BMC chemical biology最新文献

Anti-cancer activity of novel dibenzo[b,f]azepine tethered isoxazoline derivatives. 新型二苯并[b,f]氮卓系异恶唑啉衍生物的抗癌活性。

BMC chemical biology Pub Date : 2012-10-03 DOI: 10.1186/1472-6769-12-5

Maralinganadoddi Panchegowda Sadashiva, Basappa, Shivananju NanjundaSwamy, Feng Li, Kanjoormana Aryan Manu, Murugan Sengottuvelan, Doddakunche Shivaramu Prasanna, Nirvanappa Chikkagundagal Anilkumar, Gautam Sethi, Kazuyuki Sugahara, Kanchugarakoppal Subbegowda Rangappa

{"title":"Anti-cancer activity of novel dibenzo[b,f]azepine tethered isoxazoline derivatives.","authors":"Maralinganadoddi Panchegowda Sadashiva, Basappa, Shivananju NanjundaSwamy, Feng Li, Kanjoormana Aryan Manu, Murugan Sengottuvelan, Doddakunche Shivaramu Prasanna, Nirvanappa Chikkagundagal Anilkumar, Gautam Sethi, Kazuyuki Sugahara, Kanchugarakoppal Subbegowda Rangappa","doi":"10.1186/1472-6769-12-5","DOIUrl":"https://doi.org/10.1186/1472-6769-12-5","url":null,"abstract":"Background: Dibenzoazepine (DB) derivatives are important and valuable compounds in medicinal chemistry. The synthesis and chemotherapeutic properties of naturally occurring DBs and different heterocyclic moiety tethered DBs are reported. Herein, we report the DB-fused hybrid structure that containing isoxazolines (DBIs) and their anti-cancer activity, which could throw light on the structural and functional features of new molecules.Results and conclusion: The synthesis and characterization of novel ring DB tethered isoxazoline derivatives (DBIs) were carried out. After the detailed structural characterization using 2D-NMR experiments, the compounds were identified as 5-substituted isoxazolines. The effect of newly synthesized DBIs against the invasion of murine osteosarcoma (LM8G7) cells was studied. Among the tested molecules, compound 4g (5-[-3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl-methyl]-5 H-dibenzo[b,f]azepine), was found to inhibit the invasion of LM8G7 cells strongly, when compared to other structurally related compounds. Cumulatively, the compound 4g inhibited the invasion MDA-MB-231 cells completely at 10 μM. In addition to anti-invasion property the compound 4g also inhibited the migration of LM8G7 and human ovarian cancer cells (OVSAHO) dose-dependently. Compound 4g inhibited the proliferation of LM8G7, OVSAHO, human breast cancer cells (MCF-7) and human melphalan-resistant multiple myeloma (RPMI8226-LR5) cells that are comparable to cisplatin and suramin.","PeriodicalId":80682,"journal":{"name":"BMC chemical biology","volume":"12 ","pages":"5"},"PeriodicalIF":0.0,"publicationDate":"2012-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1472-6769-12-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30951676","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: 37

High toxicity and specificity of the saponin 3-GlcA-28-AraRhaxyl-medicagenate, from Medicago truncatula seeds, for Sitophilus oryzae. 山紫花苜蓿种子皂苷3-GlcA-28-AraRhaxyl-medicagenate对米象的高毒性和特异性研究。

BMC chemical biology Pub Date : 2012-07-02 DOI: 10.1186/1472-6769-12-3

Pedro Da Silva, Vanessa Eyraud, Maïté Carre-Pierrat, Catherine Sivignon, Isabelle Rahioui, Corinne Royer, Frédéric Gressent

