh7 cell lines, respectively. To summarize, compounds 40 (SET-151) and 41 (SET-152) show potential for treating NAFLD, while compound 74 (SET-171) holds potential for HCC therapy.
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| 13. |
- Iqbal, Shazia, et al.
(författare)
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Design and synthesis of novel JNK inhibitors targeting liver pyruvate kinase for the treatment of non-alcoholic fatty liver disease and hepatocellular carcinoma
- 2024
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Ingår i: BIOORGANIC CHEMISTRY. - : Elsevier BV. - 0045-2068 .- 1090-2120. ; 147
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Tidskriftsartikel (refereegranskat)abstract
- Non-alcoholic fatty liver disease (NAFLD) comprises a broad range of liver disease including hepatocellular carcinoma (HCC) with is no FDA-approved drug. Liver pyruvate kinase (PKL) is a major regulator of metabolic flux and ATP generation in liver presenting a potential target for the treatment of NAFLD. Based on our recent finding of JNK-5A's effectiveness in inhibiting PKLR expression through a drug repositioning pipeline, this study aims to improve its efficacy further. We synthesized a series of JNK-5A analogues with targeted modifications, guided by molecular docking studies. These compounds were evaluated for their activities on PKL expression, cell viability, triacylglyceride (TAG) levels, and the expressions of steatosis-related proteins in the human HepG2 cell line. Subsequently, the efficacy of these compounds was assessed in reducing TAG level and toxicity. Compounds 40 (SET-151) and 41 (SET-152) proved to be the most efficient in reducing TAG levels (11.51 +/- 0.90 % and 10.77 +/- 0.67 %) and demonstrated lower toxicity (61.60 +/- 5.00 % and 43.87 +/- 1.42 %) in HepG2 cells. Additionally, all synthesized compounds were evaluated for their anti-cancer properties revealing that compound 74 (SET-171) exhibited the highest toxicity in cell viability with IC50 values of 8.82 mu M and 2.97 mu M in HepG2 and Huh7 cell lines, respectively. To summarize, compounds 40 (SET-151) and 41 (SET-152) show potential for treating NAFLD, while compound 74 (SET-171) holds potential for HCC therapy.
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| 14. |
- Juang, Yu-Pu, et al.
(författare)
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Synthesis, distribution analysis and mechanism studies of N-acyl glucosamine-bearing oleanolic saponins
- 2020
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Ingår i: Bioorganic chemistry (Print). - : Elsevier. - 0045-2068. ; 99, s. 103835-
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Tidskriftsartikel (refereegranskat)abstract
- A series of N-acyl glucosamine-bearingtriterpenoidsaponins has been synthesized with cytotoxic activities evaluated against HL-60, PC-3, HCT-116, and CT-26 tumor cells. Saponins incorporated anoleanolic acid (OA) triterpenoidal core exhibited the highest cytotoxic activity. To study the influence of the lengths of acyl-carbon chain onN-position of glucosamine, cells were treated with28-propargylamides and then reacted with an azido-fluorogenic probe under CuAACclickreactions to visualize the intact distributions of these compounds by confocal microscopy and flow cytometry; it was found that cytotoxic-active compounds (30–32) located in the cytosol and inactivecompounds bearing longer carbon chains (33–35) were impenetrable across cell membranes.Our study demonstrated the defined lipophilic acyl-carbon chain length can precisely regulate thecytotoxic activityof saponins, which is useful for the future development of cytotoxic agents.Furthermore, using quantitative proteomics and immunolabeling,the mechanism ofcytotoxicity induced by the synthetic saponin after membrane penetration could be a result of activation of death receptor pathway and inhibition of PI3K/Akt/mTOR pathway.
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| 15. |
- Järv, Jaak, et al.
(författare)
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Phosphorylation of Sepharose-coupled peptides by protein kinase A
- 1996
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Ingår i: Bioorganic chemistry. - : Elsevier BV. - 0045-2068. ; 24:1, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- The kinetics of phosphorylation of the Sepharose-coupledpeptide RRASVA by catalytic subunit of proteinkinaseA, and diastereomers of this peptide, containingd-amino acids successively in each position, were studied. Coupling of these peptides with the amino and carboxyl termini to CH- and AH-Sepharoses had similar effects on the phosphorylation reaction, increasing theKmand decreasing theVvalues, respectively. The diastereomeric peptides were also phosphorylated by the enzyme and the rate of this reaction depended on the position of substitution ofl-amino acids with theird-analogs. However, this dependence was much less pronounced if compared with stereoselectivity of the enzyme in reactions with these peptides in solution: theKmvalues for the Sepharose-coupledpeptides were almost insensitive to the replacement ofl-amino acids withd-analogs and moderate stereoselectivity was revealed in the maximal velocity of the reaction. The Sepharose-coupledpeptide containingd-serine was also phosphorylated by proteinkinaseA while the same peptide in solution did not interact with the enzyme. Consequently, the polymer, enveloping the phosphorylatable peptide, may remarkably influence the recognition of the reaction site, altering both V and Km values.
