19 results on '"Varasi, M"'
Search Results
2. 3-Aminopyrazole Inhibitors of CDK2/Cyclin A as Antitumor Agents. 2. Lead Optimization
- Author
-
Pevarello, P., Brasca, M. G., Orsini, P., Traquandi, G., Longo, A., Nesi, M., Orzi, F., Piutti, C., Sansonna, P., Varasi, M., Cameron, A., Vulpetti, A., Roletto, F., Alzani, R., Ciomei, M., Albanese, C., Pastori, W., Marsiglio, A., Pesenti, E., Fiorentini, F., Bischoff, J. R., and Mercurio, C.
- Abstract
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. Compound13 inhibited CDK2/cyclin A with a Ki of 31 nM, counteracting tumor cell proliferation of different cell lines with an IC50 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 of13 -treated vs untreated animals.- Published
- 2005
3. 3-Aminopyrazole Inhibitors of CDK2/Cyclin A as Antitumor Agents. 1. Lead Finding
- Author
-
Pevarello, P., Brasca, M. G., Amici, R., Orsini, P., Traquandi, G., Corti, L., Piutti, C., Sansonna, P., Villa, M., Pierce, B. S., Pulici, M., Giordano, P., Martina, K., Fritzen, E. L., Nugent, R. A., Casale, E., Cameron, A., Ciomei, M., Roletto, F., Isacchi, A., Fogliatto, G., Pesenti, E., Pastori, W., Marsiglio, A., Leach, K. L., Clare, P. M., Fiorentini, F., Varasi, M., Vulpetti, A., and Warpehoski, M. A.
- Abstract
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.- Published
- 2004
4. Synthesis and Anticonvulsant Activity of a New Class of 2-[(Arylalkyl)amino]alkanamide Derivatives
- Author
-
Pevarello, P., Bonsignori, A., Dostert, P., Heidempergher, F., Pinciroli, V., Colombo, M., McArthur, R. A., Salvati, P., Post, C., Fariello, R. G., and Varasi, M.
- Abstract
Although most epilepsies are adequately treated by conventional antiepileptic therapy, there remains an unfulfilled need for safer and more effective anticonvulsant agents. Starting from milacemide, a weak anticonvulsant, and trying to elucidate its mechanism of action, we discovered a structurally novel class of potent and preclinically safe anticonvulsants. Here we report the structure−activity relationship (SAR) study within this series of compounds. Different parts of the structural lead 2-[[4-(3-chlorobenzoxy)benzyl]amino]acetamide (
6 ) were thus varied (Figure 1), and many potent anticonvulsants were found. As an outcome of this study,57 ((S)-2-[[4-(3-fluorobenzoxy)benzyl]amino]propanamide methanesulfonate, PNU-151774E) emerged as a promising candidate for further development for its potent anticonvulsant activity and outstanding therapeutic indexes (TIs) in different animal tests.- Published
- 1998
5. Phenylimidazolidin-2-one Derivatives as Selective 5-HT<INF>3</INF> Receptor Antagonists and Refinement of the Pharmacophore Model for 5-HT<INF>3</INF> Receptor Binding
- Author
-
Heidempergher, F., Pillan, A., Pinciroli, V., Vaghi, F., Arrigoni, C., Bolis, G., Caccia, C., Dho, L., McArthur, R., and Varasi, M.
- Abstract
A possible bioisosterism between the benzamido and the phenylimidazolidin-2-one moieties has been suggested on the basis of the similarity between the molecular electrostatic potential (MEP) of metoclopramide, a D
2 receptor antagonist with weak 5-HT3 receptor antagonist properties, and zetidoline, a D2 receptor antagonist. Starting from this premise, a series of phenylimidazolidin-2-one derivatives bearing a basic azabicycloalkyl or an imidazolylalkyl moiety were synthesized and evaluated for 5-HT3 receptor radioligand binding affinity ([3H]GR 43694). In vitro 5-HT3 receptor antagonist activity was tested in the guinea pig ileum assay (GPI). A number of high-affinity ligands were shown to be potent 5-HT3 receptor antagonists in vivo as determined by inhibition of the Bezold−Jarisch reflex in the anesthetized rat. In general, the imidazolylalkyl derivatives were found to be more active than azabicycloalkyls. 1-(3,5-Dichlorophenyl)-3-[(5-methyl-1H-imidazol-4-yl)methyl]imidazolidin-2-one (58 ), in particular, displayed very high affinity for the 5-HT3 receptor (Ki of 0.038 nM) with a Kb of 5.62 nM in the GPI assay, being more potent than the reference compounds (ondansetron, tropisetron, granisetron, and BRL 46470) tested.58 showed an ID50 comparable to that of ondansetron (2.2 μg/kg iv) in the Bezold−Jarisch reflex. A molecular modeling study based on this structurally novel series of compounds allowed the refinement of previously reported 5-HT3 receptor antagonist pharmacophore models.- Published
- 1997
6. Thieno[3,2-b]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 2: Structure-Based Drug Design and Structure-Activity Relationship.
