The Experts below are selected from a list of 5778 Experts worldwide ranked by ideXlab platform
Martin Schlitzer - One of the best experts on this subject based on the ideXlab platform.
-
2-(aminoacylamino)benzophenones: Farnesyltransferase inhibition and antimalarial activity.
Die Pharmazie, 2005Co-Authors: Katja Kettler, Jacek Sakowski, J. Wiesner, Regina Ortmann, H. Jomaa, K. Fucik, Martin SchlitzerAbstract:The use of amino acids as acyl substitutents at the 2-amino group of our benzophenone core structure yielded compounds with mainly good to moderate Farnesyltransferase inhibitory and moderate antimalarial activity. However, these Farnesyltransferase inhibitors display some degree of selectivity towards malarial parasites since there was no cytotoxic activity observed at 70-80 microM.
-
Novel lead structures for antimalarial Farnesyltransferase inhibitors.
Die Pharmazie, 2005Co-Authors: Katja Kettler, Jacek Sakowski, J. Wiesner, Regina Ortmann, H. Jomaa, Martin SchlitzerAbstract:Through the combination of nitrophenylfurylacryloyl moiety which has been designed to occupy an aryl binding site of Farnesyltransferase with several AA(X)-peptidomimetic substructures some novel Farnesyltransferase inhibitors were obtained. Evaluation of their antimalarial activity and some initial modifications yielded a 4-benzophenone- and a sulfonamid-based novel lead for antimalarial Farnesyltransferase inhibitors.
-
Non-thiol Farnesyltransferase inhibitors: N-(4-tolylacetylamino-3-benzoylphenyl)-3-arylfurylacrylic acid amides.
Bioorganic & medicinal chemistry, 2004Co-Authors: Andreas Mitsch, Isabel Sattler, Katrin Silber, Peter Haebel, Pia Wissner, Gerhard Klebe, Martin SchlitzerAbstract: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.
-
2-(Arylpropionylamino)- and 2-(arylacryloylamino)benzophenones: Farnesyltransferase inhibition and antimalarial activity.
Die Pharmazie, 2004Co-Authors: K. Fucik, Katja Kettler, Regina Ortmann, H. Jomaa, Jochen Wiesner, Doris Unterreitmeier, Jürgen Krauss, Franz Bracher, Martin SchlitzerAbstract:Structural variation of the 2-acylamino moiety of some benzophenone Farnesyltransferase inhibitors led to the para-trifluoromethylphenylpropionyl derivative with relatively low Farnesyltransferase inhibition but considerable antimalarial activity and no cytotoxicity.
-
Non‐thiol Farnesyltransferase Inhibitors: FTase‐Inhibition and Cellular Activity of Benzophenone‐based Bisubstrate Analogue Farnesyltransferase Inhibitors
Archiv der Pharmazie, 2003Co-Authors: Andreas Mitsch, Isabel Sattler, Silke Bergemann, Ronald Gust, Martin SchlitzerAbstract:Some 5-acylaminoacylamino-benzophenone derivatives were designed as bisubstrate analogue Farnesyltransferase inhibitors. These compounds turned out to be only weakly active against Farnesyltransferase, but displayed an antiproliferative effect rendering them suitable for further development as a novel type of cytostatic agents.
Michael H. Gelb - One of the best experts on this subject based on the ideXlab platform.
-
Second generation analogues of the cancer drug clinical candidate tipifarnib for anti-Chagas disease drug discovery.
Journal of medicinal chemistry, 2010Co-Authors: James M. Kraus, Frederick S Buckner, Naveen Kumar Chennamaneni, Hari Babu Tatipaka, Sarah A Mcguffin, Mandana Karimi, Jenifer Arif, Christophe L. M. J. Verlinde, Michael H. GelbAbstract:We previously reported that the cancer drug clinical candidate tipifarnib kills the causative agent of Chagas disease, Trypanosoma cruzi, by blocking ergosterol biosynthesis at the level of inhibition of lanosterol 14α-demethylase. Tipifarnib is an inhibitor of human protein Farnesyltransferase. We synthesized tipifarnib analogues that no longer bind to protein Farnesyltransferase and display increased potency for killing parasites. This was achieved in a structure-guided fashion by changing the substituents attached to the phenyl group at the 4-position of the quinoline ring of tipifarnib and by replacing the amino group by OMe. Several compounds that kill Trypanosoma cruzi at subnanomolar concentrations and are devoid of protein Farnesyltransferase inhibition were discovered. The compounds are shown to be advantageous over other lanosterol 14α-demethylase inhibitors in that they show only modest potency for inhibition of human cytochrome P450 (3A4). Since tipifarnib displays high oral bioavailability an...
