Publications by authors named "Claudia Piutti"

6 Publications

  • Page 1 of 1

Discovery and optimization of pyrrolo[1,2-a]pyrazinones leads to novel and selective inhibitors of PIM kinases.

Bioorg Med Chem 2013 Dec 2;21(23):7364-80. Epub 2013 Oct 2.

Oncology, Nerviano Medical Sciences, viale Pasteur 10, 20014 Nerviano (MI), Italy. Electronic address:

A novel series of PIM inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of PIM isoforms with IC50 values in the low micromolar range. The application of a rational optimization strategy, guided by the determination of the crystal structure of the complex in the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a, which is a potent PIM kinases inhibitor exhibiting excellent selectivity against a large panel of kinases, representative of each family. The synthesis, structure-activity relationship studies, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Furthermore, the cellular activities including inhibition of cell growth and modulation of downstream targets are also described.
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http://dx.doi.org/10.1016/j.bmc.2013.09.054DOI Listing
December 2013

The Piancatelli rearrangement: new applications for an intriguing reaction.

Molecules 2013 Oct 8;18(10):12290-312. Epub 2013 Oct 8.

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

Nearly forty years ago, at the University of Rome, Giovanni Piancatelli and co-workers discovered the acid-catalyzed water-mediated rearrangement of 2-furylcarbinols into 4-hydroxycyclopentenones. These motifs are core components of several pharmacologically active compounds and precursors of many natural products. The main features of this reaction are the simple experimental conditions, the stereochemical outcome and the generality of the procedure. Consequently, a re-emergence of this reaction has been seen recently, including developments of the Piancatelli rearrangement with some interesting inter- and intramolecular variants. This review will mainly focus on the general aspects of the reaction along with its more recent applications.
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http://dx.doi.org/10.3390/molecules181012290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6270237PMC
October 2013

A submarine journey: the pyrrole-imidazole alkaloids.

Mar Drugs 2009 Nov 27;7(4):705-53. Epub 2009 Nov 27.

Department of Medicinal Chemistry, Nerviano Medical Sciences, Viale Pasteur 10, Nerviano, Milan, Italy.

In his most celebrated tale "The Picture of Dorian Gray", Oscar Wilde stated that "those who go beneath the surface do so at their peril". This sentence could be a prophetical warning for the practitioner who voluntarily challenges himself with trying to synthesize marine sponge-deriving pyrrole-imidazole alkaloids. This now nearly triple-digit membered community has been growing exponentially in the last 20 years, both in terms of new representatives and topological complexity--from simple, achiral oroidin to the breathtaking 12-ring stylissadines A and B, each possessing 16 stereocenters. While the biosynthesis and the role in the sponge economy of most of these alkaloids still lies in the realm of speculations, significant biological activities for some of them have clearly emerged. This review will account for the progress in achieving the total synthesis of the more biologically enticing members of this class of natural products.
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http://dx.doi.org/10.3390/md7040705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810223PMC
November 2009

3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 2. Lead optimization.

J Med Chem 2005 Apr;48(8):2944-56

Department Chemistry, Nerviano Medical Sciences, BU-Oncology and BU-Preclinical Science, Viale Pasteur 10, 20014 Nerviano (MI), Italy.

Inhibitors of cyclin-dependent kinases (CDK) such as CDK2/cyclin A-E are currently undergoing clinical trials to verify their potential as new anticancer agents. In a previous article we described the lead discovery process of a 3-aminopyrazole class of CDK2/cyclin A-E inhibitors. The endpoint of this process was PNU-292137, a compound endowed with in vivo antitumor activity in a mouse tumor xenograft model. We optimized this lead compound to improve some physicochemical properties, notably solubility and plasma protein binding. This lead optimization process brought us to the discovery of (2S)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-[4-(2-oxo-1-pyrrolidinyl)phenyl]propanamide (PHA-533533, 13), a compound with a balanced activity vs druglike profile. Compound 13 inhibited CDK2/cyclin A with a K(i) of 31 nM, counteracting tumor cell proliferation of different cell lines with an IC(50) in the submicromolar range. Solubility was improved more than 10 times over the starting lead, while plasma protein binding was decreased from 99% to 74%. With exploitation of this globally enhanced in vitro profile, 13 was more active than PNU-292137 in vivo in the A2780 xenograft model showing a tumor growth inhibition of 70%. Proof of mechanism of action was obtained in vivo by immunohistochemical analysis of tumor slices of 13-treated vs untreated animals.
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http://dx.doi.org/10.1021/jm0408870DOI Listing
April 2005

3-Aminopyrazole inhibitors of CDK2/cyclin A as antitumor agents. 1. Lead finding.

J Med Chem 2004 Jun;47(13):3367-80

Chemistry Department, Pharmacia Italia, Viale Pasteur 10, 20014 Nerviano (MI), Italy.

Abnormal proliferation mediated by disruption of the normal cell cycle mechanisms is a hallmark of virtually all cancer cells. Compounds targeting complexes between cyclin-dependent kinases (CDK) and cyclins, such as CDK2/cyclin A and CDK2/cyclin E, and inhibiting their kinase activity are regarded as promising antitumor agents to complement the existing therapies. From a high-throughput screening effort, we identified a new class of CDK2/cyclin A/E inhibitors. The hit-to-lead expansion of this class is described. X-ray crystallographic data of early compounds in this series, as well as in vitro testing funneled for rapidly achieving in vivo efficacy, led to a nanomolar inhibitor of CDK2/cyclin A (N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(2-naphthyl)acetamide (41), PNU-292137, IC50 = 37 nM) with in vivo antitumor activity (TGI > 50%) in a mouse xenograft model at a dose devoid of toxic effects.
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http://dx.doi.org/10.1021/jm031145uDOI Listing
June 2004

Total synthesis of the amaryllidaceae alkaloid (+)-plicamine and its unnatural enantiomer by using solid-supported reagents and scavengers in a multistep sequence of reactions.

Angew Chem Int Ed Engl 2002 Jun;41(12):2194-7

Department of Chemistry, University of Cambridge, Cambridge, UK.

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http://dx.doi.org/10.1002/1521-3773(20020617)41:12<2194::aid-anie2194>3.0.co;2-4DOI Listing
June 2002