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Pagina personale di Alfonso ZAMBON

Dipartimento di Scienze Chimiche e Geologiche
Dipartimento di Scienze Chimiche e Geologiche - Sede Dipartimento di Scienze Chimiche e Geologiche

Francesca, Parenti; Mirko, Buffagni; Alfonso, Zambon; Monica, Caselli; Davide, Vanossi; Adele, Mucci ( 2017 ) - Novel oligothiophenes with reduced HOMO-LUMO band gap for Optoelectonics ( XXVI Congresso Nazionale della Società Chimica Italiana - - 10 - 14 settembre) ( - Atti del XXVI Congresso Nazionale della Società Chimica Italiana ) (Società Chimica Italiana Roma ITA ) - n. volume IV - pp. da 170 a 170 ISBN: 9788886208840 ISSN: - [Abstract in Atti di convegno (274) - Abstract in Atti di Convegno]
Abstract

Here we present the synthesis of A-π-D-π-A thiophene-based oligomers (Figure 1); in the design of these materials we incorporated both electron-donor and electron-acceptor groups by having a central donor dithienosilole, two terminal methyldicyanovinyl acceptor groups and two bithienyl units, functionalised with alkyl or alkylsulfanyl chains, as π-bridges.

Sanchez Laorden, Berta; Viros, Amaya; Girotti, Maria Romina; Pedersen, Malin; Saturno, Grazia; Zambon, Alfonso; Niculescu Duvaz, Dan; Turajlic, Samra; Hayes, Andrew; Gore, Martin; Larkin, James; Lorigan, Paul; Cook, Martin; Springer, Caroline; Marais, Richard ( 2014 ) - BRAF inhibitors induce metastasis in RAS mutant or inhibitor-resistant melanoma cells by reactivating MEK and ERK signaling - SCIENCE SIGNALING - n. volume 7 [Articolo in rivista (262) - Articolo su rivista]
Abstract

Melanoma is a highly metastatic and lethal form of skin cancer. The protein kinase BRAF is mutated in about 40% of melanomas, and BRAF inhibitors improve progression-free and overall survival in these patients. However, after a relatively short period of disease control, most patients develop resistance because of reactivation of the RAF-ERK (extracellular signal-regulated kinase) pathway, mediated in many cases by mutations in RAS. We found that BRAF inhibition induces invasion and metastasis in RAS mutant melanoma cells through a mechanism mediated by the reactivation of the MEK (mitogen-activated protein kinase kinase)-ERK pathway, increased expression and secretion of interleukin 8, and induction of protease-dependent invasion. These events were accompanied by a cell morphology switch from predominantly rounded to predominantly elongated cells. We also observed similar responses in BRAF inhibitor-resistant melanoma cells. These data show that BRAF inhibitors can induce melanoma cell invasion and metastasis in tumors that develop resistance to these drugs.

Zambon, Alfonso; Niculescu-Duvaz, Dan; Niculescu-Duvaz, Ion; Marais, Richard; Springer, Caroline J ( 2013 ) - BRAF as a therapeutic target: A patent review (2006-2012) - EXPERT OPINION ON THERAPEUTIC PATENTS - n. volume 23 - pp. da 155 a 164 ISSN: 1354-3776 [Articolo in rivista (262) - Articolo su rivista]
Abstract

Introduction: After its identification as an oncogene in 2002, mutant BRAF has become the target of a number of drug discovery programmes, primarily aimed at the treatment of late stage or unresectable melanoma. Some of the drugs thus developed, such as vemurafenib and dabrafenib, show impressive responses in melanoma patients harbouring a BRAF mutation. Areas covered: This review summarises the patent literature on BRAF from 2006 to 2012, focusing on the specific areas of inhibitors of mutant BRAF, drug combinations including BRAF inhibitors, diagnostic methods for use with mutant BRAF inhibitors & diagnosis and treatment of mutant BRAF cancers resistant to BRAF inhibitors. Expert opinion: Whilst these first-generation BRAF inhibitors initially mediate excellent responses in late stage or unresectable melanoma patients bearing the V600 mutation, resistance usually occurs and patients eventually relapse. The patent literature for new BRAF inhibitors and therapies reflects the desire to develop second-generation drugs able to overcome this resistance and combination treatments that increase the efficiency of current mutant BRAF inhibitors. © 2013 Informa UK, Ltd.