-
2 oxotetrahydroquinoline based antimalarials with high potency and metabolic stability
Journal of Medicinal Chemistry, 2008Co-Authors: Vivek J Bulbule, Christophe L. M. J. Verlinde, Wesley C. Van Voorhis, Kasey Rivas, Michael H. GelbAbstract:We report a series of novel inhibitors of protein Farnesyltransferase based on the 2-oxotetrahydroquinoline scaffold. We developed an efficient synthesis of these compounds. These compounds show selective inhibtion of the malaria versus human Farnesyltransferase and inhibit the growth of the malaria parasite in the low nanomolar range. Some of the compounds are at least an order of magnitude more stable to metabolic degradation than the corresponding tetrahydroquinolines.
-
2 oxo tetrahydro 1 8 naphthyridines as selective inhibitors of malarial protein Farnesyltransferase and as anti malarials
Bioorganic & Medicinal Chemistry Letters, 2008Co-Authors: Srinivas Olepu, Christophe L. M. J. Verlinde, Kohei Yokoyama, Wesley C. Van Voorhis, Kasey Rivas, Praveen Kumar Suryadevara, Debopam Chakrabarti, Michael H. GelbAbstract:A new class of 2-oxo-tetrahydro-1,8-naphthyridine-based protein Farnesyltransferase inhibitors were synthesized and found to inhibit protein farnesyl transferase 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 growth in culture with potencies in the sub-micromolar range. Some of the compounds also were found to be much more metabolically stable than previously described tetrahydroquinoline-based protein Farnesyltransferase inhibitors.
-
Isothiazole dioxides: synthesis and inhibition of Trypanosoma brucei protein Farnesyltransferase.
Bioorganic & medicinal chemistry letters, 2002Co-Authors: Francesca Clerici, Frederick S Buckner, Kohei Yokoyama, Wesley C. Van Voorhis, Maria Luisa Gelmi, Donato Pocar, Michael H. GelbAbstract:Abstract A series of isothiazole dioxides was synthesized and evaluated as inhibitors of protein Farnesyltransferase from the parasite that causes African sleeping sickness (Trypanosoma brucei). The most potent compound in the series inhibited the parasite enzyme with an IC50 of 2 μM and blocked the growth of the bloodstream parasite in vitro with an ED50 of 10 μM. The same compound inhibited rat protein Farnesyltransferase and protein geranylgeranyltransferase type I only at much higher concentration.
-
Cloning, heterologous expression, and distinct substrate specificity of protein Farnesyltransferase from Trypanosoma brucei.
The Journal of biological chemistry, 2000Co-Authors: Frederick S Buckner, Kohei Yokoyama, Lisa Nguyen, Anita Grewal, Hediye Erdjument-bromage, Paul Tempst, Corey Strickland, Li Xiao, Wesley C. Van Voorhis, Michael H. GelbAbstract:Abstract Protein prenylation occurs in the protozoan that causes African sleeping sickness (Trypanosoma brucei), and the protein Farnesyltransferase appears to be a good target for developing drugs. We have cloned the α- and β-subunits of T. brucei protein Farnesyltransferase (TB-PFT) using nucleic acid probes designed from partial amino acid sequences obtained from the enzyme purified from insect stage parasites. TB-PFT is expressed in both bloodstream and insect stage parasites. Enzymatically active TB-PFT was produced by heterologous expression in Escherichia coli. Compared with mammalian protein Farnesyltransferases, TB-PFT contains a number of inserts of >25 residues in both subunits that reside on the surface of the enzyme in turns linking adjacent α-helices. Substrate specificity studies with a series of 20 peptides SSCALX (where X indicates a naturally occurring amino acid) show that the recombinant enzyme behaves identically to the native enzyme and displays distinct specificity compared with mammalian protein Farnesyltransferase. TB-PFT prefers Gln and Met at theX position but not Ser, Thr, or Cys, which are good substrates for mammalian protein Farnesyltransferase. A structural homology model of the active site of TB-PFT provides a basis for understanding structure-activity relations among substrates and CAAX mimetic inhibitors.
