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Design and activity of AP endonuclease-1 inhibitors. AP内切酶-1抑制剂的设计和活性。
Journal of Chemical Biology Pub Date : 2015-04-19 eCollection Date: 2015-07-01 DOI: 10.1007/s12154-015-0131-7
Zhiwei Feng, Stanton Kochanek, David Close, LiRong Wang, Ajay Srinivasan, Abdulrahman A Almehizia, Prema Iyer, Xiang-Qun Xie, Paul A Johnston, Barry Gold
{"title":"Design and activity of AP endonuclease-1 inhibitors.","authors":"Zhiwei Feng,&nbsp;Stanton Kochanek,&nbsp;David Close,&nbsp;LiRong Wang,&nbsp;Ajay Srinivasan,&nbsp;Abdulrahman A Almehizia,&nbsp;Prema Iyer,&nbsp;Xiang-Qun Xie,&nbsp;Paul A Johnston,&nbsp;Barry Gold","doi":"10.1007/s12154-015-0131-7","DOIUrl":"https://doi.org/10.1007/s12154-015-0131-7","url":null,"abstract":"<p><p>Apurinic/apyrimidinic endonuclease-1/redox effector factor-1 (APE-1) is a critical component of base excision repair that excises abasic lesions created enzymatically by the action of DNA glycosylases on modified bases and non-enzymatically by hydrolytic depurination/depyrimidination of nucleobases. Many anticancer drugs generate DNA adducts that are processed by base excision repair, and tumor resistance is frequently associated with enhanced APE-1 expression. Accordingly, APE-1 is a potential therapeutic target to treat cancer. Using computational approaches and the high resolution structure of APE-1, we developed a 5-point pharmacophore model for APE-1 small molecule inhibitors. One of the nM APE-1 inhibitors (AJAY-4) that was identified based on this model exhibited an overall median growth inhibition (GI50) of 4.19 μM in the NCI-60 cell line panel. The mechanism of action is shown to be related to the buildup of abasic sites that cause PARP activation and PARP cleavage, and the activation of caspase-3 and caspase-7, which is consistent with cell death by apoptosis. In a drug combination growth inhibition screen conducted in 10 randomly selected NCI-60 cell lines and with 20 clinically used non-genotoxic anticancer drugs, a synergy was flagged in the SK-MEL-5 melanoma cell line exposed to combinations of vemurafenib, which targets melanoma cells with V600E mutated BRAF, and AJAY-4, our most potent APE-1 inhibitor. The synergy between AJAY-4 and vemurafenib was not observed in cell lines expressing wild-type B-Raf protein. This synergistic combination may provide a solution to the resistance that develops in tumors treated with B-Raf-targeting drugs. </p>","PeriodicalId":15296,"journal":{"name":"Journal of Chemical Biology","volume":"8 3","pages":"79-93"},"PeriodicalIF":0.0,"publicationDate":"2015-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s12154-015-0131-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33412583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 26
Synthesis and cytotoxicity studies of 1-propenyl-1,3-dihydro-benzimidazol-2-one. 1-丙烯-1,3-二氢苯并咪唑-2-酮的合成及细胞毒性研究。
Journal of Chemical Biology Pub Date : 2015-04-17 eCollection Date: 2015-07-01 DOI: 10.1007/s12154-015-0130-8
Biswadip Banerji, Sumit Kumar Pramanik
{"title":"Synthesis and cytotoxicity studies of 1-propenyl-1,3-dihydro-benzimidazol-2-one.","authors":"Biswadip Banerji,&nbsp;Sumit Kumar Pramanik","doi":"10.1007/s12154-015-0130-8","DOIUrl":"https://doi.org/10.1007/s12154-015-0130-8","url":null,"abstract":"<p><p>A heterocyclic compound 1-propenyl-1,3-dihydro-benzimidazol-2-one was synthesized by a palladium-catalyzed rearrangement reaction. Anticancer activities were confirmed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against Neura 2a (neuroblastoma cell), HEK 293 (kidney cancer) and MCF-7 (breast cancer) cell lines at low micromolar range. Furthermore, clear images from phase-contrast and fluorescence microscopes and confocal images unambiguously confirm the cancer cell death. The single X-ray crystal structure of the compound unambiguously proves the structure of the benzimidazolone compound. </p>","PeriodicalId":15296,"journal":{"name":"Journal of Chemical Biology","volume":"8 3","pages":"73-8"},"PeriodicalIF":0.0,"publicationDate":"2015-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s12154-015-0130-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33411098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 4