Girotti, Maria R.; Pedersen, Malin; Sanchez-Laorden, Berta; Viros, Amaya; Turajlic, Samra; Niculescu-Duvaz, Dan; Zambon, Alfonso; Sinclair, John; Hayes, Andrew; Gore, Martin; Lorigan, Paul; Springer, Caroline; Larkin, James; Jorgensen, Claus; Marais, Richard ( 2013 ) - Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma - CANCER DISCOVERY - n. volume 3 - pp. da 158 a 167 ISSN: 2159-8274 [Articolo in rivista (262) - Articolo su rivista]
Abstract

We generated cell lines resistant to BRAF inhibitors and show that the EGF receptor (EGFR)-SRC family kinase (SFK)-STAT3 signaling pathway was upregulated in these cells. In addition to driving proliferation of resistant cells, this pathway also stimulated invasion and metastasis. EGFR inhibitors cooperated with BRAF inhibitors to block the growth of the resistant cells in vitro and in vivo, and monotherapy with the broad specifi city tyrosine kinase inhibitor dasatinib blocked growth and metastasis in vivo. We analyzed tumors from patients with intrinsic or acquired resistance to vemurafenib and observed increased EGFR and SFK activity. Furthermore, dasatinib blocked the growth and metastasis of one of the resistant tumors in immunocompromised mice. Our data show that BRAF inhibitor-mediated activation of EGFR-SFK-STAT3 signaling can mediate resistance in patients with BRAF-mutant melanoma. We describe 2 treatments that seem to overcome this resistance and could deliver therapeutic effi cacy in patients with drug-resistant BRAF-mutant melanoma. SIGNIFICANCE: Therapies that target the driver oncogenes in cancer can achieve remarkable responses if patients are stratifi ed for treatment. However, as with conventional therapies, patients often develop acquired resistance to targeted therapies, and a proportion of patients are intrinsically resistant and fail to respond despite the presence of an appropriate driver oncogene mutation. We found that the EGFR/SFK pathway mediated resistance to vemurafenib in BRAF -mutant melanoma and that BRAF and EGFR or SFK inhibition blocked proliferation and invasion of these resistant tumors, providing potentially effective therapeutic options for these patients. © 2012 American Association for Cancer Research.

Su, F; Viros, A; Milagre, C; Trunzer, K; Bollag, G; Spleiss, O; Reis, Js; Kong, Xj; Koya, Rc; Flaherty, Kt; Chapman, Pb; Kim, Mj; Hayward, R; Martin, M; Yang, H; Wang, Qq; Hilton, H; Hang, Js; Noe, J; Lambros, M; Geyer, F; Dhomen, N; Niculescu Duvaz, I; Zambon, Alfonso; Niculescu Duvaz, D; Preece, N; Robert, L; Otte, Nj; Mok, S; Kee, D; Ma, Y; Zhang, C; Habets, G; Burton, Ea; Wong, B; Nguyen, H; Kockx, M; Andries, L; Lestini, B; Nolop, Kb; Lee, Rj; Joe, Ak; Troy, Jl; Gonzalez, R; Hutson, Te; Puzanov, I; Chmielowski, B; Springer, Cj; Mcarthur, Ga; Sosman, Ja; Rs, Lo; Ribas, A; Marais, R. ( 2012 ) - RAS Mutations in Cutaneous Squamous-Cell Carcinomas in Patients Treated with BRAF Inhibitors - NEW ENGLAND JOURNAL OF MEDICINE - n. volume 366 - pp. da 207 a 215 ISSN: 0028-4793 [Articolo in rivista (262) - Articolo su rivista]
Abstract