{"title":"High toxicity and specificity of the saponin 3-GlcA-28-AraRhaxyl-medicagenate, from Medicago truncatula seeds, for Sitophilus oryzae.","authors":"Pedro Da Silva, Vanessa Eyraud, Maïté Carre-Pierrat, Catherine Sivignon, Isabelle Rahioui, Corinne Royer, Frédéric Gressent","doi":"10.1186/1472-6769-12-3","DOIUrl":"https://doi.org/10.1186/1472-6769-12-3","url":null,"abstract":"Background: Because of the increasingly concern of consumers and public policy about problems for environment and for public health due to chemical pesticides, the search for molecules more safe is currently of great importance. Particularly, plants are able to fight the pathogens as insects, bacteria or fungi; so that plants could represent a valuable source of new molecules.Results: It was observed that Medicago truncatula seed flour displayed a strong toxic activity towards the adults of the rice weevil Sitophilus oryzae (Coleoptera), a major pest of stored cereals. The molecule responsible for toxicity was purified, by solvent extraction and HPLC, and identified as a saponin, namely 3-GlcA-28-AraRhaxyl-medicagenate. Saponins are detergents, and the CMC of this molecule was found to be 0.65 mg per mL. Neither the worm Caenorhabditis elegans nor the bacteria E. coli were found to be sensitive to this saponin, but growth of the yeast Saccharomyces cerevisiae was inhibited at concentrations higher than 100 μg per mL. The purified molecule is toxic for the adults of the rice weevils at concentrations down to 100 μg per g of food, but this does not apply to the others insects tested, including the coleopteran Tribolium castaneum and the Sf9 insect cultured cells.Conclusions: This specificity for the weevil led us to investigate this saponin potential for pest control and to propose the hypothesis that this saponin has a specific mode of action, rather than acting via its non-specific detergent properties.","PeriodicalId":80682,"journal":{"name":"BMC chemical biology","volume":" ","pages":"3"},"PeriodicalIF":0.0,"publicationDate":"2012-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1472-6769-12-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40186068","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: 31

Identification Of Small Molecule TRABID Deubiquitinase Inhibitors By Computation-Based Virtual Screen. 基于虚拟屏幕的小分子TRABID去泛素酶抑制剂鉴定。

BMC chemical biology Pub Date : 2012-05-14 DOI: 10.1186/1472-6769-12-4

Tong Shi, Ju Bao, Nick X Wang, Jie Zheng, Dianqing Wu

{"title":"Identification Of Small Molecule TRABID Deubiquitinase Inhibitors By Computation-Based Virtual Screen.","authors":"Tong Shi, Ju Bao, Nick X Wang, Jie Zheng, Dianqing Wu","doi":"10.1186/1472-6769-12-4","DOIUrl":"https://doi.org/10.1186/1472-6769-12-4","url":null,"abstract":"Background: Wnt/β-catenin-mediated gene transcription plays important roles in a wide range of biological and pathophysiological processes including tumorigenesis where β-catenin-mediated transcription activity frequently elevates. TRABID, a deubiquitinase, was shown to have a positive Wnt/β-catenin-mediated gene transcription and hence holds a promise as a putative anti-cancer target.Results: In this study, we used a combination of structure based virtual screening and an in vitro deubiquitinase (DUB) assay to identify several small molecules that inhibit TRABID DUB activity. However, these inhibitors failed to show inhibitory effects on β-catenin-mediated gene transcription. In addition, expression of TRABID shRNAs, wildtype TRABID, or the DUB activity-deficient mutant showed little effects on β-catenin-mediated gene transcription.Conclusions: TRABID may not be a critical component in canonical Wnt/β-catenin signal transduction or that a minute amount of this protein is sufficient for its role in regulating Wnt activity.","PeriodicalId":80682,"journal":{"name":"BMC chemical biology","volume":"12 ","pages":"4"},"PeriodicalIF":0.0,"publicationDate":"2012-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1472-6769-12-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30616880","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: 16

Comprehensive predictions of target proteins based on protein-chemical interaction using virtual screening and experimental verifications. 基于蛋白质-化学相互作用的综合预测，使用虚拟筛选和实验验证。

BMC chemical biology Pub Date : 2012-04-05 DOI: 10.1186/1472-6769-12-2

Hiroki Kobayashi, Hiroko Harada, Masaomi Nakamura, Yushi Futamura, Akihiro Ito, Minoru Yoshida, Shun-Ichiro Iemura, Kazuo Shin-Ya, Takayuki Doi, Takashi Takahashi, Tohru Natsume, Masaya Imoto, Yasubumi Sakakibara

