Publications by authors named "Patrick Roussel"

8 Publications

  • Page 1 of 1

The natural diyne-furan fatty acid EV-086 is an inhibitor of fungal delta-9 fatty acid desaturation with efficacy in a model of skin dermatophytosis.

Antimicrob Agents Chemother 2014 4;58(1):455-66. Epub 2013 Nov 4.

Evolva SA, Reinach, Switzerland.

Human fungal infections represent a therapeutic challenge. Although effective strategies for treatment are available, resistance is spreading, and many therapies have unacceptable side effects. A clear need for novel antifungal targets and molecules is thus emerging. Here, we present the identification and characterization of the plant-derived diyne-furan fatty acid EV-086 as a novel antifungal compound. EV-086 has potent and broad-spectrum activity in vitro against Candida, Aspergillus, and Trichophyton spp., whereas activities against bacteria and human cell lines are very low. Chemical-genetic profiling of Saccharomyces cerevisiae deletion mutants identified lipid metabolic processes and organelle organization and biogenesis as targets of EV-086. Pathway modeling suggested that EV-086 inhibits delta-9 fatty acid desaturation, an essential process in S. cerevisiae, depending on the delta-9 fatty acid desaturase OLE1. Delta-9 unsaturated fatty acids-but not saturated fatty acids-antagonized the EV-086-mediated growth inhibition, and transcription of the OLE1 gene was strongly upregulated in the presence of EV-086. EV-086 increased the ratio of saturated to unsaturated free fatty acids and phosphatidylethanolamine fatty acyl chains, respectively. Furthermore, EV-086 was rapidly taken up into the lipid fraction of the cell and incorporated into phospholipids. Together, these findings demonstrate that EV-086 is an inhibitor of delta-9 fatty acid desaturation and that the mechanism of inhibition might involve an EV-086-phospholipid. Finally, EV-086 showed efficacy in a guinea pig skin dermatophytosis model of topical Trichophyton infection, which demonstrates that delta-9 fatty acid desaturation is a valid antifungal target, at least for dermatophytoses.
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http://dx.doi.org/10.1128/AAC.01443-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3910786PMC
September 2014

Optimization of 6,6-dimethyl pyrrolo[3,4-c]pyrazoles: Identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing.

Bioorg Med Chem 2010 Mar 25;18(5):1844-53. Epub 2010 Jan 25.

Nerviano Medical Sciences Srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.

We have recently reported CDK inhibitors based on the 6-substituted pyrrolo[3,4-c]pyrazole core structure. Improvement of inhibitory potency against multiple CDKs, antiproliferative activity against cancer cell lines and optimization of the physico-chemical properties led to the identification of highly potent compounds. Compound 31 (PHA-793887) showed good efficacy in the human ovarian A2780, colon HCT-116 and pancreatic BX-PC3 carcinoma xenograft models and was well tolerated upon daily treatments by iv administration. It was identified as a drug candidate for clinical evaluation in patients with solid tumors.
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http://dx.doi.org/10.1016/j.bmc.2010.01.042DOI Listing
March 2010

Identification of potent pyrazolo[4,3-h]quinazoline-3-carboxamides as multi-cyclin-dependent kinase inhibitors.

J Med Chem 2010 Mar;53(5):2171-87

Nerviano Medical Sciences Srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano, MI, Italy.

Abnormal proliferation mediated by disruption of the mechanisms that keep the cell cycle under control is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDKs) and cyclins (Cy) and inhibiting their activity are regarded as promising antitumor agents to complement the existing therapies. An expansion of pyrazolo[4,3-h]quinazoline chemical class oriented to the development of three points of variability was undertaken leading to a series of compounds able to inhibit CDKs both in vitro and in vivo. Starting from the CDK selective but poorly soluble hit compound 1, we succeeded in obtaining several compounds showing enhanced inhibitory activity both on CDKs and on tumor cells and displaying improved physical properties and pharmacokinetic behavior. Our study led to the identification of compound 59 as a highly potent, orally bioavailable CDK inhibitor that exhibited significant in vivo efficacy on the A2780 ovarian carcinoma xenograft model. The demonstrated mechanisms of action of compound 59 on cancer cell lines and its ability to inhibit tumor growth in vivo render this compound very interesting as potential antineoplastic agent.
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http://dx.doi.org/10.1021/jm901710hDOI Listing
March 2010

Crystallographic analysis of bacterial signal peptidase in ternary complex with arylomycin A2 and a beta-sultam inhibitor.

Biochemistry 2009 Sep;48(38):8976-84

Department of Molecular Biology and Biochemistry, Simon Fraser University, South Science Building 8888 University Drive, Burnaby, British Columbia, V5A 1S6 Canada.

