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Article ; Online: Identification of unprecedented ATP-competitive choline kinase inhibitors.

Bioorganic & medicinal chemistry letters

2021 Volume 51, Page(s) 128310

Abstract: In this article we describe the identification of unprecedented ATP-competitive ChoKα inhibitors starting from initial hit NMS-P830 that binds to ChoKα in an ATP concentration-dependent manner. This result is confirmed by the co-crystal structure of NMS- ... ...

Abstract	In this article we describe the identification of unprecedented ATP-competitive ChoKα inhibitors starting from initial hit NMS-P830 that binds to ChoKα in an ATP concentration-dependent manner. This result is confirmed by the co-crystal structure of NMS-P830 in complex with Δ75-ChoKα. NMS-P830 is able to inhibit ChoKα in cells resulting in the reduction of intracellular phosphocholine formation. A structure-based medicinal chemistry program resulted in the identification of selective compounds that have good biochemical activity, solubility and metabolic stability and are suitable for further optimization. The ChoKα inhibitors disclosed in this article demonstrate for the first time the possibility to inhibit ChoKα with ATP-competitive compounds.
MeSH term(s)	Adenosine Triphosphate/antagonists & inhibitors ; Adenosine Triphosphate/metabolism ; Choline Kinase/antagonists & inhibitors ; Choline Kinase/metabolism ; Cyclohexanes/chemical synthesis ; Cyclohexanes/chemistry ; Cyclohexanes/pharmacology ; Dose-Response Relationship, Drug ; Humans ; Molecular Structure ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Structure-Activity Relationship
Chemical Substances	Cyclohexanes ; NMS-P830 ; Protein Kinase Inhibitors ; Adenosine Triphosphate (8L70Q75FXE) ; CHKA protein, human (EC 2.7.1.32) ; Choline Kinase (EC 2.7.1.32)
Language	English
Publishing date	2021-08-18
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2021.128310
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Article: Discovery of Stereospecific PARP-1 Inhibitor Isoindolinone NMS-P515.

Papeo, Gianluca / Orsini, Paolo / Avanzi, Nilla R / Borghi, Daniela / Casale, Elena / Ciomei, Marina / Cirla, Alessandra / Desperati, Viviana / Donati, Daniele / Felder, Eduard R / Galvani, Arturo / Guanci, Marco / Isacchi, Antonella / Posteri, Helena / Rainoldi, Sonia / Riccardi-Sirtori, Federico / Scolaro, Alessandra / Montagnoli, Alessia

ACS medicinal chemistry letters

2019 Volume 10, Issue 4, Page(s) 534–538

Abstract: Poly(ADP-ribose) polymerase-1 (PARP-1) is an enzyme involved in signaling and repair of DNA single strand breaks. PARP-1 employs ... ...

Abstract	Poly(ADP-ribose) polymerase-1 (PARP-1) is an enzyme involved in signaling and repair of DNA single strand breaks. PARP-1 employs NAD
Language	English
Publishing date	2019-03-13
Publishing country	United States
Document type	Journal Article
ISSN	1948-5875
ISSN	1948-5875
DOI	10.1021/acsmedchemlett.8b00569
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Article: A new glycociamidine ring precursor: syntheses of (Z)-hymenialdisine, (Z)-2-debromohymenialdisine, and (+/-)-endo-2-debromohymenialdisine.

Papeo, Gianluca / Posteri, Helena / Borghi, Daniela / Varasi, Mario

Organic letters

2005 Volume 7, Issue 25, Page(s) 5641–5644

Abstract: chemical reaction: see text]. The synthesis of the C11H5 marine sponge alkaloids, (Z)-hymenialdisine and (Z)-2-debromohymenialdisine, is described. A key step was the condensation between aldisine or its monobromo derivative and a new, efficient ... ...

Abstract	[chemical reaction: see text]. The synthesis of the C11H5 marine sponge alkaloids, (Z)-hymenialdisine and (Z)-2-debromohymenialdisine, is described. A key step was the condensation between aldisine or its monobromo derivative and a new, efficient imidazolinone-based glycociamidine precursor. In the first case, the main product turned out to be the unprecedented (+/-)-endo-2-debromohymenialdisine.
MeSH term(s)	Alkaloids/chemical synthesis ; Alkaloids/chemistry ; Animals ; Azepines/chemical synthesis ; Azepines/chemistry ; Cyclization ; Marine Biology ; Molecular Structure ; Porifera/chemistry ; Pyrroles/chemical synthesis ; Pyrroles/chemistry ; Stereoisomerism
Chemical Substances	Alkaloids ; Azepines ; Pyrroles ; debromohymenialdisine (125118-55-0) ; hymenialdisine (95569-43-0)
Language	English
Publishing date	2005-12-08
Publishing country	United States
Document type	Journal Article
ISSN	1523-7060
ISSN	1523-7060
DOI	10.1021/ol052266m
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Article ; Online: A straightforward total synthesis of (-)-chaetominine.