BACKGROUNDCutaneous squamous-cell carcinomas and keratoacanthomas are common findings in patients treated with BRAF inhibitors.METHODSWe performed a molecular analysis to identify oncogenic mutations (HRAS, KRAS, NRAS, CDKN2A, and TP53) in the lesions from patients treated with the BRAF inhibitor vemurafenib. An analysis of an independent validation set and functional studies with BRAF inhibitors in the presence of the prevalent RAS mutation was also performed.RESULTSAmong 21 tumor samples, 13 had RAS mutations (12 in HRAS). In a validation set of 14 samples, 8 had RAS mutations (4 in HRAS). Thus, 60% (21 of 35) of the specimens harbored RAS mutations, the most prevalent being HRAS Q61L. Increased proliferation of HRAS Q61L-mutant cell lines exposed to vemurafenib was associated with mitogen-activated protein kinase (MAPK)-pathway signaling and activation of ERK-mediated transcription. In a mouse model of HRAS Q61L-mediated skin carcinogenesis, the vemurafenib analogue PLX4720 was not an initiator or a promoter of carcinogenesis but accelerated growth of the lesions harboring HRAS mutations, and this growth was blocked by concomitant treatment with a MEK inhibitor.CONCLUSIONSMutations in RAS, particularly HRAS, are frequent in cutaneous squamous-cell carcinomas and keratoacanthomas that develop in patients treated with vemurafenib. The molecular mechanism is consistent with the paradoxical activation of MAPK signaling and leads to accelerated growth of these lesions. (Funded by Hoffmann-La Roche and others; ClinicalTrials.gov numbers, NCT00405587, NCT00949702, NCT01001299, and NCT01006980.)

Sanchez-Laorden, B ; Viros, A ; Girotti, R ; Pedersen, M ; Zambon, A; Niculescu-Duvaz, D ; Springer, C; Marais, R ( 2012 ) - Paradoxical activation of the MEK/ERK pathway promotes melanoma invasion and metastasis - FEBS JOURNAL. SUPPLEMENT [Abstract in rivista (266) - Abstract in Rivista]
Abstract

Paradoxical activation of the MEK/ERK pathway promotes melanoma invasion and metastasis

Zambon, Alfonso; Niculescu-Duvaz, Ion; Niculescu-Duvaz, Dan; Marais, Richard; Springer, Caroline J ( 2012 ) - Small molecule inhibitors of BRAF in clinical trials - BIOORGANIC & MEDICINAL CHEMISTRY LETTERS - n. volume 22 - pp. da 789 a 792 ISSN: 0960-894X [Articolo in rivista (262) - Articolo su rivista]
Abstract

Over the last few years, BRAF has emerged as a validated target in melanoma. This review summarises recent advances in the development of BRAF inhibitors, focussing on agents that have been assessed clinically. © 2011 Elsevier Ltd. All rights reserved.

Niculescu-Duvaz, I. and Menard, D; and Niculescu-Duvaz, D.; and Zambon, A.; and Davies, L; and Preece, N.; and Kirk, R.; and Whittaker, S.; and Marais, R.; and Springer, C. ( 2010 ) - The discovery of novel, highly potent inhibitors of BRAF - EUROPEAN JOURNAL OF CANCER - pp. da 139 a 139 ISSN: 0959-8049 [Articolo in rivista (262) - Articolo su rivista]
Abstract

We describe the synthesis and optimisation of a series of new inhibitors of BRAF, a kinase whose mutant form (V600E) is implicated in several types of cancer, with particularly high frequency in melanoma. We designed and synthesised type II inhibitors interacting with the inactive conformation of the V600EBRAF.

Mologni, Luca; Rostagno, Roberta; Brussolo, Stefania; Knowles, Phillip P.; Kjaer, Svend; Murray-Rust, Judith; Rosso, Enrico; Zambon, Alfonso; Scapozza, Leonardo; Mcdonald, Neil Q.; Lucchini, Vittorio; Gambacorti-Passerini, Carlo ( 2010 ) - Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors - BIOORGANIC & MEDICINAL CHEMISTRY - n. volume 18 - pp. da 1482 a 1496 ISSN: 0968-0896 [Articolo in rivista (262) - Articolo su rivista]
Abstract

The synthesis, structure-activity relationships (SAR) and structural data of a series of indolin-2-one inhibitors of RET tyrosine kinase are described. These compounds were designed to explore the available space around the indolinone scaffold within RET active site. Several substitutions at different positions were tested and biochemical data were used to draw a molecular model of steric and electrostatic interactions, which can be applied to design more potent and selective RET inhibitors. The crystal structures of RET kinase domain in complex with three inhibitors were solved. All three compounds bound in the ATP pocket and formed two hydrogen bonds with the kinase hinge region. Crystallographic analysis confirmed predictions from molecular modelling and helped refine SAR results. These data provide important information for the development of indolinone inhibitors for the treatment of RET-driven cancers. © 2010 Elsevier Ltd. All rights reserved.