JOCB Bulletin. JOCB公告。
Journal of Chemical Biology Pub Date : 2015-03-26 eCollection Date: 2015-04-01 DOI: 10.1007/s12154-015-0129-1
{"title":"JOCB Bulletin.","authors":"","doi":"10.1007/s12154-015-0129-1","DOIUrl":"https://doi.org/10.1007/s12154-015-0129-1","url":null,"abstract":"","PeriodicalId":15296,"journal":{"name":"Journal of Chemical Biology","volume":"8 2","pages":"67-72"},"PeriodicalIF":0.0,"publicationDate":"2015-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s12154-015-0129-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33215384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Synthesis of biologically important neutral amylo-β peptide by using improved Fmoc solid-phase peptide synthetic strategy. 利用改进的 Fmoc 固相多肽合成策略合成具有重要生物学意义的中性淀粉样β肽。
Journal of Chemical Biology Pub Date : 2015-02-26 eCollection Date: 2015-04-01 DOI: 10.1007/s12154-015-0128-2
R Selvam, E Sudha, P R Rajkumar, K P Subashchandran
{"title":"Synthesis of biologically important neutral amylo-β peptide by using improved Fmoc solid-phase peptide synthetic strategy.","authors":"R Selvam, E Sudha, P R Rajkumar, K P Subashchandran","doi":"10.1007/s12154-015-0128-2","DOIUrl":"10.1007/s12154-015-0128-2","url":null,"abstract":"<p><p>The 10 amino acid sequence of the biologically important neutral amylo-β peptide has equally hydrophilic and hydrophobic properties, which reduces the coupling efficiency during its synthesis and reduces the final yield of the peptide, and is therefore classified as a \"difficult peptide sequence.\" The method presented here minimizes the synthetic problems by the introduction of improved Fmoc chemistry and effective hydroxybenzotriazole (HoBt), diisopropylcarbodiimide (DIC)-coupling and activation strategies. In addition, we developed a PS-TPGD resin as a solid support for the synthesis of specific neutral peptides, which is still a challenge to peptide chemistry. The most essential biologically active neutral amylo-β peptide (KVKRIILARS) was successfully synthesized, and some synthetic modification was performed using the Fmoc solid-phase peptide synthesis (SPPS) method for purity and yield improvement. Graphical abstractᅟ. </p>","PeriodicalId":15296,"journal":{"name":"Journal of Chemical Biology","volume":"8 2","pages":"61-6"},"PeriodicalIF":0.0,"publicationDate":"2015-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4392012/pdf/12154_2015_Article_128.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33215383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A review of characterization of tocotrienols from plant oils and foods. 植物油和食品中生育三烯醇的特性研究进展。
Journal of Chemical Biology Pub Date : 2015-01-20 eCollection Date: 2015-04-01 DOI: 10.1007/s12154-014-0127-8
Haseeb Ahsan, Amjid Ahad, Waseem A Siddiqui
{"title":"A review of characterization of tocotrienols from plant oils and foods.","authors":"Haseeb Ahsan,&nbsp;Amjid Ahad,&nbsp;Waseem A Siddiqui","doi":"10.1007/s12154-014-0127-8","DOIUrl":"https://doi.org/10.1007/s12154-014-0127-8","url":null,"abstract":"<p><p>Tocotrienols, members of the vitamin E family, are natural compounds found in a number of vegetable oils, wheat germ, barley and certain types of nuts and grains. Vegetable oils provide the best sources of these vitamin E forms, particularly palm oil and rice bran oil contain higher amounts of tocotrienols. Other sources of tocotrienols include grape fruit seed oil, oats, hazelnuts, maize, olive oil, buckthorn berry, rye, flax seed oil, poppy seed oil and sunflower oil. Tocotrienols are of four types, viz. alpha (α), beta (β), gamma (γ) and delta (δ). Unlike tocopherols, tocotrienols are unsaturated and possess an isoprenoid side chain. A number of researchers have developed methods for the extraction, analysis, identification and quantification of different types of vitamin E compounds. This article constitutes an in-depth review of the chemistry and extraction of the unsaturated vitamin E derivatives, tocotrienols, from