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1.
Six β-carboline alkaloids (1-6) of the eudistomin Y class were isolated from the Korean ascidian Synoicum sp. These compounds were chemically converted to a known compound, eudistomin Y(1) (7) and six new derivatives, designated eudistomins Y(8)-Y(13) (8-13). Several of these natural and synthetic compounds exhibited moderate to significant antimicrobial activity, weak cytotoxic activity, and inhibitory activities toward sortase A, isocitrate lyase, and Na(+)/K(+)-ATPase. Structure-activity relationships were also deduced. 相似文献
2.
Moriarty KJ Koblish HK Garrabrant T Maisuria J Khalil E Ali F Petrounia IP Crysler CS Maroney AC Johnson DL Galemmo RA 《Bioorganic & medicinal chemistry letters》2006,16(22):5778-5783
A new class of Aurora-A inhibitors have been identified based on the 2-amino-pyrrolo[2,3-d]pyrimidine scaffold. Here, we describe the synthesis and SAR of this novel series. We report compounds which exhibit nanomolar activity in the Aurora-A biochemical assay and are able to inhibit tumor cell proliferation. This study culminates in compound 30, an inhibitor with potent activity against Aurora A (IC50=0.008 microM), anti-proliferative activity against several tumor cell lines and induces polyploidy in H460 cells. 相似文献
3.
Toshihide Yamasaki Duje Buric Christine Chacon Gérard Audran Diane Braguer Sylvain R.A. Marque Manon Carré Paul Brémond 《Bioorganic & medicinal chemistry》2019,27(10):1942-1951
Previously, we described alkoxyamines bearing a pyridine ring as new pro-drugs with low molecular weights and theranostic activity. Upon chemical stimulus, alkoxyamines undergo homolysis and release free radicals, which can, reportedly, enhance magnetic resonance imaging and trigger cancer cell death. In the present study, we describe the synthesis and the anti-cancer activity of sixteen novel alkoxyamines that contain an imidazole ring. Activation of the homolysis was conducted by protonation and/or methylation. These new molecules displayed cytotoxic activities towards human glioblastoma cell lines, including the U251-MG cells that are highly resistant to the conventional chemotherapeutic agent Temozolomide. We further showed that the biological activities of the alkoxyamines were not only related to their half-life times of homolysis. We lastly identified the alkoxyamine (RS/SR)-4a, with both a high antitumour activity and favourable logD7.4 and pKa values, which make it a robust candidate for blood-brain barrier penetrating therapeutics against brain neoplasia. 相似文献
4.
Simone Bonazzi Damien Barbaras Luc Patiny Rosario Scopelliti Patricia Schneider Stewart T. Cole Marcel Kaiser Reto Brun Karl Gademann 《Bioorganic & medicinal chemistry》2010,18(4):1464-1476
The synthesis of nine nostocarboline derivatives with substitutions of the 2-methyl group by alkyl, aryl and functionalized residues, 10 symmetrical bis cationic dimers linking 6-Cl-norharmane through the 2-position and fifteen derivatives of the marine alkaloids eudistomin N and O is reported. These compounds were evaluated in vitro against four parasites (Trypanosoma brucei rhodesiense STIB 900, Trypanosoma cruzi Tulahuen C2C4, Leishmania donovani MHOM-ET-67/L82 axenic amastigotes, and Plasmodium falciparum K1 strain), against Mycobacterium tuberculosis H37Rv, Mycobacterium smegmatis mc2155 and Corynebacterium glutamicum ATCC13032, and cytotoxicity was determined against L6 rat myoblast cells. Nostocarboline and derivatives displayed potent and selective in vitro inhibition of P. falciparum with weak cytotoxicity. The dimers displayed submicromolar inhibition of L. donovani and T. brucei, and nanomolar activity against P. falciparum, albeit with pronounced cytotoxicity. One dimer showed a MIC99 value against M. tuberculosis of 2.5 μg/ml. The alkylated eudistomin N and O derivatives displayed activities down to 18 nM against P. falciparum for N-Me Eudistomin N. Four dimers, nostocarboline and three eudostomin derivatives were evaluated in an in vivo Plasmodium berghei mouse model. No significant activity was observed for the dimers, but a 50% reduction in parasitaemia was observed at 4 × 50 mg/kg ip for nostocarboline. 相似文献
5.