Suijkerbuijk, Bart M.J.M.; Niculescu-Duvaz, Ion; Gaulon, Catherine; Dijkstra, Harmen P.; Niculescu-Duvaz, Dan; Ménard, Delphine; Zambon, Alfonso; Nourry, Arnaud; Davies, Lawrence; Manne, Helen A.; Friedlos, Frank; Ogilvie, Lesley M.; Hedley, Douglas; Lopes, Filipa; Preece, Natasha P.U.; Moreno-Farre, Javier; Raynaud, Florence I.; Kirk, Ruth; Whittaker, Steven; Marais, Richard; Springer, Caroline J ( 2010 ) - Development of novel, highly potent inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF): Increasing cellular potency through optimization of a distal heteroaromatic group - JOURNAL OF MEDICINAL CHEMISTRY - n. volume 53 - pp. da 2741 a 2756 ISSN: 0022-2623 [Articolo in rivista (262) - Articolo su rivista]
Abstract

We describe the design, synthesis, and optimization of a series of new inhibitors of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF), a kinase whose mutant form (V600E) is implicated in several types of cancer, with a particularly high frequency in melanoma. Our previously described inhibitors with a tripartite A-B-C system (where A is a hinge binding pyrido[4,5-b] imidazolone system, B is an aryl spacer group, and C is a heteroaromatic group) were potent against purified V600EBRAF in vitro but were less potent in accompanying cellular assays. Substitution of different aromatic heterocycles for the phenyl based C-ring is evaluated herein as a potential means of improving the cellular potencies of these inhibitors. Substituted pyrazoles, particularly 3-tert-butyl-1-aryl-1H-pyrazoles, increase the cellular potencies without detrimental effects on the potency on isolated V600EBRAF. Thus, compounds have been synthesized that inhibit, with low nanomolar concentrations, V600EBRAF, its downstream signaling in cells [as measured by the reduction of the phosphorylation of extracellular regulated kinase (ERK)], and the proliferation of mutant BRAF-dependent cells. Concomitant benefits are good oral bioavailability and high plasma concentrations in vivo. © 2010 American Chemical Society.

Niculescu-Duvaz, Dan; Niculescu-Duvaz, Ion; Suijkerbuijk, Bart M.J.M.; Ménard, Delphine; Zambon, Alfonso; Nourry, Arnaud; Davies, Lawrence; Manne, Helen A.; Friedlos, Frank; Ogilvie, Lesley; Hedley, Douglas; Takle, Andrew K.; Wilson, David M.; Pons, Jean-Francois; Coulter, Tom; Kirk, Ruth; Cantarino, Neus; Whittaker, Steven; Marais, Richard; Springer, Caroline J ( 2010 ) - Novel tricyclic pyrazole BRAF inhibitors with imidazole or furan central scaffolds - BIOORGANIC & MEDICINAL CHEMISTRY - n. volume 18 - pp. da 6934 a 6952 ISSN: 0968-0896 [Articolo in rivista (262) - Articolo su rivista]
Abstract

V-RAF murine sarcoma viral oncogene homolog B1 (BRAF) is a serine/threonine-specific protein kinase that is mutated with high frequency in cutaneous melanoma, and many other cancers. Inhibition of mutant BRAF is an attractive therapeutic approach for the treatment of melanoma. A triarylimidazole BRAF inhibitor bearing a phenylpyrazole group (dimethyl-[2-(4-5-[4-(1H-pyrazol-3-yl)-phenyl]-4-pyridin-4-yl-1H-imidazol-2-yl -phenoxy)-ethyl]-amine, 1a) was identified as an active BRAF inhibitor. Based on this starting point, we synthesized a series of analogues leading to the discovery of 6-2-[4-(4-methyl-piperazin-1-yl)-phenyl]-5-pyridin-4-yl-3H- imidazol-4-yl-2,4-dihydro-indeno[1,2-c]pyrazole (1j), with nanomolar activity in three assays: inhibition of purified mutant BRAF activity in vitro; inhibition of oncogenic BRAF-driven extracellular regulated kinase (ERK) activation in BRAF mutant melanoma cell lines; and inhibition of proliferation in these cells. © 2010 Elsevier Ltd. All rights reserved.