various sources using different methods. This review article lists the different techniques that are used in the characterization and purification of tocotrienols such as soxhlet and solid-liquid extractions, saponification method, chromatography (thin layer, column chromatography, gas chromatography, supercritical fluid, high performance), capillary electrochromatography and mass spectrometry. Some of the methods described were able to identify one form or type while others could analyse all the analogues of tocotrienol molecules. Hence, this article will be helpful in understanding the various methods used in the characterization of this lesser known vitamin E variant. </p>","PeriodicalId":15296,"journal":{"name":"Journal of Chemical Biology","volume":"8 2","pages":"45-59"},"PeriodicalIF":0.0,"publicationDate":"2015-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s12154-014-0127-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33215382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 108
JOCB Bulletin
Journal of Chemical Biology Pub Date : 2015-01-01 DOI: 10.1007/s12154-015-0146-0
{"title":"JOCB Bulletin","authors":"","doi":"10.1007/s12154-015-0146-0","DOIUrl":"https://doi.org/10.1007/s12154-015-0146-0","url":null,"abstract":"","PeriodicalId":15296,"journal":{"name":"Journal of Chemical Biology","volume":"57 1","pages":"189-194"},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74474193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
JOCB Bulletin. JOCB公告。
Journal of Chemical Biology Pub Date : 2014-12-23 eCollection Date: 2015-01-01 DOI: 10.1007/s12154-014-0126-9
{"title":"JOCB Bulletin.","authors":"","doi":"10.1007/s12154-014-0126-9","DOIUrl":"https://doi.org/10.1007/s12154-014-0126-9","url":null,"abstract":"","PeriodicalId":15296,"journal":{"name":"Journal of Chemical Biology","volume":"8 1","pages":"37-44"},"PeriodicalIF":0.0,"publicationDate":"2014-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s12154-014-0126-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32971170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Mitochondrial protein alterations in a familial peripheral neuropathy caused by the V144D amino acid mutation in the sphingolipid protein, SPTLC1. 鞘脂蛋白SPTLC1中V144D氨基酸突变引起的家族性周围神经病变的线粒体蛋白改变
Journal of Chemical Biology Pub Date : 2014-11-14 eCollection Date: 2015-01-01 DOI: 10.1007/s12154-014-0125-x
Scott E Stimpson, Jens R Coorssen, Simon J Myers
{"title":"Mitochondrial protein alterations in a familial peripheral neuropathy caused by the V144D amino acid mutation in the sphingolipid protein, SPTLC1.","authors":"Scott E Stimpson,&nbsp;Jens R Coorssen,&nbsp;Simon J Myers","doi":"10.1007/s12154-014-0125-x","DOIUrl":"https://doi.org/10.1007/s12154-014-0125-x","url":null,"abstract":"<p><p>Axonal degeneration is the final common path in many neurological disorders. Subsets of neuropathies involving the sensory neuron are known as hereditary sensory neuropathies (HSNs). Hereditary sensory neuropathy type I (HSN-I) is the most common subtype of HSN with autosomal dominant inheritance. It is characterized by the progressive degeneration of the dorsal root ganglion (DRG) with clinical symptom onset between the second or third decade of life. Heterozygous mutations in the serine palmitoyltransferase (SPT) long chain subunit 1 (SPTLC1) gene were identified as the pathogenic cause of HSN-I. Ultrastructural analysis of mitochondria from HSN-I patient cells has displayed unique morphological abnormalities that are clustered to the perinucleus where they are wrapped by the endoplasmic reticulum (ER). This investigation defines a small subset of proteins with major alterations in abundance in mitochondria harvested from HSN-I mutant SPTLC1 cells. Using mitochondrial protein isolates from control and patient lymphoblasts, and a combination of 2D gel electrophoresis, immunoblotting and mass spectrometry, we have shown the increased abundance of ubiquinol-cytochrome c reductase core protein 1, an electron transport chain protein, as well as the immunoglobulin, Ig kappa chain C. The regulation of these proteins may provide a new route to understanding the cellular and molecular mechanisms underlying HSN-I. </p>","PeriodicalId":15296,"journal":{"name":"Journal of Chemical Biology","volume":"8 1","pages":"25-35"},"PeriodicalIF":0.0,"publicationDate":"2014-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s12154-014-0125-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32971169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 11