- Author
-
Vianello P, Sartori L, Amigoni F, Cappa A, Fagá G, Fattori R, Legnaghi E, Ciossani G, Mattevi A, Meroni G, Moretti L, Cecatiello V, Pasqualato S, Romussi A, Thaler F, Trifiró P, Villa M, Botrugno OA, Dessanti P, Minucci S, Vultaggio S, Zagarrí E, Varasi M, and Mercurio C
- Subjects
- Cell Line, Tumor, Crystallography, X-Ray, Drug Design, Enzyme Inhibitors chemistry, Fluorescence Resonance Energy Transfer, High-Throughput Screening Assays, Histone Demethylases, Humans, Inhibitory Concentration 50, Pyrroles chemistry, Structure-Activity Relationship, Enzyme Inhibitors pharmacology, Lysine chemistry, Pyrroles pharmacology
- Abstract
The balance of methylation levels at histone H3 lysine 4 (H3K4) is regulated by KDM1A (LSD1). KDM1A is overexpressed in several tumor types, thus representing an emerging target for the development of novel cancer therapeutics. We have previously described ( Part 1, DOI 10.1021.acs.jmedchem.6b01018 ) the identification of thieno[3,2-b]pyrrole-5-carboxamides as novel reversible inhibitors of KDM1A, whose preliminary exploration resulted in compound 2 with biochemical IC
50 = 160 nM. We now report the structure-guided optimization of this chemical series based on multiple ligand/KDM1A-CoRest cocrystal structures, which led to several extremely potent inhibitors. In particular, compounds 46, 49, and 50 showed single-digit nanomolar IC50 values for in vitro inhibition of KDM1A, with high selectivity in secondary assays. In THP-1 cells, these compounds transcriptionally affected the expression of genes regulated by KDM1A such as CD14, CD11b, and CD86. Moreover, 49 and 50 showed a remarkable anticlonogenic cell growth effect on MLL-AF9 human leukemia cells.- Published
- 2017
- Full Text
- View/download PDF
7. Thieno[3,2-b]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 1: High-Throughput Screening and Preliminary Exploration.
- Author
-
Sartori L, Mercurio C, Amigoni F, Cappa A, Fagá G, Fattori R, Legnaghi E, Ciossani G, Mattevi A, Meroni G, Moretti L, Cecatiello V, Pasqualato S, Romussi A, Thaler F, Trifiró P, Villa M, Vultaggio S, Botrugno OA, Dessanti P, Minucci S, Zagarrí E, Carettoni D, Iuzzolino L, Varasi M, and Vianello P
- Subjects
- Cell Line, Tumor, Crystallography, X-Ray, Drug Design, High-Throughput Screening Assays, Humans, Proton Magnetic Resonance Spectroscopy, Pyrroles chemistry, Spectrometry, Mass, Electrospray Ionization, Structure-Activity Relationship, Enzyme Inhibitors pharmacology, Histone Demethylases antagonists & inhibitors, Pyrroles pharmacology
- Abstract
Lysine specific demethylase 1 KDM1A (LSD1) regulates histone methylation and it is increasingly recognized as a potential therapeutic target in oncology. We report on a high-throughput screening campaign performed on KDM1A/CoREST, using a time-resolved fluorescence resonance energy transfer (TR-FRET) technology, to identify reversible inhibitors. The screening led to 115 hits for which we determined biochemical IC
50 , thus identifying four chemical series. After data analysis, we have prioritized the chemical series of N-phenyl-4H-thieno[3, 2-b]pyrrole-5-carboxamide for which we obtained X-ray structures of the most potent hit (compound 19, IC50 = 2.9 μM) in complex with the enzyme. Initial expansion of this chemical class, both modifying core structure and decorating benzamide moiety, was directed toward the definition of the moieties responsible for the interaction with the enzyme. Preliminary optimization led to compound 90, which inhibited the enzyme with a submicromolar IC50 (0.162 μM), capable of inhibiting the target in cells.- Published
- 2017
- Full Text
- View/download PDF
8. Discovery of a Novel Inhibitor of Histone Lysine-Specific Demethylase 1A (KDM1A/LSD1) as Orally Active Antitumor Agent.