6.
Thewlis KM Aldegheri L Harries MH Mookherjee C Oliosi B Ward SE 《Bioorganic & medicinal chemistry letters》2010,20(23):7116-7119
A series of novel AMPA receptor positive modulators displaying CNS penetration have been discovered with sub-micromolar activity and good selectivity over the cardiac channel receptor, hERG. We describe here the synthesis of these compounds which are biaryl pyrrolidine and tetrahydrofuran sulfonamides and disclose their activities against the human GluA2 flip isoform homotetrameric receptor. 相似文献
7.
Toda A Ohki H Yamanaka T Murano K Okuda S Kawabata K Hatano K Matsuda K Misumi K Itoh K Satoh K Inoue S 《Bioorganic & medicinal chemistry letters》2008,18(17):4849-4852
We describe herein the synthesis and biological evaluation of a series of novel cephalosporins with potent activity against Pseudomonas aeruginosa. Introduction of various amino groups to the 4-position of a 3-amino-2-methylpyrazole cephalosporin 3-side chain resulted in enhanced MIC values against multiple Pseudomonas aeruginosa strains and ultimately led to the discovery of FR264205 (15) with excellent anti-bacterial activity and weak convulsion effect by direct intracerebroventricular injection assay. 相似文献
8.
Mehellou Y McGuigan C Brancale A Balzarini J 《Bioorganic & medicinal chemistry letters》2007,17(13):3666-3669
We report the synthesis of 2',3'-didehydro-2',3'-dideoxyuridine (d4U) and 2',3'-dideoxyuridine (ddU) phosphoramidate 'ProTide' derivatives and their evaluation against HIV-1 and HIV-2. In addition, we conducted molecular modeling studies on both d4U and ddU monophosphates to investigate their second phosphorylation process. The findings from the modeling studies provide compelling evidence for the lack of anti-HIV activity of d4U phosphoramidates, in contrast with the corresponding ddU phosphoramidates. 相似文献
9.
Michał Gładysz Piotr Ruszkowski Jan Milecki 《Nucleosides, nucleotides & nucleic acids》2018,37(1):53-66
We describe synthesis of novel acyclic nucleoside analogues which are building blocks for CuAAC reaction and their activity against two types of human cancer cell lines (HeLa, KB). Three of chosen compounds show promising cytotoxic activity. Synthesis pathway starting from simple and easily accessible substrates employing DMT or TBDPS protective groups is described. Adenosine and thymidine analogues containing alkyne moiety and adenosine analogue containing azido group were synthesized. The obtained units showed ability of forming triazole motif under the CuAAC reaction conditions. 相似文献
10.
Ishihara T Seki N Hirayama F Orita M Koshio H Taniuchi Y Sakai-Moritani Y Iwatsuki Y Kaku S Kawasaki T Matsumoto Y Tsukamoto S 《Bioorganic & medicinal chemistry》2007,15(12):4175-4192
We describe here our investigation of a new series of orally active fXa inhibitors based on a prodrug strategy. Solid-phase parallel synthesis identified a unique series of fXa inhibitors with a substituted benzenesulfonyl group as a novel S4 binding element. This series resulted in compound 39, which exhibited potent inhibitory activity against fXa (IC50 = 13 nM) and excellent selectivity over thrombin (>7000-fold). The masking of its highly hydrophilic groups led to the creation of related prodrug 28, which demonstrated an anticoagulant effect after oral dosing. 相似文献
11.
da Silva Ferreira W Freire-de-Lima L Saraiva VB Alisson-Silva F Mendonça-Previato L Previato JO Echevarria A de Lima ME 《Bioorganic & medicinal chemistry》2008,16(6):2984-2991
We herein describe the synthesis and characterization of nine new 1,3,4-thiadiazolium-2-phenylamine chlorides derived from natural piperine. We evaluate their toxic effects against the different evolutive forms of Trypanosoma cruzi, and the host cell (murine macrophages). The results obtained show that mesoionic hydrochloride MI possesses the best activity profile. Compound MI may be a prototype for use in the development of a new chemotherapeutic agent with high efficiency, which may be employed in the treatment of Chagas' disease. 相似文献
12.
