共查询到20条相似文献,搜索用时 15 毫秒
1.
Ibrahim M Azzouz N Gerold P Schwarz RT 《International journal for parasitology》2001,31(13):1489-1497
Prenylated proteins are involved in the regulation of DNA replication and cell cycling and have important roles in the regulation of cell proliferation. Protein farnesyltransferase and protein geranylgeranyltransferase are the two enzymes responsible for catalysing isoprene lipid modifications. Recently these enzymes have been targets for the development of cancer chemotherapeutics. Using metabolic labelling we identified isoprenylated proteins which suggests the presence of protein farnesyltransferase in Toxoplasma gondii. T. gondii protein farnesyltransferase is heat-labile and requires Mg(2+) and Zn(2+) ions for full activity. Peptidomimetic analogues as well as short synthetic peptides were tested in vitro as possible competitors for farnesyltransferase substrates. We found that the synthetic peptide (KTSCVIA) specifically inhibited T. gondiiprotein farnesyltransferase but not mammalian (HeLa cells) farnesyltransferase. Therefore this study suggests the possible development of specific inhibitors of T. gondiiprotein farnesyltransferase as an approach to parasitic protozoa therapy. 相似文献
2.
Kettler K Sakowski J Silber K Sattler I Klebe G Schlitzer M 《Bioorganic & medicinal chemistry》2003,11(7):1521-1530
We have designed the nitrophenylfurylacryl-substituted benzophenone 4f as a non-thiol farnesyltransferase inhibitor utilizing a novel aryl binding site of farnesyltransferase. Variation of the 2-acylamino substituent at the benzophenone core structure of our initial lead 4f yielded several non-thiol farnesyltransferase inhibitors with improved activity. These compounds display activity in the low nanomolar range. 相似文献
3.
Qian Y Marugan JJ Fossum RD Vogt A Sebti SM Hamilton AD 《Bioorganic & medicinal chemistry》1999,7(12):6867-3024
Cysteine farnesylation at the carboxylate terminal tetrapeptide CAAX of Ras protein is catalyzed by farnesyltransferase. This lipid modification is necessary for regulatory function of both normal and oncogenic Ras. The high frequency of Ras mutation in human cancers has prompted an intensive study on finding ways of controlling oncogenic Ras function. Inhibition of farnesyltransferase is among the most sought after targets for cancer chemotherapy. We report here the design, synthesis and biological characterization of a series of peptidomimetics as farnesyltransferase inhibitors. These compounds are extremely potent towards farnesyltransferase with IC50 values ranging from subnanomolar to low nanomolar concentrations. They have a high selectivity for farnesyltransferase over the closely related geranylgeranyltransferase-I. Structure–activity relationship studies demonstrated that a properly positioned hydrophobic group significantly enhanced inhibition potency, reflecting an improved complementarity to the large hydrophobic pocket in the CAAX binding site. 相似文献
4.
Investigations on the structure-activity relationships of benzophenone-based bisubstrate analogue farnesyltransferase inhibitors yielded a bisubstrate analogue farnesyltransferase inhibitor lacking any prenylic or peptidic substructures with nanomolar activity. This represents a considerable progress in comparison to those non-prenylic, non-peptidic bisubstrate analogue farnesyltransferase inhibitors we have described before which utilized AAX-peptidomimetic substructures different from the benzophenone since those inhibitors displayed activity only in the micromolar range. 相似文献
5.
Mitsch A Wissner P Silber K Haebel P Sattler I Klebe G Schlitzer M 《Bioorganic & medicinal chemistry》2004,12(17):4585-4600
We have designed arylfurylacryl-substituted benzophenones as non-thiol farnesyltransferase inhibitors utilizing a novel aryl binding site of farnesyltransferase. These compounds display activity in the low nanomolar range. 相似文献
6.
Design, synthesis and structure-activity relationship of a series of 3-imidazolylmethylaminophenylsulfonyltetrahydroquinolines as farnesyltransferase inhibitors are presented. A working pharmacophore of inhibiting farnesyltransferase by this series of inhibitors is proposed. 相似文献
7.
Olepu S Suryadevara PK Rivas K Yokoyama K Verlinde CL Chakrabarti D Van Voorhis WC Gelb MH 《Bioorganic & medicinal chemistry letters》2008,18(2):494-497
A new class of 2-oxo-tetrahydro-1,8-naphthyridine-based protein farnesyltransferase inhibitors were synthesized and found to inhibit protein farnesyltransferase from the malaria parasite with potencies in the low nanomolar range. The compounds were much less potent on mammalian protein prenyltransferases. Two of the compounds block the growth of malaria in culture with potencies in the sub-micromolar range. Some of the compounds were found to be much more metabolically stable than previously described tetrahydroquinoline-based protein farnesyltransferase inhibitors. 相似文献
8.