Malgesini, Beatrice / Forte, Barbara / Borghi, Daniela / Quartieri, Francesca / Gennari, Cesare / Papeo, Gianluca

Chemistry (Weinheim an der Bergstrasse, Germany)

2009 Volume 15, Issue 32, Page(s) 7922–7929

Abstract: 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 ( ...

Abstract	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.
MeSH term(s)	Drug Screening Assays, Antitumor ; Humans ; Indole Alkaloids/chemical synthesis ; Indole Alkaloids/chemistry ; Indole Alkaloids/pharmacology ; Molecular Structure ; Peptides, Cyclic/chemistry ; Quinazolines/chemistry ; Stereoisomerism
Chemical Substances	Indole Alkaloids ; Peptides, Cyclic ; Quinazolines ; chaetominine ; fumiquinazoline A ; kapakahine B
Language	English
Publishing date	2009-06-25
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1478547-X
ISSN	1521-3765 ; 0947-6539
ISSN (online)	1521-3765
ISSN	0947-6539
DOI	10.1002/chem.200900793
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Article: A practical synthesis of the major 3-hydroxy-2-pyrrolidinone metabolite of a potent CDK2/cyclin A inhibitor.

Nesi, Marcella / Borghi, Daniela / Brasca, Maria Gabriella / Fiorentini, Francesco / Pevarello, Paolo

Bioorganic & medicinal chemistry letters

2006 Volume 16, Issue 12, Page(s) 3205–3208

Abstract: The synthesis of the major metabolite of a potent 3-aminopyrazole CDK2/cyclin A inhibitor is presented. A stereoconservative approach starting from malic acid was employed to construct the hydroxy-substituted pyrrolidinone moiety. In the key step of the ... ...

Abstract	The synthesis of the major metabolite of a potent 3-aminopyrazole CDK2/cyclin A inhibitor is presented. A stereoconservative approach starting from malic acid was employed to construct the hydroxy-substituted pyrrolidinone moiety. In the key step of the synthesis the use of cyanoborohydride immobilized on Amberlyst 26 in trifluoroethanol represented a valid alternative to conventional solution-phase reducing agents.
MeSH term(s)	Animals ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cyclin A/antagonists & inhibitors ; Cyclin A/metabolism ; Cyclin-Dependent Kinase 2/antagonists & inhibitors ; Cyclin-Dependent Kinase 2/metabolism ; Humans ; Mass Spectrometry ; Molecular Structure ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Pyrrolidinones/chemistry ; Pyrrolidinones/metabolism ; Pyrrolidinones/pharmacology
Chemical Substances	3-hydroxy-2-pyrrolidinone ; Cyclin A ; Protein Kinase Inhibitors ; Pyrrolidinones ; Cyclin-Dependent Kinase 2 (EC 2.7.11.22)
Language	English
Publishing date	2006-06-15
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2006.03.051
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Article ; Online: Discovery of 2-(cyclohexylmethylamino)pyrimidines as a new class of reversible valosine containing protein inhibitors.

Cervi, Giovanni / Magnaghi, Paola / Asa, Daniela / Avanzi, Nilla / Badari, Alessandra / Borghi, Daniela / Caruso, Michele / Cirla, Alessandra / Cozzi, Liviana / Felder, Eduard / Galvani, Arturo / Gasparri, Fabio / Lomolino, Antonio / Magnuson, Steven / Malgesini, Beatrice / Motto, Ilaria / Pasi, Maurizio / Rizzi, Simona / Salom, Barbara /

Sorrentino, Graziella / Troiani, Sonia / Valsasina, Barbara / O'Brien, Thomas / Isacchi, Antonella / Donati, Daniele / D'Alessio, Roberto

Journal of medicinal chemistry

2014 Volume 57, Issue 24, Page(s) 10443–10454

Abstract: Valosine-containing protein (VCP), also known as p97 or cdc48 in yeast, is a highly abundant protein belonging to the AAA ATPase family involved in a number of essential cellular functions, including ubiquitin-proteasome mediated protein degradation, ... ...