Joelle Dubois - One of the best experts on this subject based on the ideXlab platform.
-
On the discovery of new potent human Farnesyltransferase inhibitors: emerging pyroglutamic derivatives.
Organic & biomolecular chemistry, 2017Co-Authors: Germain Homerin, Joelle Dubois, Amaury Farce, Benoît Rigo, Emmanuelle Lipka, Alina GhinetAbstract:In the current context of lack of emergence of innovative human Farnesyltransferase inhibitors families, and given all new therapeutic perspectives that open up for such molecules in rare diseases (e.g. Hutchinson-Gilford progeria syndrome), and in delta hepatitis, cardiovascular or neuroinflammatory diseases, we have just discovered a new series of powerful inhibitors. These molecules are pyroglutamic acid derivatives, and were evaluated on human Farnesyltransferase in vitro then modeled in silico on the active site of the protein. Three main points of the pyroglutamic acid cycle have undergone chemical modulations pyroglutamides in position 5 (compounds 7a-h), constrained bicyclic analogues of pyrroloimidazoledione type (compounds 1a-h), modulation of the position 3 (compounds 2-5 and 8), and allowed the first SAR in the field. Five derivatives in the current work have IC50 values in the small nanomolar range (2-5 nM). These new lead compounds open the way for the next generation of Farnesyltransferase inhibitors.
-
New indolizine-chalcones as potent inhibitors of human Farnesyltransferase: Design, synthesis and biological evaluation.
Bioorganic & medicinal chemistry letters, 2016Co-Authors: Iuliana-monica Moise, Joelle Dubois, Amaury Farce, Alina Ghinet, Dalila Belei, Elena BîcuAbstract:A new family of indolizine-chalcones was designed, synthesized and screened for the inhibitory potential on human Farnesyltransferase in vitro to identify potent antitumor agents. The most active compound was phenothiazine 2a, exhibiting an IC50 value in the low nanomolar range, similar to that of known FTI-276, highly potent Farnesyltransferase inhibitor. The newly synthesized indolizine-chalcones 2a-d constitute the most efficient inhibitors of Farnesyltransferase bearing a phenothiazine unit known to date.
-
highly improved antiparasitic activity after introduction of an n benzylimidazole moiety on protein Farnesyltransferase inhibitors
European Journal of Medicinal Chemistry, 2016Co-Authors: Damien Bosc, Elisabeth Mouray, Sandrine Cojean, Caio Haddad Franco, Philippe M Loiseau, Lucio H Freitasjunior, Carolina B Moraes, Philippe Grellier, Joelle DuboisAbstract:In our search for new protein Farnesyltransferase inhibitors with improved antiparasitic activities, we modified our previously developed 3-arylthiophene series of inhibitors by replacing the thioisopropyl group by different substituted imidazolylmethanamino moieties. Twenty four new derivatives were synthesized and evaluated against human and parasite Farnesyltransferases, and their anti-parasitic activity was determined against Plasmodium falciparum, Trypanosoma brucei, Trypanosoma cruzi, and Leishmania donovani. Introduction of a N-p-substituted-benzylimidazole led to significantly increase the inhibition of parasite proliferation in the submicromolar range. The structure of the best inhibitors was parasite dependent. Three compounds possess IC50 values at the same range as the reference miltefosine against L. donovani proliferation and other new derivatives display high level of anti-trypanosomal activity against T. cruzi, higher or in the same order of magnitude as the reference compounds benznidazole and nifurtimox.
-
Peptide chemistry applied to a new family of phenothiazine-containing inhibitors of human Farnesyltransferase.