Whittaker, Steven; Ménard, Delphine; Kirk, Ruth; Ogilvie, Lesley; Hedley, Douglas; Zambon, Alfonso; Lopes, Filipa; Preece, Natasha; Manne, Helen; Rana, Sareena; Lambros, Maryou; Reis-Filho, Jorge S.; Marais, Richard; Springer, Caroline J. ( 2010 ) - A novel, selective, and efficacious nanomolar pyridopyrazinone inhibitor of V600EBRAF - CANCER RESEARCH - n. volume 70 - pp. da 8036 a 8044 ISSN: 0008-5472 [Articolo in rivista (262) - Articolo su rivista]
Abstract

Oncogenic BRAF is a critical driver of proliferation and survival and is thus a validated therapeutic target in cancer. We have developed a potent inhibitor, termed 1t (CCT239065), of the mutant protein kinase, V600EBRAF. 1t inhibits signaling downstream of V600EBRAF in cancer cells, blocking DNA synthesis, and inhibiting proliferation. Importantly, we show that 1t is considerably more selective for mutated BRAF cancer cell lines compared with wild-type BRAF lines. The inhibitor is well tolerated in mice and exhibits excellent oral bioavailability (F = 71%). Suppression of V600EBRAF-mediated signaling in human tumor xenografts was observed following oral administration of a single dose of 1t. As expected, the growth rate in vivo of a wild-type BRAF human tumor xenograft model is unaffected by inhibitor 1t. In contrast, 1t elicits significant therapeutic responses in mutant BRAF-driven human melanoma xenografts. ©2010 AACR.

Whittaker, Steven; Kirk, Ruth; Hayward, Robert; Zambon, Alfonso; Viros, Amaya; Cantarino, Neus; Affolter, Annette; Nourry, Arnaud; Niculescu-Duvaz, Dan; Springer, Caroline; Marais, Richard ( 2010 ) - Gatekeeper mutations mediate resistance to BRAF-targeted therapies - SCIENCE TRANSLATIONAL MEDICINE - n. volume 2 [Articolo in rivista (262) - Articolo su rivista]
Abstract

BRAF is a serine-threonine - specific protein kinase that is mutated in 2% of human cancers. Oncogenic BRAF is a validated therapeutic target that constitutively activates mitogen-activated protein kinase kinase (MEK) - extracellular signal - regulated kinase (ERK) signaling, driving tumor cell proliferation and survival. Drugs designed to target BRAF have been developed, but it is difficult to prove that they mediate their antitumor effects by inhibiting BRAF rather than by working through off-target effects. We generated drug-resistant versions of oncogenic BRAF by mutating the gatekeeper residue. Signaling by the mutant proteins was resistant to the small-molecule inhibitor sorafenib, but sorafenib still inhibited the growth of tumors driven by the mutant protein. In contrast, both BRAF signaling and tumor growth were resistant to another RAF drug, PLX4720. These data provide unequivocal evidence that sorafenib mediates its antitumor effects in a manner that is independent of its ability to target oncogenic BRAF, whereas PLX4720 inhibits tumor growth by targeting oncogenic BRAF directly.