Abstract	Valosine-containing protein (VCP), also known as p97 or cdc48 in yeast, is a highly abundant protein belonging to the AAA ATPase family involved in a number of essential cellular functions, including ubiquitin-proteasome mediated protein degradation, Golgi reassembly, transcription activation, and cell cycle control. Altered expression of VCP has been detected in many cancer types sometimes associated with poor prognosis. Furthermore, VCP mutations are causative of some neurodegenerative disorders. In this paper we report the discovery, synthesis, and structure-activity relationships of substituted 2-aminopyrimidines, representing a new class of reversible VCP inhibitors. This class of compounds, identified in a HTS campaign against recombinant VCP, has been progressively expanded and manipulated to increase biochemical potency and gain cellular activity.
MeSH term(s)	Adenosine Triphosphatases/antagonists & inhibitors ; Adenosine Triphosphatases/metabolism ; Cell Cycle Proteins/antagonists & inhibitors ; Cell Cycle Proteins/metabolism ; Cell Proliferation/drug effects ; Drug Discovery ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; HCT116 Cells ; Humans ; Models, Molecular ; Molecular Structure ; Pyrimidines/chemistry ; Pyrimidines/pharmacology ; Structure-Activity Relationship ; Valosin Containing Protein
Chemical Substances	Cell Cycle Proteins ; Enzyme Inhibitors ; Pyrimidines ; Adenosine Triphosphatases (EC 3.6.1.-) ; VCP protein, human (EC 3.6.4.6) ; Valosin Containing Protein (EC 3.6.4.6) ; pyrimidine (K8CXK5Q32L)
Language	English
Publishing date	2014-12-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/jm501313x
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Article: Cerium Ammonium Nitrate Promoted Alkoxylation of Cephem Sulfoxides and Sulfones

Alpegiani, Marco / Bissolino, Pierluigi / Borghi, Daniela / Perrone, Ettore

Synlett

1994 Volume 1994, Issue 04, Page(s) 233–234

Language	English
Publishing date	1994-01-01
Publishing place	Stuttgart ; New York
Document type	Article
ZDB-ID	2042012-2
ISSN	1437-2096 ; 0936-5214
ISSN (online)	1437-2096
ISSN	0936-5214
DOI	10.1055/s-1994-22806
Database	Thieme publisher's database

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Article ; Online: Discovery of 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118): A Potent, Orally Available, and Highly Selective PARP-1 Inhibitor for Cancer Therapy.

Papeo, Gianluca / Posteri, Helena / Borghi, Daniela / Busel, Alina A / Caprera, Francesco / Casale, Elena / Ciomei, Marina / Cirla, Alessandra / Corti, Emiliana / D'Anello, Matteo / Fasolini, Marina / Forte, Barbara / Galvani, Arturo / Isacchi, Antonella / Khvat, Alexander / Krasavin, Mikhail Y / Lupi, Rosita / Orsini, Paolo / Perego, Rita /

Pesenti, Enrico / Pezzetta, Daniele / Rainoldi, Sonia / Riccardi-Sirtori, Federico / Scolaro, Alessandra / Sola, Francesco / Zuccotto, Fabio / Felder, Eduard R / Donati, Daniele / Montagnoli, Alessia

Journal of medicinal chemistry

2015 Volume 58, Issue 17, Page(s) 6875–6898

Abstract: The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both ... ...

Abstract	The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.
MeSH term(s)	Administration, Oral ; Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Biological Availability ; Cell Proliferation/drug effects ; Dacarbazine/administration & dosage ; Dacarbazine/analogs & derivatives ; Drug Screening Assays, Antitumor ; Female ; Heterografts ; High-Throughput Screening Assays ; Humans ; Isoindoles/administration & dosage ; Isoindoles/chemistry ; Isoindoles/pharmacology ; Mice, Inbred BALB C ; Mice, Nude ; Microsomes, Liver/metabolism ; Models, Molecular ; Neoplasm Transplantation ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/pathology ; Piperidines/administration & dosage ; Piperidines/chemistry ; Piperidines/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage ; Poly(ADP-ribose) Polymerase Inhibitors/chemistry ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Rats, Sprague-Dawley ; Structure-Activity Relationship ; Triple Negative Breast Neoplasms
Chemical Substances	Antineoplastic Agents ; Isoindoles ; NMS-P118 ; Piperidines ; Poly(ADP-ribose) Polymerase Inhibitors ; Dacarbazine (7GR28W0FJI) ; temozolomide (YF1K15M17Y)
Language	English
Publishing date	2015-09-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.5b00680
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Article ; Online: Identification of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as a new class of orally and selective Polo-like kinase 1 inhibitors.