Bioorganic & medicinal chemistry letters, 2014Co-Authors: Gina-mirabela Dumitriu, Joelle Dubois, Amaury Farce, Alina Ghinet, Elena Bîcu, Benoît Rigo, Dalila BeleiAbstract:Novel phenothiazine derivatives bearing an amino acid residue were synthesized via peptide chemistry, and evaluated for their inhibitory potential on human Farnesyltransferase. The phenothiazine unit proved to be an important bulky unit in the structure of the synthesized inhibitors. Propargyl ester 20 bearing a tyrosine residue exhibited the best biological potential in vitro in the present study. Further syntheses and biological evaluation of phenothiazine derivatives are necessary in order to gain a full view of SAR in this family of Farnesyltransferase inhibitors.
-
Synthesis and biological evaluation of a new series of N-ylides as protein Farnesyltransferase inhibitors.
Bioorganic & medicinal chemistry letters, 2013Co-Authors: Cristina-maria Abuhaie, Joelle Dubois, Amaury Farce, Alina Ghinet, Benoît Rigo, Elena BîcuAbstract:A new family of 30 benzoylated N-ylides 4 and 5 was synthesized and evaluated for the inhibitory activity on human protein Farnesyltransferase. Most of these novel compounds possessed in vitro inhibition potencies in the micromolar range. The nature of the substituents on the pyridine and phenyl units proved to be important in determining inhibitory activity and generally, the replacement of the cyanoacrylonitrile function by a cyanoethylacrylate group decreased the biological potential on Farnesyltransferase. These results completed our SAR study on this original class of N-ylides.
Fuyuhiko Tamanoi - One of the best experts on this subject based on the ideXlab platform.
-
protein farnesylation in mammalian cells effects of Farnesyltransferase inhibitors on cancer cells
Cellular and Molecular Life Sciences, 2001Co-Authors: Fuyuhiko Tamanoi, Chialing Gau, Chen Jiang, H Edamatsu, Juran KatostankiewiczAbstract:Protein farnesylation, catalyzed by protein Farnesyltransferase, plays important roles in the membrane association and protein-protein interaction of a number of eukaryotic proteins. Recent development of Farnesyltransferase inhibitors (FTIs) has led to further insight into the biological significance of farnesylation in cancer cells. A number of reports point to the dramatic effects FTIs exert on cancer cells. In addition to inhibiting anchorage-independent growth, FTIs cause changes in the cell cycle either at the G1/S or at the G2/M phase. Furthermore, induction of apoptosis by FTIs has been reported. FTIs also affects the actin cytoskeleton and cell morphology. This review summarizes these reports and discusses implications for farnesylated proteins responsible for these FTI effects.
-
Advances in the development of Farnesyltransferase inhibitors: substrate recognition by protein Farnesyltransferase.
Journal of Cellular Biochemistry, 1997Co-Authors: Wenli Yang, Keith Del Villar, Jun Urano, Hiroshi Mitsuzawa, Fuyuhiko TamanoiAbstract:A variety of compounds that show promise in cancer chemotherapy and chemoprevention have been identified as Farnesyltransferase inhibitors. These can be classified into mainly two different types of inhibitors, farnesyl diphosphate competitors and CAAX peptidomimetics. The former type acts by competitively inhibiting Farnesyltransferase with respect to one of the substrates, farnesyl diphosphate, whereas the latter type acts by mimicking the other substrate, the C-terminal CAAX motif of Ras protein. One example of a farnesyl diphosphate competitor is manumycin, an antibiotic detected in the culture media of a Streptomyces strain. The CAAX peptidomimetics were developed based on the unique property of Farnesyltransferase to recognize the CAAX motif at the C-terminus of the protein substrate. Our recent studies have focused on understanding the structural basis of this CAAX recognition. By using in vitro mutagenesis, residues of yeast Farnesyltransferase important for the recognition of the CAAX motif have been identified. Two of these residues are closely located at the C-terminal region of the beta-subunit of Farnesyltransferase. These and other results on the structural basis of the CAAX recognition may provide information valuable for structure-based design of Farnesyltransferase inhibitors.