Lucchini, Vittorio; Borsato, Giuseppe; Canovese, Luciano; Santo, Claudio; Visentin, Fabiano; Zambon, Alfonso ( 2009 ) - Qualitative and quantitative discrimination of fake and true alkene rotation processes in pd(η2-olefin) complexes. A new bimolecular mechanism - INORGANICA CHIMICA ACTA - n. volume 362 - pp. da 2715 a 2721 ISSN: 0020-1693 [Articolo in rivista (262) - Articolo su rivista]
Abstract

The fluxional behaviour of [Pd(η2-fn)(N-SMe)] (2) (fn = fumaronitrile, N-SMe = 2-methylthiomethylpyridine) and of [Pd(η2-tmetc)(N-N′-4-anisyl)] (3) (tmetc = tetramethylethylenetetracarboxylate, N-N′-4-anisyl = 2-(4-methoxyphenyliminomethane)pyridine) were monitored by 1H NMR spectroscopy and quantitatively determined by line-shape analyses (for 2) and selective inversion recovery experiments (for 3). The coalescence of the AB multiplet of fn hydrogens of 2 is concentration dependent and presents a strongly negative ΔS≠, suggesting the intermediacy of a dimeric complex and ruling out the hypothesis of olefin rotation. The accurate evaluation of all spectral features also allows determination of the approaching mode of the monomeric units. The inversion transfer between the tmetc methyls of 3 reveals a true propeller-like olefin rotation. The presence of a nucleophilic electron pair at sulfur in 2 triggers the formation of the dimeric intermediate. © 2008 Elsevier B.V. All rights reserved.

Menard, Delphine; Niculescu-Duvaz Ion; Dijkstra, Harmen P; I Niculescu-Duvaz,Dan; Suijkerbuijk, Bart M. J. M.; Zambon, Alfonso; Nourry, Arnaud ; Roman, Esteban ; Davies, Lawrence; Marine; Friedlos, Frank; Helen A. and; Kirk, Ruth and; Gill, Adrian; Whittaker, Steven; Taylor, Richard D; Marais,Richard; Springer, Caroline ( 2009 ) - Novel Potent BRAF Inhibitors: Toward 1 nM Compounds through Optimization of the Central Phenyl Ring - JOURNAL OF MEDICINAL CHEMISTRY - pp. da 3881 a 3891 ISSN: 0022-2623 [Articolo in rivista (262) - Articolo su rivista]
Abstract

BRAF, a serine/threonine specific protein kinase that is part of the MAPK pathway and acts as a downstream effector of RAS, is a potential therapeutic target in melanoma. We have developed a series of small-molecule BRAF inhibitors based on a 1H-imidazo[4,5-b]pyridine-2(3H)-one scaffold (ring A) as the hinge binding moiety and a number of substituted phenyl rings C that interact with the allosteric binding site. The introduction of various groups on the central phenyl ring B combined with appropriate A- and C-ring modifications afford very potent compounds that inhibit V600EBRAF kinase activity in vitro and oncogenic BRAF signaling in melanoma cells. Substitution on the central phenyl ring of a 3-fluoro, a naphthyl, or a 3-thiomethyl group improves activity to yield compounds with an IC50 of 1 nM for purified V600EBRAF and nanomolar activity in cells.

Niculescu-Duvaz, Dan; Gaulon, Catherine; Dijkstra, Harmen P.; Niculescu-Duvaz, Ion; Zambon, Alfonso; Menard, Delphine; Suijkerbuijk, Bart M. J. M.; Nourry, Arnaud; Davies, Lawrence; Manne, Helen; Friedlos, Frank; Ogilvie, Lesley; Hedley, Douglas; Whittaker, Steven; Kirk, Ruth; Gill, Adrian; Taylor, Richard D.; Raynaud, Florence I.; Moreno-Farre, Javier; Marais, Richard; Springer, Caroline J ( 2009 ) - Pyridoimidazolones as novel potent inhibitors of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF) - JOURNAL OF MEDICINAL CHEMISTRY - n. volume 52 - pp. da 2255 a 2264 ISSN: 0022-2623 [Articolo in rivista (262) - Articolo su rivista]
Abstract

BRAF is a serine/threonine kinase that is mutated in a range of cancers, including 50-70% of melanomas, and has been validated as a therapeutic target. We have designed and synthesized mutant BRAF inhibitors containing pyridoimidazolone as a new hinge-binding scaffold. Compounds have been obtained which have low nanomolar potency for mutant BRAF (12 nM for compound 5i) and low micromolar cellular potency against a mutant BRAF melanoma cell line, WM266.4. The series benefits from very low metabolism, and pharmacokinetics (PK) that can be modulated by methylation of the NH groups of the imidazolone, resulting in compounds with fewer H-donors and a better PK profile. These compounds have great potential in the treatment of mutant BRAF melanomas. © 2009 American Chemical Society.