JOCB Bulletin. JOCB公告。
Journal of Chemical Biology Pub Date : 2014-09-27 eCollection Date: 2014-10-01 DOI: 10.1007/s12154-014-0123-z
{"title":"JOCB Bulletin.","authors":"","doi":"10.1007/s12154-014-0123-z","DOIUrl":"https://doi.org/10.1007/s12154-014-0123-z","url":null,"abstract":"","PeriodicalId":15296,"journal":{"name":"Journal of Chemical Biology","volume":"7 4","pages":"163-70"},"PeriodicalIF":0.0,"publicationDate":"2014-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s12154-014-0123-z","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32752052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Targeting the cyclin-binding groove site to inhibit the catalytic activity of CDK2/cyclin A complex using p27(KIP1)-derived peptidomimetic inhibitors. 利用p27(KIP1)衍生的拟肽抑制剂靶向细胞周期蛋白结合槽位点抑制CDK2/cyclin A复合物的催化活性。
Journal of Chemical Biology Pub Date : 2014-09-18 eCollection Date: 2015-01-01 DOI: 10.1007/s12154-014-0124-y
Arumugasamy Karthiga, Sunil Kumar Tripathi, Ramasamy Shanmugam, Venkatesan Suryanarayanan, Sanjeev Kumar Singh
{"title":"Targeting the cyclin-binding groove site to inhibit the catalytic activity of CDK2/cyclin A complex using p27(KIP1)-derived peptidomimetic inhibitors.","authors":"Arumugasamy Karthiga,&nbsp;Sunil Kumar Tripathi,&nbsp;Ramasamy Shanmugam,&nbsp;Venkatesan Suryanarayanan,&nbsp;Sanjeev Kumar Singh","doi":"10.1007/s12154-014-0124-y","DOIUrl":"https://doi.org/10.1007/s12154-014-0124-y","url":null,"abstract":"<p><p>Functionally activated cyclin-dependent kinase 2 (CDK2)/cyclin A complex has been validated as an interesting therapeutic target to develop the efficient antineoplastic drug based on the cell cycle arrest. Cyclin A binds to CDK2 and activates the kinases as well as recruits the substrate and inhibitors using a hydrophobic cyclin-binding groove (CBG). Blocking the cyclin substrate recruitment on CBG is an alternative approach to override the specificity hurdle of the currently available ATP site targeting CDK2 inhibitors. Greater understanding of the interaction of CDK2/cyclin A complex with p27 (negative regulator) reveals that the Leu-Phe-Gly (LFG) motif region of p27 binds with the CBG site of cyclin A to arrest the malignant cell proliferation that induces apoptosis. In the present study, Replacement with Partial Ligand Alternatives through Computational Enrichment (REPLACE) drug design strategies have been applied to acquire LFG peptide-derived peptidomimetics library. The peptidomimetics function is equivalent with respect to substrate p27 protein fashion but does not act as an ATP antagonist. The combined approach of molecular docking, molecular dynamics (MD), and molecular electrostatic potential and ADME/T prediction were carried out to evaluate the peptidomimetics. Resultant interaction and electrostatic potential maps suggested that smaller substituent is desirable at the position of phenyl ring to interact with Trp217, Arg250, and Gln254 residues in the active site. The best docked poses were refined by the MD simulations which resulted in conformational changes. After equilibration, the structure of the peptidomimetic and receptor complex was stable. The results revealed that the various substrate protein-derived peptidomimetics could serve as perfect leads against CDK2 protein. </p>","PeriodicalId":15296,"journal":{"name":"Journal of Chemical Biology","volume":"8 1","pages":"11-24"},"PeriodicalIF":0.0,"publicationDate":"2014-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/s12154-014-0124-y","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32971168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 11
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