- Author
-
Vianello P, Botrugno OA, Cappa A, Dal Zuffo R, Dessanti P, Mai A, Marrocco B, Mattevi A, Meroni G, Minucci S, Stazi G, Thaler F, Trifiró P, Valente S, Villa M, Varasi M, and Mercurio C
- Subjects
- Administration, Oral, Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacology, Cell Line, Tumor, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Enzyme Inhibitors therapeutic use, Histone Demethylases metabolism, Humans, Leukemia, Promyelocytic, Acute metabolism, Structure-Activity Relationship, Tranylcypromine administration & dosage, Tranylcypromine pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use, Histone Demethylases antagonists & inhibitors, Leukemia, Promyelocytic, Acute drug therapy, Tranylcypromine chemistry, Tranylcypromine therapeutic use
- Abstract
We report the stereoselective synthesis and biological activity of a novel series of tranylcypromine (TCPA) derivatives (14a-k, 15, 16), potent inhibitors of KDM1A. The new compounds strongly inhibit the clonogenic potential of acute leukemia cell lines. In particular three molecules (14d, 14e, and 14g) showing selectivity versus MAO A and remarkably inhibiting colony formation in THP-1 human leukemia cells, were assessed in mouse for their preliminary pharmacokinetic. 14d and 14e were further tested in vivo in a murine acute promyelocytic leukemia model, resulting 14d the most effective. Its two enantiomers were synthesized: the (1S,2R) enantiomer 15 showed higher activity than its (1R,2S) analogue 16, in both biochemical and cellular assays. Compound 15 exhibited in vivo efficacy after oral administration, determining a 62% increased survival in mouse leukemia model with evidence of KDM1A inhibition. The biological profile of compound 15 supports its further investigation as a cancer therapeutic.
- Published
- 2016
- Full Text
- View/download PDF
9. New Indole Tubulin Assembly Inhibitors Cause Stable Arrest of Mitotic Progression, Enhanced Stimulation of Natural Killer Cell Cytotoxic Activity, and Repression of Hedgehog-Dependent Cancer.
- Author
-
La Regina G, Bai R, Coluccia A, Famiglini V, Pelliccia S, Passacantilli S, Mazzoccoli C, Ruggieri V, Verrico A, Miele A, Monti L, Nalli M, Alfonsi R, Di Marcotullio L, Gulino A, Ricci B, Soriani A, Santoni A, Caraglia M, Porto S, Da Pozzo E, Martini C, Brancale A, Marinelli L, Novellino E, Vultaggio S, Varasi M, Mercurio C, Bigogno C, Dondio G, Hamel E, Lavia P, and Silvestri R
- Subjects
- Animals, Cell Division drug effects, Cell Line, Tumor, Drug Resistance, Neoplasm, Humans, Killer Cells, Natural immunology, Mice, NIH 3T3 Cells, Neoplasms immunology, Tubulin chemistry, Cytotoxicity, Immunologic drug effects, Hedgehog Proteins physiology, Indoles pharmacology, Killer Cells, Natural drug effects, Mitosis drug effects, Neoplasms pathology, Tubulin drug effects
- Abstract
We designed 39 new 2-phenylindole derivatives as potential anticancer agents bearing the 3,4,5-trimethoxyphenyl moiety with a sulfur, ketone, or methylene bridging group at position 3 of the indole and with halogen or methoxy substituent(s) at positions 4-7. Compounds 33 and 44 strongly inhibited the growth of the P-glycoprotein-overexpressing multi-drug-resistant cell lines NCI/ADR-RES and Messa/Dx5. At 10 nM, 33 and 44 stimulated the cytotoxic activity of NK cells. At 20-50 nM, 33 and 44 arrested >80% of HeLa cells in the G2/M phase of the cell cycle, with stable arrest of mitotic progression. Cell cycle arrest was followed by cell death. Indoles 33, 44, and 81 showed strong inhibition of the SAG-induced Hedgehog signaling activation in NIH3T3 Shh-Light II cells with IC50 values of 19, 72, and 38 nM, respectively. Compounds of this class potently inhibited tubulin polymerization and cancer cell growth, including stimulation of natural killer cell cytotoxic activity and repression of Hedgehog-dependent cancer.