Bacterial type I signal peptidase (SPase I), an essential membrane-bound endopeptidase with a unique Ser/Lys dyad mechanism, is being investigated as a potential novel antibiotic target. We present here binding and inhibition assays along with crystallographic data that shows that the lipohexapeptide-based natural product arylomycin A2 and the morpholino-beta-sultam derivative (BAL0019193) inhibit SPase I by binding to non-overlapping subsites near the catalytic center. The 2.0 A resolution crystal structure of the soluble catalytic domain of Escherichia coli SPase I (SPase I Delta2-75) in ternary complex with arylomycin A2 and BAL0019193 reveals the position of BAL0019193 adjacent to arylomycin A2 within the SPase I binding site. BAL0019193 binds in a noncovalent manner in close proximity to SPase I residues Ser88, Ser90, Lys145, Asn277, Ala279, and Glu307, as well as atom O45 of arylomycin A2. The binding mode of arylomycin A2 in this 2.0 A resolution ternary complex is compared to that seen in the previous 2.5 A resolution arylomycin A2-SPase cocrystal structure. This work contributes to our understanding of SPase I inhibitor/substrate recognition and should prove helpful in the further development of novel antibiotics based on the inhibition of SPase I.
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http://dx.doi.org/10.1021/bi9009538DOI Listing
September 2009

Investigation of the species-dependent in vitro metabolism of BAL30630 by stable isotope labeling and isotope exchange experiments analyzed by capillary liquid chromatography coupled to mass spectrometry.

J Chromatogr A 2009 May 13;1216(18):3946-53. Epub 2009 Mar 13.

Analytics, Basilea Pharmaceutica International Ltd., Grenzacherstrasse 487, CH-4005 Basel, Switzerland.

The in vitro metabolic profile of BAL30630, an antifungal piperazine propanol derivative, which inhibits the 1,3-beta-D-glucansynthase, was investigated by incubation with microsomes of several species and with rat hepatocytes. For the spotting of the metabolites, mixtures of BAL30630 with a stable isotope (deuterium) labeled analogue were incubated. The metabolic pattern comprises several oxidized metabolites. Based on isotope exchange experiments, their structures could be assigned to epoxide- and hydroxylated metabolites. In hepatocyte incubations, several glucuronides formed from these oxidized metabolites could be observed. From the analysis of the metabolic pattern in microsomes, products of carbamate hydrolysis were characterized. This hydrolysis was highly species dependent. In activated incubations and in rat hepatocytes, those metabolites were further oxidized. In incubations without NADPH activation, the resulting hydrolytic metabolites could be enriched without the subsequent oxidation. Final structural elucidation of the metabolites was performed using accurate mass determination and isotope exchange experiments, in which incubations were analyzed by deuterium exchange and capillary HPLC-QTof-MS and MS/MS. The use of non-radioactive, stabile isotope labeled drug analogues in combination with isotope exchange studies was essential in particular for a defined assignment of the functional groups in the structures of the investigated metabolites.
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http://dx.doi.org/10.1016/j.chroma.2009.03.022DOI Listing
May 2009

6-Substituted pyrrolo[3,4-c]pyrazoles: an improved class of CDK2 inhibitors.

ChemMedChem 2007 Jun;2(6):841-52

Oncology Business Unit, Department of Chemistry, Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano MI, Italy.

We have recently reported a new class of CDK2/cyclin A inhibitors based on a bicyclic tetrahydropyrrolo[3,4-c]pyrazole scaffold. The introduction of small alkyl or cycloalkyl groups in position 6 of this scaffold allowed variation at the other two diversity points. Conventional and polymer-assisted solution phase chemistry provided a way of generating compounds with improved biochemical and cellular activity. Optimization of the physical properties and pharmacokinetic profile led to a compound which exhibited good efficacy in vivo on A2780 human ovarian carcinoma.
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http://dx.doi.org/10.1002/cmdc.200600302DOI Listing
June 2007

Synthesis and pharmacological evaluation of a new class of peroxisome proliferator-activated receptor modulators.

Bioorg Med Chem Lett 2002 Dec;12(24):3565-7

Biovitrum AB, Department of Medicinal Chemistry, Rapsgatan 7, Uppsala 751-37, Stockholm, Sweden.

A series of 5-substituted 2-benzoylaminobenzoic acids has been synthesized and assayed for PPARalpha/gamma activity. Both dual activators and selective PPARgamma agonists have been identified. This class of compounds was shown to activate the PPARgamma receptor through interaction with a novel binding site.
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http://dx.doi.org/10.1016/s0960-894x(02)00791-6DOI Listing
December 2002

Synthesis and antiaggregant properties of Stabilized analogues of polyunsaturated fatty acid metabolites.

Bioorg Med Chem Lett 2002 Sep;12(18):2511-4

ENSCR, Synthèses et Activations de Biomolécules, CNRS UMR 6052, Avenue du Gal Leclerc, 35700, Rennes, France.

New aromatic and heteroaromatic analogues of polyunsaturated fatty acid metabolites have been prepared using short and versatile strategies. Preliminary studies of their activity as inhibitors of platelet aggregation are reported.
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http://dx.doi.org/10.1016/s0960-894x(02)00507-3DOI Listing
September 2002