{"title":"Comprehensive predictions of target proteins based on protein-chemical interaction using virtual screening and experimental verifications.","authors":"Hiroki Kobayashi, Hiroko Harada, Masaomi Nakamura, Yushi Futamura, Akihiro Ito, Minoru Yoshida, Shun-Ichiro Iemura, Kazuo Shin-Ya, Takayuki Doi, Takashi Takahashi, Tohru Natsume, Masaya Imoto, Yasubumi Sakakibara","doi":"10.1186/1472-6769-12-2","DOIUrl":"https://doi.org/10.1186/1472-6769-12-2","url":null,"abstract":"Background: Identification of the target proteins of bioactive compounds is critical for elucidating the mode of action; however, target identification has been difficult in general, mostly due to the low sensitivity of detection using affinity chromatography followed by CBB staining and MS/MS analysis.Results: We applied our protocol of predicting target proteins combining in silico screening and experimental verification for incednine, which inhibits the anti-apoptotic function of Bcl-xL by an unknown mechanism. One hundred eighty-two target protein candidates were computationally predicted to bind to incednine by the statistical prediction method, and the predictions were verified by in vitro binding of incednine to seven proteins, whose expression can be confirmed in our cell system.As a result, 40% accuracy of the computational predictions was achieved successfully, and we newly found 3 incednine-binding proteins.Conclusions: This study revealed that our proposed protocol of predicting target protein combining in silico screening and experimental verification is useful, and provides new insight into a strategy for identifying target proteins of small molecules.","PeriodicalId":80682,"journal":{"name":"BMC chemical biology","volume":"12 ","pages":"2"},"PeriodicalIF":0.0,"publicationDate":"2012-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1472-6769-12-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30554362","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: 7

HIV-1 Nef interaction influences the ATP-binding site of the Src-family kinase, Hck. HIV-1 Nef相互作用影响src家族激酶Hck的atp结合位点。

BMC chemical biology Pub Date : 2012-03-15 DOI: 10.1186/1472-6769-12-1

Teodora Pene-Dumitrescu, Sherry T Shu, Thomas E Wales, John J Alvarado, Haibin Shi, Purushottam Narute, Jamie A Moroco, Joanne I Yeh, John R Engen, Thomas E Smithgall

{"title":"HIV-1 Nef interaction influences the ATP-binding site of the Src-family kinase, Hck.","authors":"Teodora Pene-Dumitrescu, Sherry T Shu, Thomas E Wales, John J Alvarado, Haibin Shi, Purushottam Narute, Jamie A Moroco, Joanne I Yeh, John R Engen, Thomas E Smithgall","doi":"10.1186/1472-6769-12-1","DOIUrl":"https://doi.org/10.1186/1472-6769-12-1","url":null,"abstract":"Background: Nef is an HIV-1 accessory protein essential for viral replication and AIDS progression. Nef interacts with a multitude of host cell signaling partners, including members of the Src kinase family. Nef preferentially activates Hck, a Src-family kinase (SFK) strongly expressed in macrophages and other HIV target cells, by binding to its regulatory SH3 domain. Recently, we identified a series of kinase inhibitors that preferentially inhibit Hck in the presence of Nef. These compounds also block Nef-dependent HIV replication, validating the Nef-SFK signaling pathway as an antiretroviral drug target. Our findings also suggested that by binding to the Hck SH3 domain, Nef indirectly affects the conformation of the kinase active site to favor inhibitor association.Results: To test this hypothesis, we engineered a \"gatekeeper\" mutant of Hck with enhanced sensitivity to the pyrazolopyrimidine tyrosine kinase inhibitor, NaPP1. We also modified the RT loop of the Hck SH3 domain to enhance interaction of the kinase with Nef. This modification stabilized Nef:Hck interaction in solution-based kinase assays, as a way to mimic the more stable association that likely occurs at cellular membranes. Introduction of the modified RT loop rendered Hck remarkably more sensitive to activation by Nef, and led to a significant decrease in the Km for ATP as well as enhanced inhibitor potency.Conclusions: These observations suggest that stable interaction with Nef may induce Src-family kinase active site conformations amenable to selective inhibitor targeting.","PeriodicalId":80682,"journal":{"name":"BMC chemical biology","volume":" ","pages":"1"},"PeriodicalIF":0.0,"publicationDate":"2012-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1472-6769-12-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40167616","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: 20

