Inhibition of Hepatitis C Replication by Targeting the Molecular Chaperone Hsp90: Synthesis and Biological Evaluation of 4,5,6,7-Tetrahydrobenzo[1,2-d]thiazole Derivatives.


:Cellular chaperones that belong to the heat-shock protein 90 (Hsp90) family are a prerequisite for successful viral propagation for most viruses. The hepatitis C virus (HCV) uses Hsp90 for maturation, folding, and modification of viral proteins. Based on our previous discovery that marine alkaloid analogues with a 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole-2-amine structure show inhibition of HCV replication and binding to Hsp90, a series of twelve novel compounds based on this scaffold was designed and synthesized. The aim was improved Hsp90 affinity and anti-HCV activity. Through structural optimization, improved binding to Hsp90 and specific HCV inhibition in genotype 1b and 2a replicon models was achieved for three compounds belonging to the newly synthesized series. Furthermore, these compounds efficiently inhibited replication of full-length HCV genotype 2a in a reporter virus RNA assay with IC50 values ranging from 0.03 to 0.6 μm.






Lillsunde KE,Tomašič T,Schult P,Lohmann V,Kikelj D,Tammela P




Has Abstract


2019-02-05 00:00:00












  • The Molecular Basis for Dual Fatty Acid Amide Hydrolase (FAAH)/Cyclooxygenase (COX) Inhibition.

    abstract::The design of multitarget-directed ligands is a promising strategy for discovering innovative drugs. Here, we report a mechanistic study that clarifies key aspects of the dual inhibition of the fatty acid amide hydrolase (FAAH) and the cyclooxygenase (COX) enzymes by a new multitarget-directed ligand named ARN2508 (2-...


    pub_type: 杂志文章


    authors: Palermo G,Favia AD,Convertino M,De Vivo M

    更新日期:2016-06-20 00:00:00

  • Design, synthesis, biological evaluation, and molecular modeling studies of TIBO-like cyclic sulfones as non-nucleoside HIV-1 reverse transcriptase inhibitors.

    abstract::TIBO- and TBO-like sulfone derivatives 1 and 2 were designed, synthesized, and tested for their ability to block the replication cycle of HIV-1 in infected cells. The anti-HIV-1 activities of sulfones 3, which were intermediates in the syntheses of 1 and 2, were also evaluated. Surprisingly, the sulfone analogues of T...


    pub_type: 杂志文章


    authors: Di Santo R,Costi R,Artico M,Ragno R,Lavecchia A,Novellino E,Gavuzzo E,La Torre F,Cirilli R,Cancio R,Maga G

    更新日期:2006-01-01 00:00:00

  • Synthesis and quantitative structure-activity relationships of selective BCRP inhibitors.

    abstract::The breast cancer resistance protein (BCRP/ABCG2) is a member of the ABC transporter superfamily. This protein has a number of physiological functions, including protection of the human body from xenobiotics. The overexpression of BCRP in certain tumor cell lines causes cross-resistance against various drugs used in c...


    pub_type: 杂志文章


    authors: Marighetti F,Steggemann K,Hanl M,Wiese M

    更新日期:2013-01-01 00:00:00

  • The Design of Potent, Selective and Drug-Like RGD αvβ1 Small-Molecule Inhibitors Derived from non-RGD α4β1 Antagonists.

    abstract::Up to 45 % of deaths in developed nations can be attributed to chronic fibroproliferative diseases, highlighting the need for effective therapies. The RGD (Arg-Gly-Asp) integrin αvβ1 was recently investigated for its role in fibrotic disease, and thus warrants therapeutic targeting. Herein we describe the identificati...


    pub_type: 杂志文章


    authors: Hatley RJD,Barrett TN,Slack RJ,Watson ME,Baillache DJ,Gruszka A,Washio Y,Rowedder JE,Pogány P,Pal S,Macdonald SJF

    更新日期:2019-07-17 00:00:00

  • Discovery of isoerianin analogues as promising anticancer agents.

    abstract::The cytotoxic activity of a series of 23 new isoerianin derivatives with modifications on both the A and B rings was studied. Several compounds exhibited excellent antiproliferative activity at nanomolar concentrations against a panel of human cancer cell lines. The most cytotoxic compound, isoerianin (3), strongly in...