Prendergast GC 《Current opinion in cell biology》2000,12(2):166-173
Recent work suggests that farnesyltransferase inhibitors suppress cancer cell proliferation through mechanisms other than inhibiting Ras isoprenylation, which is not a crucial event. Recent evidence also suggests that the antineoplastic properties of farnesyltransferase inhibitors are due to alterations in the isoprenylation of RhoB, an endosomal Rho protein that functions in receptor trafficking. A shift in conceptual focus from Ras to Rho to understand how farnesyltransferase inhibitors act provides a new vantage to address old questions in the field and suggests strategies to improve and potentially widen clinical applications. 相似文献
9.
Belei D Dumea C Samson A Farce A Dubois J Bîcu E Ghinet A 《Bioorganic & medicinal chemistry letters》2012,22(14):4517-4522
The biological screening of the chemical library of our Organic Chemistry Department, carried out on an automated fluorescence-based FTase assay, allowed us to discover that a phenothiazine derivative (1d) was an inhibitor of farnesyltransferase. Three new series of human farnesyltransferase inhibitors, based on a phenothiazine scaffold, were synthesized with protein farnesyltransferase inhibition potencies in the low micromolar range. Ester derivative 9d was the most active compound in these series. Four synthesized compounds were evaluated for their antiproliferative activity on a NCI-60 cancer cell line panel. The modest results obtained in this preliminary investigation showed that mixing the phenothiazine and the 1,2,3-triazole motif in the structure of a single compound can lead to new scaffolds in the field of farnesyltransferase inhibitors. 相似文献
10.
3-Aryl-4-aryloyl-1-(1H-imidazol-5-yl)methylpyrrole, a novel class of farnesyltransferase inhibitors.
H Lee J Lee Y Shin W Jung J H Kim K Park S Ro H H Chung J S Koh 《Bioorganic & medicinal chemistry letters》2001,11(22):2963-2965
Design, synthesis and structure-activity relationship of a class of 3-aryl-4-aryloyl-1-(1H-imidazol-5-yl)methylpyrroles as farnesyltransferase inhibitors are described. Compound 7 inhibits farnesyltransferase with an IC(50) value of 4.6 nM. 相似文献
11.
Several CAAX-peptidomimetics were linked to homofarnesoic acid via a beta-alanyl spacer with the intention to obtain a novel type of bisubstrate analogue farnesyltransferase inhibitors. However, the compounds were found to be only weakly active in the farnesyltransferase inhibition assay. Nevertheless, they displayed antiproliferative activity against different tumor cell lines in the low micromolar range. Replacement of the beta-alanine moiety by aspartic acid-1-methyl ester resulted in a compound which inhibited the farnesyltransferase with an IC50 of 860 nM. The corresponding free acid showed a eightfold loss in activity (IC50 = 6.9 microM). 相似文献
12.
Angibaud P Saha AK Bourdrez X End DW Freyne E Lezouret P Mannens G Mevellec L Meyer C Pilatte I Poncelet V Roux B Smets G Van Dun J Venet M Wouters W 《Bioorganic & medicinal chemistry letters》2003,13(24):4361-4364
Replacement of the 1-methylimidazol-5-yl moiety in the farnesyltransferase inhibitor ZARNESTRA™ series by a 4-methyl-1,2,4-triazol-3-yl group gave us compounds with similar structure–activity relationship profiles showing that this triazole is potentially a good surrogate to imidazole for farnesyltransferase inhibition. 相似文献
13.
Ayumi Tanaka Mohamed O. Radwan Akiyuki Hamasaki Asumi Ejima Emiko Obata Ryoko Koga Hiroshi Tateishi Yoshinari Okamoto Mikako Fujita Mitsuyoshi Nakao Kazuo Umezawa Fuyuhiko Tamanoi Masami Otsuka 《Bioorganic & medicinal chemistry letters》2017,27(16):3862-3866
Protein prenylation such as farnesylation and geranylgeranylation is associated with various diseases. Thus, many inhibitors of prenyltransferase have been developed. We report novel inhibitors of farnesyltransferase with a zinc-site recognition moiety and a farnesyl/dodecyl group. Molecular docking analysis showed that both parts of the inhibitor fit well into the catalytic domain of farnesyltransferase. The synthesized inhibitors showed activity against farnesyltransferase in vitro and inhibited proliferation of the pancreatic cell line AsPC-1. Among the compounds with farnesyl and dodecyl groups, the inhibitor with a farnesyl group was found to have stronger and more selective activity. 相似文献
14.
15.