Development of an HPLC method for determination of pentachloronitrobenzene, hexachlorobenzene and their possible metabolites. 建立HPLC法测定五氯硝基苯、六氯苯及其可能代谢物的方法。

BMC chemical biology Pub Date : 2011-11-23 DOI: 10.1186/1472-6769-11-2

Fazlurrahman Khan, Dhan Prakash, Rk Jain

{"title":"Development of an HPLC method for determination of pentachloronitrobenzene, hexachlorobenzene and their possible metabolites.","authors":"Fazlurrahman Khan, Dhan Prakash, Rk Jain","doi":"10.1186/1472-6769-11-2","DOIUrl":"https://doi.org/10.1186/1472-6769-11-2","url":null,"abstract":"Background: Pentachloronitrobenzene (PCNB) and hexachlorobenzene (HCB) are highly toxic and widespread in every environmental compartment. Some of metabolic products such as amino/nitro containing chlorinated aromatic compounds can be determined by gas chromatography coupled with electron capture detector (GC-ECD). However, it is difficult to identify some of chlorophenolic and chloroquinolic intermediates produced from PCNB and HCB by the above mentioned technique. Therefore, for analysis of these compounds and their metabolites, we have developed a high performance liquid chromatography (HPLC) based method.Results: The extraction of PCNB and HCB from soil and minimal salt medium was carried out with ethyl acetate and hexane respectively with good recoveries (98% for PCNB and 97% for HCB). The validation of the proposed extraction and HPLC method was done by analysis of PCNB and HCB biodegradation and their metabolites identification from anaerobic enriched soil samples.Conclusion: A rapid, sensitive and simple HPLC based analytical method was developed for the analysis of PCNB, HCB and their possible intermediates.","PeriodicalId":80682,"journal":{"name":"BMC chemical biology","volume":"11 ","pages":"2"},"PeriodicalIF":0.0,"publicationDate":"2011-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1472-6769-11-2","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30133442","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: 8

Chemical modification of L-glutamine to alpha-amino glutarimide on autoclaving facilitates Agrobacterium infection of host and non-host plants: A new use of a known compound. l -谷氨酰胺在高压灭菌中化学修饰为α -氨基谷氨酰胺，促进了农杆菌感染宿主和非宿主植物:一种已知化合物的新用途。

BMC chemical biology Pub Date : 2011-05-31 DOI: 10.1186/1472-6769-11-1

Indra Sandal, Amita Bhattacharya, Uksha Saini, Devinder Kaur, Shveta Sharma, Ashu Gulati, Jonnala K Kumar, Neeraj Kumar, Jyotsna Dayma, Pralay Das, Bikram Singh, Paramvir S Ahuja

{"title":"Chemical modification of L-glutamine to alpha-amino glutarimide on autoclaving facilitates Agrobacterium infection of host and non-host plants: A new use of a known compound.","authors":"Indra Sandal, Amita Bhattacharya, Uksha Saini, Devinder Kaur, Shveta Sharma, Ashu Gulati, Jonnala K Kumar, Neeraj Kumar, Jyotsna Dayma, Pralay Das, Bikram Singh, Paramvir S Ahuja","doi":"10.1186/1472-6769-11-1","DOIUrl":"https://doi.org/10.1186/1472-6769-11-1","url":null,"abstract":"Background: Accidental autoclaving of L-glutamine was found to facilitate the Agrobacterium infection of a non host plant like tea in an earlier study. In the present communication, we elucidate the structural changes in L-glutamine due to autoclaving and also confirm the role of heat transformed L-glutamine in Agrobacterium mediated genetic transformation of host/non host plants.Results: When autoclaved at 121°C and 15 psi for 20 or 40 min, L-glutamine was structurally modified into 5-oxo proline and 3-amino glutarimide (α-amino glutarimide), respectively. Of the two autoclaved products, only α-amino glutarimide facilitated Agrobacterium infection of a number of resistant to susceptible plants. However, the compound did not have any vir gene inducing property.Conclusions: We report a one pot autoclave process for the synthesis of 5-oxo proline and α-amino glutarimide from L-glutamine. Xenobiotic detoxifying property of α-amino glutarimide is also proposed.","PeriodicalId":80682,"journal":{"name":"BMC chemical biology","volume":"11 ","pages":"1"},"PeriodicalIF":0.0,"publicationDate":"2011-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1472-6769-11-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30203314","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: 5