    pub_type: 杂志文章


    authors: Messaoudi S,Hamze A,Provot O,Tréguier B,Rodrigo De Losada J,Bignon J,Liu JM,Wdzieczak-Bakala J,Thoret S,Dubois J,Brion JD,Alami M

    更新日期:2011-03-07 00:00:00

  • Discovery and Mechanistic Elucidation of a Class of Protein Disulfide Isomerase Inhibitors for the Treatment of Glioblastoma.

    abstract::Protein disulfide isomerase (PDI) is overexpressed in glioblastoma, the most aggressive form of brain cancer, and folds nascent proteins responsible for the progression and spread of the disease. Herein we describe a novel nanomolar PDI inhibitor, pyrimidotriazinedione 35G8, that is toxic in a panel of human glioblast...


    pub_type: 杂志文章


    authors: Kyani A,Tamura S,Yang S,Shergalis A,Samanta S,Kuang Y,Ljungman M,Neamati N

    更新日期:2018-01-22 00:00:00

  • Structure-activity relationships of a novel group of large-conductance Ca(2+)-activated K(+) (BK) channel modulators: the GoSlo-SR family.

    abstract::Opening up ion channels: We synthesised a series of anthraquinone analogues, called the GoSlo-SR family. Their effects on bladder smooth muscle BK channels were examined and, as shown, shifted voltage dependent activation >-100 mV (at 10 μM). They were more efficacious than NS11021 and could provide a new scaffold for...


    pub_type: 杂志文章


    authors: Roy S,Morayo Akande A,Large RJ,Webb TI,Camarasu C,Sergeant GP,McHale NG,Thornbury KD,Hollywood MA

    更新日期:2012-10-01 00:00:00

  • Ribonuclease A inhibition by carboxymethylsulfonyl-modified xylo- and arabinopyrimidines.

    abstract::A group of acidic nucleosides were synthesized to develop a new class of ribonuclease A (RNase A) inhibitors. Our recent study on carboxymethylsulfonyl-modified nucleosides revealed some interesting results in RNase A inhibition. This positive outcome triggered an investigation of the role played by secondary sugar hy...


    pub_type: 杂志文章


    authors: Datta D,Dasgupta S,Pathak T

    更新日期:2014-09-01 00:00:00

  • A glucose derivative as natural alternative to the cyclohexane-1,2-diamine ligand in the anticancer drug oxaliplatin?

    abstract::Having oxaliplatin as archetype, several platinum complexes with a carbohydrate moiety resembling the cyclohexane-1,2-diamine ligand of oxaliplatin have been prepared. As leaving groups, the anionic ligands iodide, oxalate, and malonate were utilized, and for comparison purposes the chloro complex was employed. All co...


    pub_type: 杂志文章


    authors: Berger I,Nazarov AA,Hartinger CG,Groessl M,Valiahdi SM,Jakupec MA,Keppler BK

    更新日期:2007-04-01 00:00:00

  • Synthesis of aryl-substituted naphthalene-linked pyrrolobenzodiazepine conjugates as potential anticancer agents with apoptosis-inducing ability.

    abstract::A library of new aryl-substituted naphthalene C8-linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates with various linker architectures were designed, synthesized, and evaluated for their anticancer activity against a panel of 11 human cancer cell lines. All 32 conjugates show anticancer potential, with some of t...


    pub_type: 杂志文章


    authors: Kamal A,Reddy MK,Ramaiah MJ,Srikanth YV,Rajender,Reddy VS,Kumar GB,Pushpavalli SN,Bag I,Juvekar A,Sen S,Zingde SM,Pal-Bhadra M

    更新日期:2011-09-05 00:00:00

  • trans,cis,cis-bis(benzoato)dichlorido(cyclohexane-1R,2R-diamine)platinum(IV): a prodrug candidate for the treatment of oxaliplatin-refractory colorectal cancer.

    abstract::The gold standard for the treatment of metastatic colorectal cancer consists of combination chemotherapy. Over time, however, the development of chemoresistant tumor clones leads to relapse. It may be possible to overcome oxaliplatin chemoresistance in colorectal cancer cells by exploiting a complex obtained from the ...


    pub_type: 杂志文章


    authors: Gandin V,Marzano C,Pelosi G,Ravera M,Gabano E,Osella D

    更新日期:2014-06-01 00:00:00

  • Selective inhibitors of the protein tyrosine phosphatase SHP2 block cellular motility and growth of cancer cells in vitro and in vivo.