Gwaltney SL O'Connor SJ Nelson LT Sullivan GM Imade H Wang W Hasvold L Li Q Cohen J Gu WZ Tahir SK Bauch J Marsh K Ng SC Frost DJ Zhang H Muchmore S Jakob CG Stoll V Hutchins C Rosenberg SH Sham HL 《Bioorganic & medicinal chemistry letters》2003,13(7):1363-1366
Inhibitors of farnesyltransferase are effective against a variety of tumors in mouse models of cancer. Clinical trials to evaluate these agents in humans are ongoing. In our effort to develop new farnesyltransferase inhibitors, we have discovered bioavailable aryl tetrahydropyridines that are potent in cell culture. The design, synthesis, SAR and biological properties of these compounds will be discussed. 相似文献
16.
Mitsch A Böhm M Wissner P Sattler I Schlitzer M 《Bioorganic & medicinal chemistry》2002,10(8):2657-2662
We recently described a novel aryl binding site of farnesyltransferase. The 2-naphthylacryloyl residue was developed as an appropriate substituent for our benzophenone-based AAX-peptidomimetic capable of occupying this binding site, resulting in a non-thiol farnesyltransferase inhibitor with nanomolar activity. The activity of this inhibitor is readily explained on the basis of docking studies which show the 2-naphthyl residue fitting into the aryl binding site. 相似文献
17.
Gwaltney SL O'Connor SJ Nelson LT Sullivan GM Imade H Wang W Hasvold L Li Q Cohen J Gu WZ Tahir SK Bauch J Marsh K Ng SC Frost DJ Zhang H Muchmore S Jakob CG Stoll V Hutchins C Rosenberg SH Sham HL 《Bioorganic & medicinal chemistry letters》2003,13(7):1359-1362
Inhibitors of farnesyltransferase are effective against a variety of tumors in mouse models of cancer. Clinical trials to evaluate these agents in humans are ongoing. In our effort to develop new farnesyltransferase inhibitors, we have discovered a series of aryl tetrahydropyridines that incorporate substituted glycine, phenylalanine and histidine residues. The design, synthesis, SAR and biological properties of these compounds will be discussed. 相似文献
18.
Protein farnesyltransferase and geranylgeranyltransferase share a common alpha subunit 总被引:24,自引:0,他引:24
Mammalian farnesyltransferase, which attaches a 15 carbon isoprenoid, farnesyl, to a cysteine in p21ras proteins, contains two subunits, alpha and beta. The beta subunit is known to bind p21ras proteins. We show here that the alpha subunit is shared with another prenyltransferase that attaches 20 carbon geranylgeranyl to Ras-related proteins. Farnesyltransferase and geranylgeranyltransferase have similar molecular weights on gel filtration, but are separated by ion exchange chromatography. Both enzymes are precipitated and immunoblotted by multiple antibodies directed against the alpha subunit of farnesyltransferase. The two transferases have different specificities for the protein acceptor; farnesyltransferase prefers methionine or serine at the COOH-terminus and geranylgeranyltransferase prefers leucine. The current data indicate that both prenyltransferases are heterodimers that share a common alpha subunit with different beta subunits. 相似文献
19.
cDNA cloning and expression of the peptide-binding beta subunit of rat p21ras farnesyltransferase, the counterpart of yeast DPR1/RAM1 总被引:15,自引:0,他引:15
Protein farnesyltransferase is a heterodimeric enzyme that attaches a farnesyl group to cysteine in ras proteins and other membrane-associated proteins. The beta subunit contains the recognition site for the peptide substrates, but is inactive in the absence of the alpha subunit. A cloned cDNA for the rat beta subunit predicts a protein of 437 amino acids whose mRNA is present in many tissues. Transfection of the beta subunit cDNA produced farnesyltransferase activity in human kidney cells, but only when it was transfected together with a cDNA encoding part of the alpha subunit. Each of the subunits appeared to be unstable in the transfected cells unless the other subunit was present. The rat beta subunit shows 37% sequence identity with the protein encoded by the yeast DPR1/RAM1 gene, indicating that DPR1/RAM1 is the yeast counterpart of the peptide-binding subunit of the mammalian farnesyltransferase. 相似文献
20.
We have developed the 4-nitrocinnamoyl substituted benzophenone 4a as a novel non-thiol farnesyltransferase inhibitor. Replacement of the p-tolyl moiety of our initial lead structure 4a by different para and ortho substituted phenyl residues as well as by 1-naphthyl resulted in derivatives with considerably enhanced activity displaying IC(50) values between 42 and 52 nM. These compounds represent novel, readily accessible non-thiol farnesyltransferase inhibitors being more active than the corresponding thiol-containing analogues. 相似文献