The Terebridae and teretoxins: Combining phylogeny and anatomy for concerted discovery of bioactive compounds. Terebridae和teretoxins:结合系统发育和解剖学一致发现的生物活性化合物。

BMC chemical biology Pub Date : 2010-09-17 DOI: 10.1186/1472-6769-10-7

Nicolas Puillandre, Mandë Holford

{"title":"The Terebridae and teretoxins: Combining phylogeny and anatomy for concerted discovery of bioactive compounds.","authors":"Nicolas Puillandre, Mandë Holford","doi":"10.1186/1472-6769-10-7","DOIUrl":"https://doi.org/10.1186/1472-6769-10-7","url":null,"abstract":" The Conoidea superfamily, comprised of cone snails, terebrids, and turrids, is an exceptionally promising group for the discovery of natural peptide toxins. The potential of conoidean toxins has been realized with the distribution of the first Conus (cone snail) drug, Prialt (ziconotide), an analgesic used to alleviate chronic pain in HIV and cancer patients. Cone snail toxins (conotoxins) are highly variable, a consequence of a high mutation rate associated to duplication events and positive selection. As Conus and terebrids diverged in the early Paleocene, the toxins from terebrids (teretoxins) may demonstrate highly divergent and unique functionalities. Recent analyses of the Terebridae, a largely distributed family with more than 300 described species, indicate they have evolutionary and pharmacological potential. Based on a three gene (COI, 12S and 16S) molecular phylogeny, including ~50 species from the West-Pacific, five main terebrid lineages were discriminated: two of these lineages independently lost their venom apparatus, and one venomous lineage was previously unknown. Knowing the phylogenetic relationships within the Terebridae aids in effectively targeting divergent lineages with novel peptide toxins. Preliminary results indicate that teretoxins are similar in structure and composition to conotoxins, suggesting teretoxins are an attractive line of research to discover and develop new therapeutics that target ion channels and receptors. Using conotoxins as a guideline, and innovative natural products discovery strategies, such as the Concerted Discovery Strategy, the potential of the Terebridae and their toxins are explored as a pioneering pharmacological resource.","PeriodicalId":80682,"journal":{"name":"BMC chemical biology","volume":" ","pages":"7"},"PeriodicalIF":0.0,"publicationDate":"2010-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1472-6769-10-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40075004","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: 43

Chemical-genetic profile analysis of five inhibitory compounds in yeast. 酵母中5种抑菌化合物的化学-遗传谱分析。