Bacchelli C Condom R Patino N Aubertin AM 《Nucleosides, nucleotides & nucleic acids》2000,19(3):567-584
We describe the synthesis of two series of acyclonucleosides:carbaacyclonucleosides and 1'-oxaacyclonucleosides which possess the same aglycone as clitocine 3 which is a natural nucleoside exhibiting interesting biological properties. These compounds have been obtained by condensation of 4-aminobutanol or 3-silyloxypropoxyamine with 4,6-dichloro-5-nitropyrimidine. Structural modifications have been made on the heterocyclic base and the side chain to enhance their potential activity. All these compounds have been tested against different viruses: HIV-1, HSV-1, HSV-2, CMV, VZV, EBV. The carbaacyclonucleoside 10 was associated with an anti-EBV activity (EC50 = 0.86 microg/mL). 相似文献
13.
Yoon-Suk Lee Sun Min Park Hwan Mook Kim Song-Kyu Park Kiho Lee Chang Woo Lee Byeang Hyean Kim 《Bioorganic & medicinal chemistry letters》2009,19(16):4688-4691
We describe (i) a simple method for the synthesis of C5-modified nucleosides from 5-iodo-2′-deoxyuridine and (ii) their activity against six types of human cancer cell lines (HCT15, MM231, NCI-H23, NUGC-3, PC-3, ACHN). We generated nitrile oxides in situ from oximes using a commercial bleaching agent; their cycloadditions with 5-ethynyl-2′-deoxyuridine yielded isoxazole derivatives possessing activity against the cancer cell lines. We synthesized several azides from benzylic bromides and their click reactions with 5-ethynyl-2′-deoxyuridine provided triazole derivatives. 相似文献
14.
2''-O-methyl, 2''-O-ethyl oligoribonucleotides and phosphorothioate oligodeoxyribonucleotides as inhibitors of the in vitro U7 snRNP-dependent mRNA processing event. 总被引:5,自引:5,他引:0
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M Cotten B Oberhauser H Brunar A Holzner G Issakides C R Noe G Schaffner E Wagner M L Birnstiel 《Nucleic acids research》1991,19(10):2629-2635
We describe the synthesis of 2'-O-methyl, 2'-O-ethyl oligoribonucleotides and phosphorothioate oligodeoxyribonucleotides and demonstrate their utility as inhibitors of the in vitro U7 snRNP-dependent mRNA processing event. These 2'-O-modified compounds were designed to possess the binding affinity of an RNA molecule towards a complementary RNA target with an enhanced stability against nucleases. The 2'-O-methyl and 2'-O-ethyl antisense compounds function as potent inhibitors of the reaction at 1-10 nM, approximately 5-fold more effective than a natural antisense RNA molecule and requiring an approximate 5-fold excess over the target RNA for 80% inhibition of the processing reaction. 相似文献
15.
Gudmundsson KS Johns BA Wang Z Turner EM Allen SH Freeman GA Boyd FL Sexton CJ Selleseth DW Moniri KR Creech KL 《Bioorganic & medicinal chemistry》2005,13(18):5346-5361
Herpesviruses are a significant source of human disease; amongst these herpes simplex virus 1 (HSV-1) and HSV-2 are very prevalent and cause recurrent infections. We recently identified a pyrazolo[1,5-a]pyridine scaffold that showed promising activity against HSV-1 and HSV-2 in Vero cell antiviral assays. Here, we describe the synthesis and anti-herpetic activity of several 3-pyrimidinyl-2-phenylpyrazolo[1,5-a]pyridines with differing 2-phenyl substitution patterns. Approaches to rapidly access a number of analogs with different 2-phenyl substitution patterns are outlined. Several of the compounds described have comparable activity to acyclovir against HSV-1 and HSV-2. 相似文献
16.