- Published
- 2015
- Full Text
- View/download PDF
10. New pyrrole derivatives with potent tubulin polymerization inhibiting activity as anticancer agents including hedgehog-dependent cancer.
- Author
-
La Regina G, Bai R, Coluccia A, Famiglini V, Pelliccia S, Passacantilli S, Mazzoccoli C, Ruggieri V, Sisinni L, Bolognesi A, Rensen WM, Miele A, Nalli M, Alfonsi R, Di Marcotullio L, Gulino A, Brancale A, Novellino E, Dondio G, Vultaggio S, Varasi M, Mercurio C, Hamel E, Lavia P, and Silvestri R
- Subjects
- Aniline Compounds chemical synthesis, Aniline Compounds pharmacology, Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Cell Death drug effects, Cell Line, Tumor, Cell Membrane Permeability drug effects, Cell Proliferation drug effects, Cell Survival drug effects, Colchicine chemistry, Drug Screening Assays, Antitumor, Guanidines chemical synthesis, Guanidines pharmacology, Hedgehog Proteins antagonists & inhibitors, Humans, M Phase Cell Cycle Checkpoints drug effects, Mice, Molecular Docking Simulation, Neoplasms drug therapy, Neoplasms pathology, Polymerization, Protein Binding, Pyrroles chemical synthesis, Pyrroles pharmacology, Signal Transduction, Structure-Activity Relationship, Tubulin chemistry, Tubulin Modulators chemical synthesis, Tubulin Modulators pharmacology, Aniline Compounds chemistry, Antineoplastic Agents chemistry, Guanidines chemistry, Hedgehog Proteins metabolism, Neoplasms metabolism, Pyrroles chemistry, Tubulin Modulators chemistry
- Abstract
We synthesized 3-aroyl-1-arylpyrrole (ARAP) derivatives as potential anticancer agents having different substituents at the pendant 1-phenyl ring. Both the 1-phenyl ring and 3-(3,4,5-trimethoxyphenyl)carbonyl moieties were mandatory to achieve potent inhibition of tubulin polymerization, binding of colchicine to tubulin, and cancer cell growth. ARAP 22 showed strong inhibition of the P-glycoprotein-overexpressing NCI-ADR-RES and Messa/Dx5MDR cell lines. Compounds 22 and 27 suppressed in vitro the Hedgehog signaling pathway, strongly reducing luciferase activity in SAG treated NIH3T3 Shh-Light II cells, and inhibited the growth of medulloblastoma D283 cells at nanomolar concentrations. ARAPs 22 and 27 represent a new potent class of tubulin polymerization and cancer cell growth inhibitors with the potential to inhibit the Hedgehog signaling pathway.
- Published
- 2014
- Full Text
- View/download PDF
11. Cinnamic anilides as new mitochondrial permeability transition pore inhibitors endowed with ischemia-reperfusion injury protective effect in vivo.