BMC chemical biology Pub Date : 2010-08-06 DOI: 10.1186/1472-6769-10-6

Md Alamgir, Veronika Erukova, Matthew Jessulat, Ali Azizi, Ashkan Golshani

{"title":"Chemical-genetic profile analysis of five inhibitory compounds in yeast.","authors":"Md Alamgir, Veronika Erukova, Matthew Jessulat, Ali Azizi, Ashkan Golshani","doi":"10.1186/1472-6769-10-6","DOIUrl":"https://doi.org/10.1186/1472-6769-10-6","url":null,"abstract":"Background: Chemical-genetic profiling of inhibitory compounds can lead to identification of their modes of action. These profiles can help elucidate the complex interactions between small bioactive compounds and the cell machinery, and explain putative gene function(s).Results: Colony size reduction was used to investigate the chemical-genetic profile of cycloheximide, 3-amino-1,2,4-triazole, paromomycin, streptomycin and neomycin in the yeast Saccharomyces cerevisiae. These compounds target the process of protein biosynthesis. More than 70,000 strains were analyzed from the array of gene deletion mutant yeast strains. As expected, the overall profiles of the tested compounds were similar, with deletions for genes involved in protein biosynthesis being the major category followed by metabolism. This implies that novel genes involved in protein biosynthesis could be identified from these profiles. Further investigations were carried out to assess the activity of three profiled genes in the process of protein biosynthesis using relative fitness of double mutants and other genetic assays.Conclusion: Chemical-genetic profiles provide insight into the molecular mechanism(s) of the examined compounds by elucidating their potential primary and secondary cellular target sites. Our follow-up investigations into the activity of three profiled genes in the process of protein biosynthesis provided further evidence concerning the usefulness of chemical-genetic analyses for annotating gene functions. We termed these genes TAE2, TAE3 and TAE4 for translation associated elements 2-4.","PeriodicalId":80682,"journal":{"name":"BMC chemical biology","volume":"10 ","pages":"6"},"PeriodicalIF":0.0,"publicationDate":"2010-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1472-6769-10-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"29171744","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: 52

Novel protein kinase D inhibitors cause potent arrest in prostate cancer cell growth and motility. 新型蛋白激酶D抑制剂可有效抑制前列腺癌细胞的生长和运动。

BMC chemical biology Pub Date : 2010-05-05 DOI: 10.1186/1472-6769-10-5

Courtney R Lavalle, Karla Bravo-Altamirano, Karthik V Giridhar, Jun Chen, Elizabeth Sharlow, John S Lazo, Peter Wipf, Q Jane Wang

{"title":"Novel protein kinase D inhibitors cause potent arrest in prostate cancer cell growth and motility.","authors":"Courtney R Lavalle, Karla Bravo-Altamirano, Karthik V Giridhar, Jun Chen, Elizabeth Sharlow, John S Lazo, Peter Wipf, Q Jane Wang","doi":"10.1186/1472-6769-10-5","DOIUrl":"https://doi.org/10.1186/1472-6769-10-5","url":null,"abstract":"Background: Protein kinase D (PKD) has been implicated in a wide range of cellular processes and pathological conditions including cancer. However, targeting PKD therapeutically and dissecting PKD-mediated cellular responses remains difficult due to lack of a potent and selective inhibitor. Previously, we identified a novel pan-PKD inhibitor, CID755673, with potency in the upper nanomolar range and high selectivity for PKD. In an effort to further enhance its selectivity and potency for potential in vivo application, small molecule analogs of CID755673 were generated by modifying both the core structure and side-chains.Results: After initial activity screening, five analogs with equal or greater potencies as CID755673 were chosen for further analysis: kb-NB142-70, kb-NB165-09, kb-NB165-31, kb-NB165-92, and kb-NB184-02. Our data showed that modifications to the aromatic core structure in particular significantly increased potency while retaining high specificity for PKD. When tested in prostate cancer cells, all compounds inhibited PMA-induced autophosphorylation of PKD1, with kb-NB142-70 being most active. Importantly, these analogs caused a dramatic arrest in cell proliferation accompanying elevated cytotoxicity when applied to prostate cancer cells. Cell migration and invasion were also inhibited by these analogs with varying potencies that correlated to their cellular activity.Conclusions: Throughout the battery of experiments, the compounds kb-NB142-70 and kb-NB165-09 emerged as the most potent and specific analogs in vitro and in cells. These compounds are undergoing further testing for their effectiveness as pharmacological tools for dissecting PKD function and as potential anti-cancer agents in the treatment of prostate cancer.","PeriodicalId":80682,"journal":{"name":"BMC chemical biology","volume":"10 ","pages":"5"},"PeriodicalIF":0.0,"publicationDate":"2010-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/1472-6769-10-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"28967047","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: 91