    abstract::Selective inhibitors of the protein tyrosine phosphatase SHP2 (src homology region 2 domain phosphatase; PTPN11), an enzyme that is deregulated in numerous human tumors, were generated through a combination of chemical synthesis and structure-based rational design. Seventy pyridazolon-4-ylidenehydrazinyl benzenesulfon...


    pub_type: 杂志文章


    authors: Grosskopf S,Eckert C,Arkona C,Radetzki S,Böhm K,Heinemann U,Wolber G,von Kries JP,Birchmeier W,Rademann J

    更新日期:2015-05-01 00:00:00

  • MT1-selective melatonin receptor ligands: synthesis, pharmacological evaluation, and molecular dynamics investigation of N-{[(3-O-substituted)anilino]alkyl}amides.

    abstract::The design of compounds selective for the MT1 melatonin receptor is still a challenging task owing to the limited knowledge of the structural features conferring selectivity for the MT1 subtype, and only few selective compounds have been reported so far. N-(Anilinoalkyl)amides are a versatile class of melatonin recept...


    pub_type: 杂志文章


    authors: Rivara S,Pala D,Lodola A,Mor M,Lucini V,Dugnani S,Scaglione F,Bedini A,Lucarini S,Tarzia G,Spadoni G

    更新日期:2012-11-01 00:00:00

  • Structure-activity relationships and mechanism of action of Eph-ephrin antagonists: interaction of cholanic acid with the EphA2 receptor.

    abstract::The Eph-ephrin system, including the EphA2 receptor and the ephrinA1 ligand, plays a critical role in tumor and vascular functions during carcinogenesis. We previously identified (3α,5β)-3-hydroxycholan-24-oic acid (lithocholic acid) as an Eph-ephrin antagonist that is able to inhibit EphA2 receptor activation; it is ...


    pub_type: 杂志文章


    authors: Tognolini M,Incerti M,Hassan-Mohamed I,Giorgio C,Russo S,Bruni R,Lelli B,Bracci L,Noberini R,Pasquale EB,Barocelli E,Vicini P,Mor M,Lodola A

    更新日期:2012-06-01 00:00:00

  • Synthesis of imidazothiazole-chalcone derivatives as anticancer and apoptosis inducing agents.

    abstract::A new class of imidazo[2,1-b]thiazole chalcone derivatives were synthesized and evaluated for their anticancer activity. These chalcone derivatives show promising activity, with log GI(50) values ranging from -7.51 to -4.00. The detailed biological aspects of these derivatives toward the MCF-7 cell line were studied. ...


    pub_type: 杂志文章


    authors: Kamal A,Dastagiri D,Ramaiah MJ,Reddy JS,Bharathi EV,Srinivas C,Pushpavalli SN,Pal D,Pal-Bhadra M

    更新日期:2010-11-08 00:00:00

  • The binding mode of side chain- and C3-modified epothilones to tubulin.

    abstract::The tubulin-binding mode of C3- and C15-modified analogues of epothilone A (Epo A) was determined by NMR spectroscopy and computational methods and compared with the existing structural models of tubulin-bound natural Epo A. Only minor differences were observed in the conformation of the macrocycle between Epo A and t...


    pub_type: 杂志文章


    authors: Erdélyi M,Navarro-Vázquez A,Pfeiffer B,Kuzniewski CN,Felser A,Widmer T,Gertsch J,Pera B,Díaz JF,Altmann KH,Carlomagno T

    更新日期:2010-06-07 00:00:00

  • N-cyano sulfoximines: COX inhibition, anticancer activity, cellular toxicity, and mutagenicity.

    abstract::From insects to cancer: N-Cyano sulfoximines were evaluated for COX inhibition and antiproliferative activity against a panel of cancer cell lines. The most active compound exhibited potent COX-2 inhibition, some selectivity for COX-2 over COX-1, only slight cytotoxicity towards healthy cells (HaCaT skin cells), and n...


    pub_type: 杂志文章


    authors: Park SJ,Baars H,Mersmann S,Buschmann H,Baron JM,Amann PM,Czaja K,Hollert H,Bluhm K,Redelstein R,Bolm C

    更新日期:2013-02-01 00:00:00

  • Cyclic RGD-containing functionalized azabicycloalkane peptides as potent integrin antagonists for tumor targeting.