Zambon, Alfonso; Borsato, Giuseppe; Brussolo, Stefania; Frascella, Pietrogiulio; Lucchini, Vittorio ( 2008 ) - Efficient access to 5-substituted thiazoles by a novel metallotropic rearrangement - TETRAHEDRON LETTERS - n. volume 49 - pp. da 66 a 69 ISSN: 0040-4039 [Articolo in rivista (262) - Articolo su rivista]
Abstract

A novel rearrangement process involving the migration of trimethylstannanyl or trimethylsilanyl groups around the thiazole ring provides access to either 2- or 5-metallated thiazoles by tuning the reaction conditions. The proposed mechanism, based on experimental evidence, is characterized by the catalytic role of thiazole bisadducts as metal-transfer agents. © 2007 Elsevier Ltd. All rights reserved.

Puttini, Miriam; Redaelli, Sara; Moretti, Loris; Brussolo, Stefania; Gunby, Rosalind H.; Mologni, Luca; Marchesi, Edoardo; Cleris, Loredana; Donella-Deana, Arianna; Drueckes, Peter; Sala, Elisa; Lucchini, Vittorio; Kubbutat, Michael; Formelli, Franca; Zambon, Alfonso; Scapozza, Leonardo; Gambacorti-Passerini, Carlo ( 2008 ) - Characterization of compound 584, an Abl kinase inhibitor with lasting effects - HAEMATOLOGICA - n. volume 93 - pp. da 653 a 661 ISSN: 0390-6078 [Articolo in rivista (262) - Articolo su rivista]
Abstract

Background: Resistance to imatinib is an important clinical issue in the treatment of Philadelphia chromosomepositive leukemias which is being tackled by the development of new, more potent drugs, such as the dual Src/Abl tyrosine kinase inhibitors dasatinib and bosutinib and the imatinib analog nilotinib. In the current study we describe the design, synthesis and biological properties of an imatinib analog with a chlorine-substituted benzamide, namely compound 584 (cmp-584). Design and Methods: To increase the potency, we rationally designed cmp-584, a compound with enhanced shape complementarity with the kinase domain of Abl. cmp-584 was synthesized and characterized in vitro against a panel of 67 serine/threonine and tyrosine kinases using radioactive and enzyme-linked immunosorbent kinase assays. We studied inhibitory cellular activity using Bcr/Abl-positive human cell lines, murine transfectants in proliferation experiments, and a murine xenotransplanted model. Kinase assays on isolated Bcr/Abl protein were also performed. Finally, we used a wash-out approach on whole cells to study the binding kinetics of the inhibitor. Results: cmp-584 showed potent anti-Abl activity both on recombinant protein (IC50: 8 nM) and in cell-based assays (IC50: 0.1-10 nM). The drug maintained inhibitory activity against platelet-derived growth factor receptors and c-KIT and was also active against Lyn (IC50: 301 nM). No other kinase of the panel was inhibited at nanomolar doses. cmp-584 was 20- to 300-fold more active than imatinib in cells. This superior activity was evident in intact cells, in which full-length Bcr-Abl is present. In vivo experiments confirmed the activity of cmp-584. Wash-out experiments showed that short exposure to the drug impaired cell proliferation and Bcr-Abl phosphorylation for a substantially longer period of time than imatinib. Conclusions: The present results suggest a slower off-rate (dissociation rate) of cmp-584 compared to imatinib as an explanation for the increased cellular activity of the former. ©2008 Ferrata Storti Foundation.