- Author
-
Fancelli D, Abate A, Amici R, Bernardi P, Ballarini M, Cappa A, Carenzi G, Colombo A, Contursi C, Di Lisa F, Dondio G, Gagliardi S, Milanesi E, Minucci S, Pain G, Pelicci PG, Saccani A, Storto M, Thaler F, Varasi M, Villa M, and Plyte S
- Subjects
- 1-Naphthylamine chemical synthesis, 1-Naphthylamine chemistry, 1-Naphthylamine pharmacology, Acrylamides chemical synthesis, Acrylamides pharmacology, Anilides chemical synthesis, Anilides pharmacology, Animals, Calcium metabolism, Cinnamates chemical synthesis, Cinnamates pharmacology, Female, Male, Mice, Inbred C57BL, Mitochondria, Heart metabolism, Mitochondria, Liver metabolism, Mitochondrial Membrane Transport Proteins metabolism, Mitochondrial Permeability Transition Pore, Mitochondrial Swelling drug effects, Myocardial Infarction drug therapy, Myocardial Infarction metabolism, Myocardial Reperfusion Injury metabolism, Rabbits, Stereoisomerism, Structure-Activity Relationship, 1-Naphthylamine analogs & derivatives, Acrylamides chemistry, Anilides chemistry, Cinnamates chemistry, Mitochondrial Membrane Transport Proteins antagonists & inhibitors, Myocardial Reperfusion Injury drug therapy
- Abstract
In this account, we report the development of a series of substituted cinnamic anilides that represents a novel class of mitochondrial permeability transition pore (mPTP) inhibitors. Initial class expansion led to the establishment of the basic structural requirements for activity and to the identification of derivatives with inhibitory potency higher than that of the standard inhibitor cyclosporine-A (CsA). These compounds can inhibit mPTP opening in response to several stimuli including calcium overload, oxidative stress, and thiol cross-linkers. The activity of the cinnamic anilide mPTP inhibitors turned out to be additive with that of CsA, suggesting for these inhibitors a molecular target different from cyclophylin-D. In vitro and in vivo data are presented for (E)-3-(4-fluoro-3-hydroxy-phenyl)-N-naphthalen-1-yl-acrylamide 22, one of the most interesting compounds in this series, able to attenuate opening of the mPTP and limit reperfusion injury in a rabbit model of acute myocardial infarction.
- Published
- 2014
- Full Text
- View/download PDF
12. Toward highly potent cancer agents by modulating the C-2 group of the arylthioindole class of tubulin polymerization inhibitors.
- Author
-
La Regina G, Bai R, Rensen WM, Di Cesare E, Coluccia A, Piscitelli F, Famiglini V, Reggio A, Nalli M, Pelliccia S, Da Pozzo E, Costa B, Granata I, Porta A, Maresca B, Soriani A, Iannitto ML, Santoni A, Li J, Miranda Cona M, Chen F, Ni Y, Brancale A, Dondio G, Vultaggio S, Varasi M, Mercurio C, Martini C, Hamel E, Lavia P, Novellino E, and Silvestri R
- Subjects
- Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Caco-2 Cells, Cell Cycle drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Cytochrome P-450 Enzyme Inhibitors, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor, Humans, Imidazoles chemistry, Imidazoles pharmacology, Indoles chemistry, Indoles pharmacology, Liver Neoplasms blood supply, Liver Neoplasms drug therapy, Membrane Potential, Mitochondrial drug effects, Mice, Microsomes, Liver metabolism, Mitosis drug effects, Permeability, Polymerization, Pyridines chemistry, Pyridines pharmacology, Reactive Oxygen Species metabolism, Rhabdomyosarcoma blood supply, Rhabdomyosarcoma drug therapy, Solubility, Structure-Activity Relationship, Tubulin chemistry, Tubulin Modulators chemistry, Tubulin Modulators pharmacology, Antineoplastic Agents chemical synthesis, Imidazoles chemical synthesis, Indoles chemical synthesis, Pyridines chemical synthesis, Tubulin Modulators chemical synthesis
- Abstract
New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed IC₅₀ = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes.
- Published
- 2013
- Full Text
- View/download PDF
13. Design and synthesis of 2-heterocyclyl-3-arylthio-1H-indoles as potent tubulin polymerization and cell growth inhibitors with improved metabolic stability.