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| 16. |
- Järv, Jaak, et al.
(författare)
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Quantitative structure-activity relationships in protein kinase C reaction with synthetic peptides derived from myelin basic protein
- 1996
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Ingår i: Bioorganic chemistry (Print). - : Elsevier BV. - 0045-2068. ; 24:2, s. 159-168
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Tidskriftsartikel (refereegranskat)abstract
- A set of peptides, Lys-Arg-Pro-Ser-X-Arg-Ala-Lys-Ala, where X stands for Ala, Val, Leu, Ile, Phe, Pro, Lys, Arg, Asp, Glu, Asn, Gln, and His, was synthesized and the kinetics of their phosphorylation by protein kinase C was studied. All compounds, except the peptide with Pro at the position X, were effectively phosphorylated by this enzyme, and for these substrates the kinetic constantsKm, maximal velocity constantsV, and second-order rate constantskIIwere determined. The data were analyzed by means of quantitative structure–activity relationships, taking into account hydrophobicity of the variable amino acids, bulkiness of their side groups quantified by molecular refractivity constants MR, and ionic status of these substituents by using an independent variable +1 for cationic, −1 for anionic, and 0 for nonionic substituents. These structural factors influenced theKmvalues, while the maximal velocity of phosphorylation depended mostly on the ionic status of the variable amino acid. The latter effect seems to characterize electrostatic interaction between the substrate molecule and some negative charge located in the enzyme active center.
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| 17. |
- Labriere, Christophe, et al.
(författare)
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Heterocyclic cellular lipid peroxidation inhibitors inspired by the marine antioxidant barettin
- 2019
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Ingår i: Bioorganic chemistry (Print). - : Elsevier BV. - 0045-2068. ; 84, s. 106-114
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Tidskriftsartikel (refereegranskat)abstract
- The marine environment remains a rich source for the discovery and development of novel bioactive compounds. The present paper describes the design, synthesis and biological evaluation of a library of small molecule heterocyclic mimetics of the marine 2,5-diketopiperazine barettin which is a powerful natural antioxidant. By mainly focusing on the influence from the brominated indole and heterocyclic core of barettin, a library of 19 compounds was prepared. The compounds comprised a heterocyclic core, either a 2,5 diketopiperazine, an imidazolidinedione or a thioxothiazolidinone, which were mainly monosubstituted with ranging bulky substituents. The prepared compounds were screened for activity in a cellular lipid peroxidation assay using HepG2 cells. Several of the synthetic compounds showed antioxidant properties superior to the positive control barettin. Two of the prepared compounds displayed inhibitory activity similar to commercial antioxidants with significant inhibition at low µg/mL concentrations. The toxicity of the compounds was also investigated against MRC-5 lung fibroblasts and none of the included compounds displayed any toxicity at 50 µg/mL.
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| 18. |
- Loog, Mart, et al.
(författare)
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Comparision of substrate specificities of protein kinases A and C based on peptide substrates
- 1994
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Ingår i: Bioorganic chemistry. - : Elsevier BV. - 0045-2068. ; 22:3, s. 328-336
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Tidskriftsartikel (refereegranskat)abstract
- Peptides, obtained by gradual removal of amino acids from both ends of pEKRPSQRSKYL, and stereoisomeric nonapeptides KRPSQRAKY with one D-amino acid residue successively in each position, were tested as substrates for protein kinase A, All these compounds were phosphorylated but at quite different rates by the enzyme. Comparison of the kinetic data with the appropriate results for protein kinase C, measured earlier, was used to analyze and compare the specificity determining factors of these enzymes. The analysis of the cross-specificity points to the possibility that only a short part, mainly the sequence of 1 to 2 amino acids around the phosphorylatable serine residue, is important for differentiation of substrates by these enzymes, while the remaining part of the peptide structure has similar influence on their reactivity in the case of these two protein kinases. Thus, the active center of these enzymes can be conventionally divided into two parts, which are responsible for selectivity and effectiveness of the phosphorylation reaction, respectively.