Beria, Italo / Ballinari, Dario / Bertrand, Jay Aaron / Borghi, Daniela / Bossi, Roberto Tiberio / Brasca, Maria Gabriella / Cappella, Paolo / Caruso, Michele / Ceccarelli, Walter / Ciavolella, Antonella / Cristiani, Cinzia / Croci, Valter / De Ponti, Anna / Fachin, Gabriele / Ferguson, Ronald Dale / Lansen, Jacqueline / Moll, Jurgen Karl / Pesenti, Enrico / Posteri, Helena /

Perego, Rita / Rocchetti, Maurizio / Storici, Paola / Volpi, Daniele / Valsasina, Barbara

Journal of medicinal chemistry

2010 Volume 53, Issue 9, Page(s) 3532–3551

Abstract: Polo-like kinase 1 (Plk1) is a fundamental regulator of mitotic progression whose overexpression is often associated with oncogenesis and therefore is recognized as an attractive therapeutic target in the treatment of proliferative diseases. Here we ... ...

Abstract	Polo-like kinase 1 (Plk1) is a fundamental regulator of mitotic progression whose overexpression is often associated with oncogenesis and therefore is recognized as an attractive therapeutic target in the treatment of proliferative diseases. Here we discuss the structure-activity relationship of the 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline class of compounds that emerged from a high throughput screening (HTS) campaign as potent inhibitors of Plk1 kinase. Furthermore, we describe the discovery of 49, 8-{[2-methoxy-5-(4-methylpiperazin-1-yl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, as a highly potent and specific ATP mimetic inhibitor of Plk1 (IC(50) = 0.007 microM) as well as its crystal structure in complex with the methylated Plk1(36-345) construct. Compound 49 was active in cell proliferation against different tumor cell lines with IC(50) values in the submicromolar range and active in vivo in the HCT116 xenograft model where it showed 82% tumor growth inhibition after repeated oral administration.
MeSH term(s)	Adenosine Triphosphate ; Administration, Oral ; Animals ; Antineoplastic Agents/chemistry ; Cell Cycle Proteins/antagonists & inhibitors ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Evaluation, Preclinical ; Drug Screening Assays, Antitumor ; Humans ; Molecular Mimicry ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Protein Serine-Threonine Kinases/antagonists & inhibitors ; Proto-Oncogene Proteins/antagonists & inhibitors ; Quinazolines/chemistry ; Quinazolines/pharmacology ; Quinazolines/therapeutic use ; Structure-Activity Relationship ; Tumor Burden ; Xenograft Model Antitumor Assays ; Polo-Like Kinase 1
Chemical Substances	Antineoplastic Agents ; Cell Cycle Proteins ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins ; Quinazolines ; Adenosine Triphosphate (8L70Q75FXE) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2010-04-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/jm901713n
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Article ; Online: Optimization of 6,6-dimethyl pyrrolo[3,4-c]pyrazoles: Identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing.

Bioorganic & medicinal chemistry

2010 Volume 18, Issue 5, Page(s) 1844–1853

Abstract: 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- ... ...

Abstract	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.
MeSH term(s)	Animals ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacokinetics ; Binding Sites ; Cell Line, Tumor ; Crystallography, X-Ray ; Cyclin-Dependent Kinases/antagonists & inhibitors ; Cyclin-Dependent Kinases/metabolism ; HCT116 Cells ; Humans ; Injections, Intravenous ; Mice ; Mice, Nude ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacokinetics ; Pyrazoles/chemical synthesis ; Pyrazoles/chemistry ; Pyrazoles/pharmacokinetics ; Pyrroles/chemical synthesis ; Pyrroles/chemistry ; Pyrroles/pharmacokinetics ; Xenograft Model Antitumor Assays
Chemical Substances	Antineoplastic Agents ; N-(6,6-dimethyl-5-((1-methylpiperidin-4-yl)carbonyl)-1,4,5,6-tetrahydropyrrolo(3,4-c)pyrazol-3-yl)-3-methylbutanamide ; Protein Kinase Inhibitors ; Pyrazoles ; Pyrroles ; Cyclin-Dependent Kinases (EC 2.7.11.22)
Language	English
Publishing date	2010-03-01
Publishing country	England
Document type	Journal Article
ZDB-ID	1161284-8
ISSN	1464-3391 ; 0968-0896
ISSN (online)	1464-3391
ISSN	0968-0896
DOI	10.1016/j.bmc.2010.01.042
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