- Author
-
La Regina G, Bai R, Rensen W, Coluccia A, Piscitelli F, Gatti V, Bolognesi A, Lavecchia A, Granata I, Porta A, Maresca B, Soriani A, Iannitto ML, Mariani M, Santoni A, Brancale A, Ferlini C, Dondio G, Varasi M, Mercurio C, Hamel E, Lavia P, Novellino E, and Silvestri R
- Subjects
- Administration, Oral, Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Biological Availability, Caspase 3 metabolism, Cell Cycle drug effects, Cell Line, Cell Line, Tumor, Cell Proliferation drug effects, Drug Design, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor, Furans chemical synthesis, Furans chemistry, Furans pharmacology, Humans, In Vitro Techniques, Indoles chemistry, Indoles pharmacology, Injections, Intravenous, Male, Mice, Mice, Nude, Microsomes, Liver metabolism, Pyrroles chemical synthesis, Pyrroles chemistry, Pyrroles pharmacology, Solubility, Structure-Activity Relationship, Thiophenes chemical synthesis, Thiophenes chemistry, Thiophenes pharmacology, Tubulin Modulators chemical synthesis, Tubulin Modulators chemistry, Tubulin Modulators pharmacology, Antineoplastic Agents chemical synthesis, Indoles chemical synthesis
- Abstract
New arylthioindoles (ATIs) were obtained by replacing the 2-alkoxycarbonyl group with a bioisosteric 5-membered heterocycle nucleus. The new ATIs 5, 8, and 10 inhibited tubulin polymerization, reduced cell growth of a panel of human transformed cell lines, and showed higher metabolic stability than the reference ester 3. These compounds induced mitotic arrest and apoptosis at a similar level as combretastatin A-4 and vinblastine and triggered caspase-3 expression in a significant fraction of cells in both p53-proficient and p53-defective cell lines. Importantly, ATIs 5, 8, and 10 were more effective than vinorelbine, vinblastine, and paclitaxel as growth inhibitors of the P-glycoprotein-overexpressing cell line NCI/ADR-RES. Compound 5 was shown to have medium metabolic stability in both human and mouse liver microsomes, in contrast to the rapidly degraded reference ester 3, and a pharmacokinetic profile in the mouse characterized by a low systemic clearance and excellent oral bioavailability.
- Published
- 2011
- Full Text
- View/download PDF
14. Discovery, synthesis, and pharmacological evaluation of spiropiperidine hydroxamic acid based derivatives as structurally novel histone deacetylase (HDAC) inhibitors.
- Author
-
Varasi M, Thaler F, Abate A, Bigogno C, Boggio R, Carenzi G, Cataudella T, Dal Zuffo R, Fulco MC, Rozio MG, Mai A, Dondio G, Minucci S, and Mercurio C
- Subjects
- Administration, Oral, Animals, Biological Availability, Cell Line, Tumor, Drug Evaluation, Preclinical, Histone Deacetylase Inhibitors chemical synthesis, Humans, Hydroxamic Acids chemical synthesis, Magnetic Resonance Spectroscopy, Mice, Molecular Structure, Spectrometry, Mass, Electrospray Ionization, Histone Deacetylase Inhibitors chemistry, Histone Deacetylase Inhibitors pharmacology, Hydroxamic Acids chemistry, Hydroxamic Acids pharmacology
- Abstract
New spiro[chromane-2,4'-piperidine] and spiro[benzofuran-2,4'-piperidine] hydroxamic acid derivatives as HDAC inhibitors have been identified by combining privileged structures with a hydroxamic acid moiety as zinc binding group. The compounds were evaluated for their ability to inhibit nuclear extract HDACs and for their in vitro antiproliferative activity on different tumor cell lines. This work resulted in the discovery of spirocycle 30d that shows good oral bioavailability and tumor growth inhibition in an HCT-116 murine xenograft model.