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| 19. |
- Magoulas, George E., et al.
(författare)
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Synthesis and antiproliferative activity of two diastereomeric lignan amides serving as dimeric caffeic acid-l-DOPA hybrids
- 2016
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Ingår i: Bioorganic Chemistry. - : Elsevier BV. - 0045-2068. ; 66, s. 132-144
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Tidskriftsartikel (refereegranskat)abstract
- Two new diastereomeric lignan amides (4 and 5) serving as dimeric caffeic acid-l-DOPA hybrids were synthesized. The synthesis involved the FeCl3-mediated phenol oxidative coupling of methyl caffeate to afford trans-diester 1a as a mixture of enantiomers, protection of the catechol units, regioselective saponification, coupling with a suitably protected l-DOPA derivative, separation of the two diastereomers thus obtained by flash column chromatography and finally global chemoselective deprotection of the catechol units. The effect of hybrids 4 and 5 and related compounds on the proliferation of two breast cancer cell lines with different metastatic potential and estrogen receptor status (MDA-MB-231 and MCF-7) and of one epithelial lung cancer cell line, namely A-549, was evaluated for concentrations ranging from 1 to 256 μM and periods of treatment of 24, 48 and 72 h. Both hybrids showed interesting and almost equipotent antiproliferative activities (IC50 64-70 μM) for the MDA-MB-231 cell line after 24-48 h of treatment, but they were more selective and much more potent (IC50 4-16 μM) for the MCF-7 cells after 48 h of treatment. The highest activity for both hybrids and both breast cancer lines was observed after 72 h of treatment (IC50 1-2 μM), probably as the result of slow hydrolysis of their methyl ester functions.
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| 20. |
- Nilsson, Jakob, et al.
(författare)
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3-Alkyl- and 3-amido-isothiazoloquinolin-4-ones as ligands for the benzodiazepine site of GABA(A) receptors.
- 2011
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Ingår i: Bioorganic & Medicinal Chemistry Letters. - : Elsevier BV. - 0960-894X.
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Tidskriftsartikel (refereegranskat)abstract
- Based on a pharmacophore model of the benzodiazepine binding site of the GABA(A) receptors, developed with synthetic flavones and potent 3-carbonylquinolin-4-ones, 3-alkyl- and 3-amido-6-methylisothiazoloquinolin-4-ones were designed, prepared and assayed. The suggestion that the interaction between the hydrogen bond donor site H1 with the 3-carbonyl oxygen in 3-carbonylquinolin-4-ones can be replaced by an interaction between H1 and N-2 in the isothiazoloquinolin-4-ones, was confirmed. As with the 3-carbonylquinolin-4-ones, the length of the chain in position 3 is critical for an efficient interaction with the lipophilic pockets of the pharmacophore model. The most potent 3-alkyl derivative, 3-pentyl-6-methylisothiazoloquinolin-4-one, has an affinity (K(i) value) for the benzodiazepine binding site of the GABA(A) receptors of 13nM. However, by replacing the 3-pentyl with a 3-butyramido group an even more potent compound was obtained, with a K(i) value of 2.8nM, indicating that the amide function facilitates additional interactions with the binding site.
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| 21. |
- Sevastik, Robin, et al.
(författare)
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Quantum chemical modeling of enzymatic reactions : the case of 4-oxalocrotonate tautomerase
- 2007
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Ingår i: Bioorganic chemistry (Print). - : Elsevier BV. - 0045-2068. ; 35:6, s. 444-457
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Tidskriftsartikel (refereegranskat)abstract
- The reaction mechanism of 4-oxalocrotonate tautomerase (4-OT) is studied using the density functional theory method B3LYP. This enzyme catalyzes the isomerisation of unconjugated alpha-keto acids to their conjugated isomers. Two different quantum chemical models of the active site are devised and the potential energy curves for the reaction are computed. The calculations support the proposed reaction mechanism in which Pro-1 acts as a base to shuttle a proton from the C3 to the C5 position of the substrate. The first step (proton transfer from C3 to proline) is shown to be the rate-limiting step. The energy of the charge-separated intermediate (protonated proline-deprotonated substrate) is calculated to be quite low, in accordance with measured pK(a) values. The results of the two models are used to evaluate the methodology employed in modeling enzyme active sites using quantum chemical cluster models.
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| 22. |
- Shleev, Sergey, et al.
