Publications by authors named "Samuele Joppolo di Ventimiglia"

5 Publications

  • Page 1 of 1

Synthesis and biological evaluation of N-hydroxyphenylacrylamides and N-hydroxypyridin-2-ylacrylamides as novel histone deacetylase inhibitors.

J Med Chem 2010 Jan;53(2):822-39

Genextra Group, Congenia s.r.l., Via Adamello 16, 20139 Milan, Italy.

The histone deacetylases (HDACs) are able to regulate gene expression, and histone deacetylase inhibitors (HDACi) emerged as a new class of agents in the treatment of cancer as well as other human disorders such as neurodegenerative diseases. In the present investigation, we report on the synthesis and biological evaluation of compounds derived from the expansion of a HDAC inhibitor scaffold having N-hydroxy-3-phenyl-2-propenamide and N-hydroxy-3-(pyridin-2-yl)-2-propenamide as core structures and containing a phenyloxopropenyl moiety, either unsubstituted or substituted by a 4-methylpiperazin-1-yl or 4-methylpiperazin-1-ylmethyl group. The compounds were evaluated for their ability to inhibit nuclear HDACs, as well as for their in vitro antiproliferative activity. Moreover, their metabolic stability in microsomes and aqueous solubility were studied and selected compounds were further characterized by in vivo pharmacokinetic experiments. These compounds showed a remarkable stability in vivo, compared to hydroxamic acid HDAC inhibitors that have already entered clinical trials. The representative compound 30b showed in vivo antitumor activity in a human colon carcinoma xenograft model.
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http://dx.doi.org/10.1021/jm901502pDOI Listing
January 2010

Synthesis of novel pyrrolo[3,4-d]pyrazole-dicarboxylic acids and evaluation of their interaction with glutamate receptors.

Chem Biodivers 2008 Apr;5(4):657-63

Istituto di Chimica Farmaceutica e Tossicologica Pietro Pratesi, Università degli Studi di Milano, Via Mangiagalli 25, I-20133 Milano.

Chiral pyrazoline amino acids (3aR,4S,6aR)-1a and (3aR,4S,6aR)-1b, and (3aS,6S,6aS)-2a and (3aS,6S,6aS)-2b, which are conformationally constrained analogues of glutamic and homoglutamic acid, respectively, were prepared via a strategy based on the 1,3-dipolar cycloaddition of a nitrile imine to methyl N-Boc-3,4-didehydro-(S)-prolinate. The new 'amino acids' were tested for activity at ionotropic glutamate receptors. Solely the derivative (3aR,4S,6aR)-1a, which is structurally related to the previously described 4,5-dihydroisoxazole analogue (S)-CIP-A, turned out to be a potent and selective agonist for the AMPA receptors. The biological activity is due to the interaction with the orthosteric glutamate binding site.
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http://dx.doi.org/10.1002/cbdv.200890061DOI Listing
April 2008

Synthesis of novel N1-substituted bicyclic pyrazole amino acids and evaluation of their interaction with glutamate receptors.

Chem Biodivers 2005 Jun;2(6):748-57

Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Milano, Viale Abruzzi 42, I-20131 Milano.

N1-substituted bicyclic pyrazole amino acids (S)-9a-9c and (R)-9a-9c, which are conformationally constrained analogues of glutamic acid, were prepared via a strategy based on a 1,3-dipolar cycloaddition. The new amino acids were tested for activity at ionotropic and metabotropic glutamate receptors. Some of them turned out to be selective for the NMDA receptors, where they behaved as weak antagonists. The biological activity is mainly due to the interaction with the glutamate binding site, and not with the glycine co-agonist site.
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http://dx.doi.org/10.1002/cbdv.200590052DOI Listing
June 2005

Synthesis and anticonvulsant activity of novel bicyclic acidic amino acids.

J Med Chem 2003 Jul;46(14):3102-8

Istituto di Chimica Farmaceutica e Tossicologica, Università degli Studi di Milano, Viale Abruzzi 42, 20131 Milano, Italy.

Bicyclic acidic amino acids (+/-)-6 and (+/-)-7, which are conformationally constrained homologues of glutamic acid, were prepared via a strategy based on a 1,3-dipolar cycloaddition. The new amino acids were tested toward ionotropic and metabotropic glutamate receptor subtypes; both of them behaved as antagonists at mGluR1,5 and as agonists at mGluR2. Furthermore, whereas (+/-)-6 was inactive at all ionotropic glutamate receptors, (+/-)-7 displayed a quite potent antagonism at the NMDA receptors. In the in vivo tests on DBA/2 mice, the compounds displayed an anticonvulsant activity. The interesting pharmacological profile of (+/-)-7 qualifies it as a lead of novel neuroprotective agents.
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http://dx.doi.org/10.1021/jm0308085DOI Listing
July 2003

A combinatorial biocatalysis approach to an array of cholic acid derivatives.

Biotechnol Bioeng 2003 Feb;81(4):391-6

Istituto di Chimica del Riconoscimento Molecolare del CNR, via Mario Bianco 9, 20131 Milano, Italy.

A 39-member library of bile acid derivatives was prepared starting from 3alpha,7alpha,12alpha-trihydroxy-5beta-cholan-24-oic acid methyl ester using a combinatorial biocatalytic approach. A regioselective oxidation step, catalyzed by hydroxysteroid dehydrogenases, followed by an acylation step with a series of different acyl donors catalyzed by Candida antarctica lipase B, led to the modification of the bile acid scaffold. Each member of the library was obtained in high purity and good yield.
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http://dx.doi.org/10.1002/bit.10486DOI Listing
February 2003