    abstract::Cyclic RGD-containing functionalized azabicycloalkane peptides were synthesized with the aim of developing high-affinity selective integrin ligands as carriers for therapeutic and diagnostic purposes. Herein we describe the synthesis and in vitro screening of these RGD derivatives, as well as the determination of thei...


    pub_type: 杂志文章


    authors: Manzoni L,Belvisi L,Arosio D,Civera M,Pilkington-Miksa M,Potenza D,Caprini A,Araldi EM,Monferini E,Mancino M,Podestà F,Scolastico C

    更新日期:2009-04-01 00:00:00

  • Synthesis and activity of a trinuclear platinum complex: [{trans-PtCl(NH3)2}2mu-{trans-Pt(3-hydroxypyridine)2(H2N(CH2)6NH2)2}]Cl4 in ovarian cancer cell lines.

    abstract::This paper describes the synthesis, characterisation, and cytotoxicity of a novel trinuclear platinum complex code named TH1. In addition to its activity against human ovarian cancer cell lines: A2780, A2780(cisR), and A2780(ZD0473R), cell uptake, DNA-binding, and the nature of the compound interaction with pBR322 pla...


    pub_type: 杂志文章


    authors: Tayyem H,Huq F,Yu JQ,Beale P,Fisher K

    更新日期:2008-01-01 00:00:00

  • Homology modeling of the serotonin transporter: insights into the primary escitalopram-binding site.

    abstract::The serotonin transporter (SERT) is one of the neurotransmitter transporters that plays a critical role in the regulation of endogenous amine concentrations and therefore is an important target for therapeutic agents affecting the central nervous system. The recently published, high resolution X-ray structure of the c...


    pub_type: 杂志文章


    authors: Jørgensen AM,Tagmose L,Jørgensen AM,Topiol S,Sabio M,Gundertofte K,Bøgesø KP,Peters GH

    更新日期:2007-06-01 00:00:00

  • Deuterated Curcuminoids: Synthesis, Structures, Computational/Docking and Comparative Cell Viability Assays against Colorectal Cancer.

    abstract::A series of deuterated curcuminoids (CUR) were synthesized, bearing two to six OCD3 groups, in some cases in combination with methoxy groups, and in others together with fluorine or chlorine atoms. A model ring-deuterated hexamethoxy-CUR-BF2 and its corresponding CUR compound were also synthesized from a 2,4,6-trimeth...


    pub_type: 杂志文章


    authors: Laali KK,Zwarycz AT,Bunge SD,Borosky GL,Nukaya M,Kennedy GD

    更新日期:2019-06-18 00:00:00

  • Isoprenoid Biosynthesis Inhibitors Targeting Bacterial Cell Growth.

    abstract::We synthesized potential inhibitors of farnesyl diphosphate synthase (FPPS), undecaprenyl diphosphate synthase (UPPS), or undecaprenyl diphosphate phosphatase (UPPP), and tested them in bacterial cell growth and enzyme inhibition assays. The most active compounds were found to be bisphosphonates with electron-withdraw...


    pub_type: 杂志文章


    authors: Desai J,Wang Y Dr,Wang K Dr,Malwal SR Dr,Oldfield E

    更新日期:2016-10-06 00:00:00

  • Structural Re-engineering of the α-Helix Mimetic JY-1-106 into Small Molecules: Disruption of the Mcl-1-Bak-BH3 Protein-Protein Interaction with 2,6-Di-Substituted Nicotinates.

    abstract::The disruption of aberrant protein-protein interactions (PPIs) with synthetic agents remains a challenging goal in contemporary medicinal chemistry but some progress has been made. One such dysregulated PPI is that between the anti-apoptotic Bcl-2 proteins, including myeloid cell leukemia-1 (Mcl-1), and the α-helical ...


    pub_type: 杂志文章


    authors: Drennen B,Scheenstra JA,Yap JL,Chen L,Lanning ME,Roth BM,Wilder PT,Fletcher S

    更新日期:2016-04-19 00:00:00

  • A Flexible Strategy for Modular Synthesis of Curcuminoid-BF2 /Curcuminoid Pairs and Their Comparative Antiproliferative Activity in Human Cancer Cell Lines.