(författare)
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Characterization of two new multiforms of Trametes pubescens laccase
- 2007
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Ingår i: Bioorganic Chemistry. - : Elsevier BV. - 0045-2068. ; 35:1, s. 35-49
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Tidskriftsartikel (refereegranskat)abstract
- Electrochemical properties of two multiforms of laccase from Trametes pubescens basidiomycete (LACI and LAC2) have been studied. The standard redox potentials of the T1 sites of the enzymes were found to be 746 and 738 mV us. NHE for LACI and LAC2, respectively. Bioelectroreduction of oxygen based on direct electron transfer between each of the two forms of Trametes pubescens laccase and spectrographic graphite electrodes has been demonstrated and studied. It. is concluded that the T1 site of laccase is the first electron acceptor, both in solution (homogeneous case) and when the enzymes are adsorbed on the surface of the graphite electrode (heterogeneous case). Thus, the previously proposed mechanism of oxygen bioelectroreduction by adsorbed fungal laccase was additionally confirmed using two forms of the enzyme. Moreover, the assumed need for extracellular laccase to communicate directly and electronically with a solid matrix (lignin) in the course of lignin degradation is discussed. In summary, the possible roles of multiforms of the enzyme based on their electrochemical, biochemical, spectral, and kinetic properties have been suggested to consist in broadening of the substrate specificity of the enzyme, in turn yielding the possibility to dynamically regulate the process of lignin degradation according to the real-time survival needs of the organism.
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| 23. |
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| 24. |
- Zare, Somayeh, et al.
(författare)
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Antidiabetic and cytotoxic polyhydroxylated oleanane and ursane type triterpenoids from Salvia grossheimii
- 2020
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Ingår i: Bioorganic chemistry. - : Elsevier BV. - 0045-2068. ; 104
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Tidskriftsartikel (refereegranskat)abstract
- Two polyhydroxylated oleanane and seven ursane triterpenoids were isolated from aerial parts of Salvia grossheimii. The chemical structures of the undescribed triterpenoids (1–6) were characterized using 1 and 2 D NMR and ESI-MS spectral data as; 2α, 3β, 11α –trihydroxy-olean-12- ene (1), 2α, 3β, 11α-trihydroxy-olean-18-ene (2), 2α- acetoxy-urs-12-ene-3β, 11α, 20β-triol (3), 3-keto-urs-12-ene-1β, 11α, 20β -triol (4), 2α, 3β-diacetoxy-urs-12-ene-1β, 11α, 20β -triol (5), and 3β-acetoxy-urs-12-ene-1β, 11α, 20β –triol (6). All compounds were evaluated for the in vitro α-glucosidase inhibitory and cytotoxic activities against MCF-7 human cancer cell line. Compounds 1, 2, 4, and 6 showed in vitro α-glucosidase inhibitory activity with IC50 = 43.6–198.4 µM, which were more potent than the antidiabetic medicine, acarbose. The remaining compounds; 3, and 7–9 showed potent cytotoxic activity (IC50 = 6.2–31.9 µM) against the cancerous cell line, while the potent α-glucosidase inhibitors were inactive. Molecular docking analysis and kinetic studies were applied to investigate the structure activity relationships and mechanisms of the human and Saccharomyces cerevisiae α-glucosidase inhibitory of the purified compounds. Comparing the high cytotoxicity and α-glucosidase inhibitory of the oleanane and ursane type triterpenoids suggest them as potential lead compounds for further research in anticancer and antidiabetic research.
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| 25. |
- Zarei, Omid, et al.
(författare)
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Structure-based discovery of novel small molecule inhibitors of platelet-derived growth factor-B
- 2020
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Ingår i: Bioorganic chemistry (Print). - : Elsevier BV. - 0045-2068. ; 94
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Tidskriftsartikel (refereegranskat)abstract
- Platelet-derived growth factor (PDGF) is a family of growth factors with mitogenic and chemotactic activity. However, uncontrolled and overactivated PDGF signaling has been implicated in a variety of diseases, such as cancers and atherosclerosis. In this context, inhibition of PDGF-PDGFR signaling is of paramount importance in progression of such diseases. The purpose of the current study was to identify novel PDGF-B inhibitors using virtual screening methods. To this end, a combination of molecular modeling techniques such as molecular docking and dynamics simulation, as well as drug likeness filtering criteria, was applied to select anti-PDGF peptidomimetic candidates based on crystallography solved structure of an anti-PDGF-B monoclonal antibody named, MOR8457. In vitro biological assays of the selected compounds revealed two of them being active at micromolar IC50, concentrations. The presented work can provide a framework for systematic peptidomimetic identification for anti-PDGF-B agents from large chemical libraries.
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