Publications by authors named "Francesca Quartieri"

7 Publications

  • Page 1 of 1

Insights into PARP Inhibitors' Selectivity Using Fluorescence Polarization and Surface Plasmon Resonance Binding Assays.

J Biomol Screen 2014 Sep 10;19(8):1212-9. Epub 2014 Jun 10.

Nerviano Medical Sciences S.r.l., Nerviano, Italy

PARP inhibitors are an exciting new class of antineoplastic drugs that have been proven to be efficacious as single agents in cancer settings with inherent DNA repair defects, as well as in combination with DNA-damaging chemotherapeutics. Currently, they are designed to target the catalytic domain of PARP-1, the most studied member of the family, with a key role in the DNA-damage repair process. Because PARP inhibitors are substrate (NAD(+)) competitors, there is a need for a deeper understanding of their cross-reactivity. This is particularly relevant for PARP-2, the PARP-1 closest homologue, for which an embryonic lethal phenotype has been observed in double knockout mice. In this study, we describe the development and validation of binding assays based on fluorescence polarization (FP) and surface plasmon resonance (SPR) techniques. PARP-1, PARP-2, PARP-3, and TNKS-1 FP displacement assays are set up by employing ad hoc synthesized probes. These assays are suitable for high-throughput screening (HTS) and selectivity profiling, thus allowing the identification of NAD(+)binding site selective inhibitors. The PARP-1 and PARP-2 complementary SPR binding assays confirm displacement data and the in-depth inhibitor characterization. Moreover, these formats have the potential to be broadly applicable to other members of the PARP family.
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http://dx.doi.org/10.1177/1087057114538319DOI Listing
September 2014

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

Synthesis and SAR of new pyrazolo[4,3-h]quinazoline-3-carboxamide derivatives as potent and selective MPS1 kinase inhibitors.

Bioorg Med Chem Lett 2011 Aug 14;21(15):4507-11. Epub 2011 Jun 14.

Nerviano Medical Sciences srl, Business Unit Oncology, Nerviano, MI, Italy.

The synthesis and SAR of a series of novel pyrazolo-quinazolines as potent and selective MPS1 inhibitors are reported. We describe the optimization of the initial hit, identified by screening the internal library collection, into an orally available, potent and selective MPS1 inhibitor.
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http://dx.doi.org/10.1016/j.bmcl.2011.05.122DOI Listing
August 2011

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

Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor.

J Med Chem 2009 Aug;52(16):5152-63

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

The discovery of a novel class of inhibitors of cyclin dependent kinases (CDKs) is described. Starting from compound 1, showing good potency as inhibitor of CDKs but being poorly selective against a panel of serine-threonine and tyrosine kinases, new analogues were synthesized. Enhancement in selectivity, antiproliferative activity against A2780 human ovarian carcinoma cells, and optimization of the physical properties and pharmacokinetic profile led to the identification of highly potent and orally available compounds. Compound 28 (PHA-848125), which in the preclinical xenograft A2780 human ovarian carcinoma model showed good efficacy and was well tolerated upon repeated daily treatments, was identified as a drug candidate for further development. Compound 28 is currently undergoing phase I and phase II clinical trials.
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http://dx.doi.org/10.1021/jm9006559DOI Listing
August 2009

A straightforward total synthesis of (-)-chaetominine.

Chemistry 2009 Aug;15(32):7922-9

Chemical Core Technologies, Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano (MI), Italy.

A total synthesis of the tripeptide alkaloid (-)-chaetominine (1) was achieved in 9.3% overall yield starting from commercially available D-tryptophan methyl ester, based on a short and straightforward (nine steps) sequence. The early stage introduction (first step) of the quinazolinone moiety and the late stage introduction (penultimate step) of the hydroxy group allowed a synthetic strategy devoid of protective groups. The key step of the process is the a-c tricyclic ring construction via an unprecedented NCS-mediated N-acyl cyclization on an indole ring to give tetrahydro-1H-pyrido[2,3-b]indole 11. In the penultimate step, oxidation of the tetracyclic intermediate 14 with oxaziridine 15 gave only one of the four possible diastereoisomers, the cis-diastereoisomer 16 resulting from the attack of the oxaziridine to the double bond face opposite to the c-d ring substituents. In the last step, the complete stereocontrol of the Et(3)SiH/TFA reduction of compound 16, probably involving a N-acyliminium ion, can be attributed to ring constrain, which forces the b-c ring junction in the more stable cis-orientation. (-)-Chaetominine (1) showed a negligible inhibitory activity on several cancer cell lines.
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http://dx.doi.org/10.1002/chem.200900793DOI Listing
August 2009

Trifluoroacetic anhydride-mediated solid-phase version of the Robinson-Gabriel synthesis of oxazoles.

J Comb Chem 2005 May-Jun;7(3):463-73

Department of Chemistry, Nerviano Medical Sciences, Viale Pasteur 10, 20014 Nerviano (MI), Italy.

A traceless solid-phase synthesis of oxazoles 4 via Robinson-Gabriel reaction of solid-supported alpha-acylamino ketones 2 has been achieved. The reaction requires that the cyclization precursor be linked to a benzhydrylic-type linker (compounds 2) and that trifluoroacetic anhydride be used as the cyclodehydrating agent. The solvent has a dramatic effect on the latter reaction, which goes to completion and follows a cyclative-type mechanism only when an ethereal solvent is used. Different synthetic routes have been investigated toward assembling compounds 2. The most straightforward one, which we have validated more extensively, comprises the reaction of Merrifield alpha-methoxyphenyl (MAMP) resin with an alpha-amino ketone to form compounds 1, which are, in turn, acylated. Other methodologies and strategies allowing for the synthesis of compounds 1 that have been investigated include direct alkylation of Rink amide resin; reductive amination of the latter with alpha-keto aldehydes; reaction of MAMP resin with alpha-amino alcohols, followed by oxidation; and protection of Rink amide resin with either 2,4-dinitrosulfonyl or allyl group, followed by alkylation and removal of protecting group. In addition, we disclose a novel variant of the Ugi four-component reaction that allows for the preparation of compounds 2 in a single synthetic step.
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http://dx.doi.org/10.1021/cc049831hDOI Listing
July 2005