- Published
- 2011
- Full Text
- View/download PDF
15. Cdc7 kinase inhibitors: 5-heteroaryl-3-carboxamido-2-aryl pyrroles as potential antitumor agents. 1. Lead finding.
- Author
-
Menichincheri M, Albanese C, Alli C, Ballinari D, Bargiotti A, Caldarelli M, Ciavolella A, Cirla A, Colombo M, Colotta F, Croci V, D'Alessio R, D'Anello M, Ermoli A, Fiorentini F, Forte B, Galvani A, Giordano P, Isacchi A, Martina K, Molinari A, Moll JK, Montagnoli A, Orsini P, Orzi F, Pesenti E, Pillan A, Roletto F, Scolaro A, Tatò M, Tibolla M, Valsasina B, Varasi M, Vianello P, Volpi D, Santocanale C, and Vanotti E
- Subjects
- Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Biological Availability, Cell Line, Tumor, Drug Screening Assays, Antitumor, Humans, Mice, Mice, Nude, Neoplasm Transplantation, Pyrimidines chemistry, Pyrimidines pharmacology, Pyrroles chemistry, Pyrroles pharmacology, Structure-Activity Relationship, Transplantation, Heterologous, Antineoplastic Agents chemical synthesis, Cell Cycle Proteins antagonists & inhibitors, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyrimidines chemical synthesis, Pyrroles chemical synthesis
- Abstract
Cdc7 serine/threonine kinase is a key regulator of DNA synthesis in eukaryotic organisms. Cdc7 inhibition through siRNA or prototype small molecules causes p53 independent apoptosis in tumor cells while reversibly arresting cell cycle progression in primary fibroblasts. This implies that Cdc7 kinase could be considered a potential target for anticancer therapy. We previously reported that pyrrolopyridinones (e.g., 1) are potent and selective inhibitors of Cdc7 kinase, with good cellular potency and in vitro ADME properties but with suboptimal pharmacokinetic profiles. Here we report on a new chemical class of 5-heteroaryl-3-carboxamido-2-substituted pyrroles (1A) that offers advantages of chemistry diversification and synthetic simplification. This work led to the identification of compound 18, with biochemical data and ADME profile similar to those of compound 1 but characterized by superior efficacy in an in vivo model. Derivative 18 represents a new lead compound worthy of further investigation toward the ultimate goal of identifying a clinical candidate.
- Published
- 2010
- Full Text
- View/download PDF
16. Synthesis and biological evaluation of N-hydroxyphenylacrylamides and N-hydroxypyridin-2-ylacrylamides as novel histone deacetylase inhibitors.
- Author
-
Thaler F, Colombo A, Mai A, Amici R, Bigogno C, Boggio R, Cappa A, Carrara S, Cataudella T, Fusar F, Gianti E, di Ventimiglia SJ, Moroni M, Munari D, Pain G, Regalia N, Sartori L, Vultaggio S, Dondio G, Gagliardi S, Minucci S, Mercurio C, and Varasi M
- Subjects
- Acrylamides pharmacology, Antineoplastic Agents pharmacokinetics, Benzene Derivatives, Cell Proliferation drug effects, Colonic Neoplasms drug therapy, Drug Stability, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacokinetics, Enzyme Inhibitors therapeutic use, HeLa Cells, Histone Deacetylase Inhibitors pharmacokinetics, Histone Deacetylase Inhibitors therapeutic use, Humans, Pyridines, Structure-Activity Relationship, Xenograft Model Antitumor Assays, Acrylamides chemical synthesis, Antineoplastic Agents chemical synthesis, Histone Deacetylase Inhibitors chemical synthesis
- Abstract
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.
- Published
- 2010
- Full Text
- View/download PDF
17. First Cdc7 kinase inhibitors: pyrrolopyridinones as potent and orally active antitumor agents. 2. Lead discovery.
- Author
-
Menichincheri M, Bargiotti A, Berthelsen J, Bertrand JA, Bossi R, Ciavolella A, Cirla A, Cristiani C, Croci V, D'Alessio R, Fasolini M, Fiorentini F, Forte B, Isacchi A, Martina K, Molinari A, Montagnoli A, Orsini P, Orzi F, Pesenti E, Pezzetta D, Pillan A, Poggesi I, Roletto F, Scolaro A, Tatò M, Tibolla M, Valsasina B, Varasi M, Volpi D, Santocanale C, and Vanotti E
- Subjects
- Administration, Oral, Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacokinetics, Cell Line, Tumor, Chromatography, High Pressure Liquid, Dogs, Drug Discovery, Humans, Magnetic Resonance Spectroscopy, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacokinetics, Pyridones chemistry, Pyridones pharmacokinetics, Rats, Rats, Wistar, Spectrometry, Mass, Electrospray Ionization, Spectrophotometry, Ultraviolet, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Cell Cycle Proteins antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyridones pharmacology
- Abstract
Cdc7 kinase is a key regulator of the S-phase of the cell cycle, known to promote the activation of DNA replication origins in eukaryotic organisms. Cdc7 inhibition can cause tumor-cell death in a p53-independent manner, supporting the rationale for developing Cdc7 inhibitors for the treatment of cancer. In this paper, we conclude the structure-activity relationships study of the 2-heteroaryl-pyrrolopyridinone class of compounds that display potent inhibitory activity against Cdc7 kinase. Furthermore, we also describe the discovery of 89S, [(S)-2-(2-aminopyrimidin-4-yl)-7-(2-fluoro-ethyl)-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one], as a potent ATP mimetic inhibitor of Cdc7. Compound 89S has a Ki value of 0.5 nM, inhibits cell proliferation of different tumor cell lines with an IC50 in the submicromolar range, and exhibits in vivo tumor growth inhibition of 68% in the A2780 xenograft model.