    abstract::A facile protocol that enables synthetic interconversion of CUR-BF2 and CUR compounds is described that significantly widens the preparative scope of curcuminoids, providing access to larger libraries of compounds, thus enabling comparative antiproliferative and apoptotic study of a larger library of synthetic analogs...


    pub_type: 杂志文章


    authors: Abonia R,Laali KK,Raja Somu D,Bunge SD,Wang EC

    更新日期:2020-02-17 00:00:00

  • Design, synthesis, and biological evaluation of the first podophyllotoxin analogues as potential vascular-disrupting agents.

    abstract::We designed and synthesized two novel series of azapodophyllotoxin analogues as potential antivascular agents. A linker was inserted between the trimethoxyphenyl ring E and the tetracyclic ABCD moiety of the 4-aza-1,2-didehydropodophyllotoxins. In the first series, the linker enables free rotation between the two moie...


    pub_type: 杂志文章


    authors: Labruère R,Gautier B,Testud M,Seguin J,Lenoir C,Desbène-Finck S,Helissey P,Garbay C,Chabot GG,Vidal M,Giorgi-Renault S

    更新日期:2010-12-03 00:00:00

  • Fragmental modeling of human glutamate transporter EAAT1 and analysis of its binding modes by docking and pharmacophore mapping.

    abstract::The objective of the study was to generate a reliable model of the homotrimeric structure for the human glutamate transporter EAAT1, based on experimental folding of transporter homologue from Pyrococcus horikoshii. The monomer structure was derived using a fragmental approach and the homotrimer was assembled using pr...


    pub_type: 杂志文章


    authors: Pedretti A,De Luca L,Sciarrillo C,Vistoli G

    更新日期:2008-01-01 00:00:00

  • Comparative Pharmacological Study of Common NMDA Receptor Open Channel Blockers Regarding Their Affinity and Functional Activity toward GluN2A and GluN2B NMDA Receptors.

    abstract::Because only a few studies have investigated the affinity and functional activity of NMDA receptor open channel blockers under the same assay conditions, a comparative study of common open channel blockers is of major interest. The pharmacological activities of MK-801, phencyclidine (PCP), dexoxadrol, etoxadrol, (S)- ...


    pub_type: 杂志文章


    authors: Temme L,Schepmann D,Schreiber JA,Frehland B,Wünsch B

    更新日期:2018-03-06 00:00:00

  • Discovery of Vilaprisan (BAY 1002670): A Highly Potent and Selective Progesterone Receptor Modulator Optimized for Gynecologic Therapies.

    abstract::Progesterone plays an important role in the female reproductive system. However, there is also evidence that gynecologic disorders/diseases such as uterine fibroids and endometriosis are progesterone-dependent. Steroidal and non-steroidal selective progesterone receptor modulators (SPRMs) have shown potential for the ...


    pub_type: 杂志文章


    authors: Möller C,Bone W,Cleve A,Klar U,Rotgeri A,Rottmann A,Schultze-Mosgau MH,Wagenfeld A,Schwede W

    更新日期:2018-11-06 00:00:00

  • Phosphopeptide ligands of the SHP-1 N-SH2 domain: effects on binding and stimulation of phosphatase activity.

    abstract::Src homology 2 (SH2)-domain-mediated interactions with phosphotyrosine (pY)-containing ligands are critical for the regulation of SHP-1 phosphatase activity. Peptides based on a binding site from receptor tyrosine kinase Ros (EGLN-pY2267-MVL, 1) have recently been shown to bind to the SHP-1 N-terminal SH2 domain (N-SH...


    pub_type: 杂志文章


    authors: Hampel K,Kaufhold I,Zacharias M,Böhmer FD,Imhof D

    更新日期:2006-08-01 00:00:00

  • A Bisbenzamidine Phosphonate as a Janus-faced Inhibitor for Trypsin-like Serine Proteases.

    abstract::A hybrid approach was applied for the design of an inhibitor of trypsin-like serine proteases. Compound 16 [(R,R)- and (R,S)-diphenyl (4-(1-(4-amidinobenzylamino)-1-oxo-3-phenylpropan-2-ylcarbamoyl)phenylamino)(4-amidinophenyl)methylphosphonate hydrochloride], prepared in a convergent synthetic procedure, possesses a ...


    pub_type: 杂志文章


    authors: Häußler D,Scheidt T,Stirnberg M,Steinmetzer T,Gütschow M

    更新日期:2015-10-01 00:00:00