U1 small nuclear RNAs with altered specificity can be stably expressed in mammalian cells and promote permanent changes in pre-mRNA splicing. 总被引:5,自引:3,他引:2
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Pre-mRNA 5' splice site activity depends, at least in part, on base complementarity to U1 small nuclear RNA. In transient coexpression assays, defective 5' splice sites can regain activity in the presence of U1 carrying compensatory changes, but it is unclear whether such mutant U1 RNAs can be permanently expressed in mammalian cells. We have explored this issue to determine whether U1 small nuclear RNAs with altered specificity may be of value to rescue targeted mutant genes or alter pre-mRNA processing profiles. This effort was initiated following our observation that U1 with specificity for a splice site associated with an alternative H-ras exon substantially reduced the synthesis of the potentially oncogenic p21ras protein in transient assays. We describe the development of a mammalian complementation system that selects for removal of a splicing-defective intron placed within a drug resistance gene. Complementation was observed in proportion to the degree of complementarity between transfected mutant U1 genes and different defective splice sites, and all cells selected in this manner were found to express mutant U1 RNA. In addition, these cells showed specific activation of defective splice sites presented by an unlinked reporter gene. We discuss the prospects of this approach to permanently alter the expression of targeted genes in mammalian cells. 相似文献
17.
Jong Yeon Hwang Marc Peter Windisch Suyeon Jo Keumhyun Kim Sunju Kong Hyoung Cheul Kim Soohyun Kim Heeyoung Kim Myung Eun Lee Youngmi Kim Jihyun Choi Dong-Sik Park Eunjung Park Jeongjin Kwon Jiyoun Nam Sujin Ahn Jonathan Cechetto Junwon Kim Michel Liuzzi Zaesung No Jinhwa Lee 《Bioorganic & medicinal chemistry letters》2012,22(24):7297-7301
We describe a novel 7-aminopyrazolo[1,5-a]pyrimidine (7-APP) derivative as a potent hepatitis C virus (HCV) inhibitor. A series of 7-APPs was synthesized and evaluated for inhibitory activity against HCV in different cell culture systems. The synthesis and preliminary structure-activity relationship study of 7-APP are reported. 相似文献
18.
Tabart M Picaut G Desconclois JF Dutka-Malen S Huet Y Berthaud N 《Bioorganic & medicinal chemistry letters》2001,11(7):919-921
We describe here the synthesis and biological evaluation of a series of benzo[b]naphthyridones, a new family of tricyclic antibacterial compounds that have a gram-positive spectrum of activity. RP60556A, one of the most potent of these compounds, is bactericidal against multiresistant cocci, especially multiresistant Staphylococcus aureus strains. Its physico-chemical and biological properties make it particularly suitable for topical antibacterial use. 相似文献
19.
《Bioorganic & medicinal chemistry letters》2014,24(11):2415-2419
We describe the synthesis and biological evaluation of (+)-neopeltolide analogues with structural modifications in the oxazole-containing side chain. Evaluation of the antiproliferative activity of newly synthesized analogues against A549 human lung adenocarcinoma cells and PANC-1 human pancreatic carcinoma cells have shown that the C19–C20 and C26–C27 double bonds within the oxazole-containing side chain and the terminal methyl carbamate group are essential for potent activity. 相似文献
20.
Giuseppe Giannini Mauro Marzi Riccardo Pezzi Tiziana Brunetti Gianfranco Battistuzzi Maria Di Marzo Walter Cabri Loredana Vesci Claudio Pisano 《Bioorganic & medicinal chemistry letters》2009,19(8):2346-2349
With the aim to discover novel HDAC inhibitors with high potency and good safety profiles, we have designed a small library based on a N-hydroxy-(4-oxime)-cinnamide scaffold. We describe the synthesis of these novel compounds and some preliminary in vitro cytotoxic activity on three tumor cell lines, NB4, H460 and HCT116, as well as their inhibitory activity against class I, II and IV HDAC. Several 4-oxime derivatives demonstrated a promising inhibitory activity on HDAC6 and HDAC8 coupled to a good selectivity profile. 相似文献