- Published
- 2009
- Full Text
- View/download PDF
18. Cdc7 kinase inhibitors: pyrrolopyridinones as potential antitumor agents. 1. Synthesis and structure-activity relationships.
- Author
-
Vanotti E, Amici R, Bargiotti A, Berthelsen J, Bosotti R, Ciavolella A, Cirla A, Cristiani C, D'Alessio R, Forte B, Isacchi A, Martina K, Menichincheri M, Molinari A, Montagnoli A, Orsini P, Pillan A, Roletto F, Scolaro A, Tibolla M, Valsasina B, Varasi M, Volpi D, and Santocanale C
- Subjects
- Amino Acid Sequence, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Binding Sites, Cell Cycle Proteins chemistry, Cell Line, Tumor, Drug Screening Assays, Antitumor, Furans chemical synthesis, Furans chemistry, Furans pharmacology, Humans, Models, Molecular, Molecular Sequence Data, Protein Binding, Protein Serine-Threonine Kinases chemistry, Pyridones chemistry, Pyridones pharmacology, Pyrroles chemistry, Pyrroles pharmacology, Sequence Homology, Amino Acid, Structure-Activity Relationship, Antineoplastic Agents chemical synthesis, Cell Cycle Proteins antagonists & inhibitors, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyridones chemical synthesis, Pyrroles chemical synthesis
- Abstract
Cdc7 kinase is an essential protein that promotes DNA replication in eukaryotic organisms. Genetic evidence indicates that Cdc7 inhibition can cause selective tumor-cell death in a p53-independent manner, supporting the rationale for developing Cdc7 small-molecule inhibitors for the treatment of cancers. In this paper, the synthesis and structure-activity relationships of 2-heteroaryl-pyrrolopyridinones, the first potent Cdc7 kinase inhibitors, are described. Starting from 2-pyridin-4-yl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one, progress toward a simple scaffold, tailored for Cdc7 inhibition, is reported.
- Published
- 2008
- Full Text
- View/download PDF
19. 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles: identification of a potent Aurora kinase inhibitor with a favorable antitumor kinase inhibition profile.
- Author
-
Fancelli D, Moll J, Varasi M, Bravo R, Artico R, Berta D, Bindi S, Cameron A, Candiani I, Cappella P, Carpinelli P, Croci W, Forte B, Giorgini ML, Klapwijk J, Marsiglio A, Pesenti E, Rocchetti M, Roletto F, Severino D, Soncini C, Storici P, Tonani R, Zugnoni P, and Vianello P
- Subjects
- Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Aurora Kinases, Cell Line, Tumor, Drug Screening Assays, Antitumor, Male, Mice, Models, Molecular, Pyrazoles pharmacokinetics, Pyrazoles pharmacology, Pyrroles pharmacokinetics, Pyrroles pharmacology, Solubility, Structure-Activity Relationship, Antineoplastic Agents chemical synthesis, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyrazoles chemical synthesis, Pyrroles chemical synthesis
- Abstract
The optimization of a series of 5-phenylacetyl 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives toward the inhibition of Aurora kinases led to the identification of compound 9d. This is a potent inhibitor of Aurora kinases that also shows low nanomolar potency against additional anticancer kinase targets. Based on its high antiproliferative activity on different cancer cell lines, favorable chemico-physical and pharmacokinetic properties, and high efficacy in in vivo tumor models, compound 9d was ultimately selected for further development.
- Published
- 2006
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.