-
[5] In vivo assays for Farnesyltransferase inhibitors with Saccharomyces cereuisiae
Methods in enzymology, 1995Co-Authors: Hiroshi Mitsuzawa, Fuyuhiko TamanoiAbstract:Publisher Summary This chapter describes simple plate assays for Farnesyltransferase inhibitors using yeast gpal and RAS2Val-9 mutants. The methods are useful in screening natural products for inhibitors and in evaluating synthetic inhibitors. Protein farnesylation is important for protein function. The modification is catalyzed by Farnesyltransferase, which transfers a farnesyl group from farnesyl diphosphate to a cysteine residue located in a carboxyl-terminal tetrapeptide sequence (the CaaX motif) of an acceptor protein. Farnesylated proteins include Ras proteins, nuclear lamins, the γ subunits of transducin and yeast heterotrimeric G protein, and fungal mating pheromones. Farnesyltransferase inhibitors provide valuable tools for the understanding of the catalytic mechanism of the enzyme. The assays are used to evaluate synthetic inhibitors such as peptidomimetics because the yeast system provides simple in vivo assays. It is possible that the effects of inhibitors are different between the yeast and mammalian enzymes and that the penetration and degradation of inhibitors are different between yeast and mammalian cells.
-
Inhibitors of ras Farnesyltransferases
Trends in biochemical sciences, 1993Co-Authors: Fuyuhiko TamanoiAbstract:Farnesyltransferase catalyses the post-translational modification of proteins by a cholesterol precursor, farnesylpyrophosphate. One of the substrates of this enzyme is the product of the ras oncogene. Recently, inhibitors of Farnesyltransferase have been identified through two different approaches: microbial screens for natural compounds, and substrate analogues. These inhibitors may be useful in blocking the action of Ras proteins, in further characterizing protein prenyltransferases, and in elucidating the regulation of cholesterol metabolism.
Isabel Sattler - One of the best experts on this subject based on the ideXlab platform.
-
Non-thiol Farnesyltransferase inhibitors: N-(4-tolylacetylamino-3-benzoylphenyl)-3-arylfurylacrylic acid amides.
Bioorganic & medicinal chemistry, 2004Co-Authors: Andreas Mitsch, Isabel Sattler, Katrin Silber, Peter Haebel, Pia Wissner, Gerhard Klebe, Martin SchlitzerAbstract: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.
-
Non‐thiol Farnesyltransferase Inhibitors: FTase‐Inhibition and Cellular Activity of Benzophenone‐based Bisubstrate Analogue Farnesyltransferase Inhibitors
Archiv der Pharmazie, 2003Co-Authors: Andreas Mitsch, Isabel Sattler, Silke Bergemann, Ronald Gust, Martin SchlitzerAbstract:Some 5-acylaminoacylamino-benzophenone derivatives were designed as bisubstrate analogue Farnesyltransferase inhibitors. These compounds turned out to be only weakly active against Farnesyltransferase, but displayed an antiproliferative effect rendering them suitable for further development as a novel type of cytostatic agents.
-
Non-thiol Farnesyltransferase inhibitors: FTase-inhibition and cellular activity of benzophenone-based bisubstrate analogue Farnesyltransferase inhibitors.
Archiv der Pharmazie, 2003Co-Authors: Andreas Mitsch, Isabel Sattler, Silke Bergemann, Ronald Gust, Martin SchlitzerAbstract:Some 5-acylaminoacylamino-benzophenone derivatives were designed as bisubstrate analogue Farnesyltransferase inhibitors. These compounds turned out to be only weakly active against Farnesyltransferase, but displayed an antiproliferative effect rendering them suitable for further development as a novel type of cytostatic agents.
-
Non-thiol Farnesyltransferase inhibitors: structure–activity relationships of benzophenone-based bisubstrate analogue Farnesyltransferase inhibitors
Bioorganic & medicinal chemistry, 2002Co-Authors: Martin Schlitzer, Markus Böhm, Isabel SattlerAbstract: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.
-
Non-thiol Farnesyltransferase inhibitors: utilization of an aryl binding site by 5-arylacryloylaminobenzophenones.
Bioorganic & medicinal chemistry, 2002Co-Authors: Andreas Mitsch, Isabel Sattler, Markus Böhm, Pia Wissner, Martin SchlitzerAbstract: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.