Borsato, Giuseppe; Linden, Anthony; De Lucchi, Ottorino; Lucchini, Vittorio; Wolstenholme, David; Zambon, Alfonso ( 2007 ) - Chiral polycyclic ketones via desymmetrization of dihaloolefins - JOURNAL OF ORGANIC CHEMISTRY - n. volume 72 - pp. da 4272 a 4275 ISSN: 0022-3263 [Articolo in rivista (262) - Articolo su rivista]
Abstract

(Chemical Equation Presented) 3-Chloronorbornenone (R)-1a (98% ee) was obtained from trichloronorbornene 5 in two steps by the in situ generation of dichloronorbornadiene 2a with t-BuOK and desymmetrization with (-)-ephedrine, followed by hydrolysis with PPTS. The generality of this desymmetrization with (-)-ephedrine was tested with dibromonorbornadiene 2c and other substituted dichloronorbornadienes. © 2007 American Chemical Society.

Kuettel, Sabine; Zambon, Alfonso; Kaiser, Marcel; Brun, Reto; Scapozza, Leonardo; Perozzo, Remo ( 2007 ) - Synthesis and evaluation of antiparasitic activities of new 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine derivatives - JOURNAL OF MEDICINAL CHEMISTRY - n. volume 50 - pp. da 5833 a 5839 ISSN: 0022-2623 [Articolo in rivista (262) - Articolo su rivista]
Abstract

A series of new 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine derivatives, prepared by two synthetic routes, were in vitro assayed against three Trypanosoma strains, Leishmania donovani, and Plasmodium falciparum K1. Seven out of 17 compounds showed moderate to very good activity against blood stage T. b. rhodesiense, with 10 and 17 exhibiting highest potency (IC 50 of 1.0 and 1.1 μM. respectively). Interestingly, the β-diketone precursors 1-3 had good antitrypanosomal activity toward the insect stage, with IC50 values of 1.0-3.4 μM. Among different compounds with moderate activity against T. cruzi, compound 17 showed the lowest IC50 value of 9.5 μM; thus, the series seemed to act selectively toward the different Trypanosoma parasites. Eight compounds were moderately active against L. donovani, with 2, 3, and 12 being the most promising ones (IC50 values of 2.3-5.2 μM), whereas compound 14 was the only derivative with good activity against P. falciparum (IC50 of 3.7 μM). © 2007 American Chemical Society.

Zambon, A ; Goekjian, P; Lucchini, V. ( 2006 ) - Synthetic approach to novel NMP/ALK inhibitors - EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES [Abstract in rivista (266) - Abstract in Rivista]
Abstract

Synthetic approach to novel NMP/ALK inhibitors

Gunby, R; Ahmed, S; Zambon, A; Gasser, M ; Bertola, L; Porchia, F ; Tartari, C; Sottocornola, R ; Donella, A ; Goekjian, P; Scapozza, L; Gambacorti-Passerini, C ( 2006 ) - Rational design of inhibitors of the anaplastic lymphoma kinase - EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES [Abstract in rivista (266) - Abstract in Rivista]
Abstract

Rational design of inhibitors of the anaplastic lymphoma kinase

Borsato, Giuseppe; Crisma, Marco; De Lucchi, Ottorino; Lucchini, Vittorio; Zambon, Alfonso ( 2005 ) - "Hexacarboxytrindanes": Benzene rings with homotopic faces as scaffolds for the construction of D3 chiral architectures - ANGEWANDTE CHEMIE. INTERNATIONAL EDITION - n. volume 44 - pp. da 7435 a 7439 ISSN: 1433-7851 [Articolo in rivista (262) - Articolo su rivista]
Abstract

(Figure Presented) Thermodynamically driven epimerization at the trindane benzylic positions of "hexacarboxytrindanes" generates benzene rings with D3 symmetry and with R or S homotopic faces. Almost total resolution towards S trindanes was achieved by epimerization and transesterification with lithium (-)-mentholate. These structures are attractive cores for the construction of macromolecules in which asymmetry is induced by the center of the molecule. © 2005 Wiley-VCH Verlag GmbH & Co. KGaA.

Argese, E; Bettiol, C.; Marchetto, D.; De Vettori, S.; Zambon, A.; Miana, P.; Ghetti, P.F. ( 2005 ) - Study on the toxicity of phenolic and phenoxy herbicides using the submitochondrial particle assay - TOXICOLOGY IN VITRO - n. volume 19 - pp. da 1035 a 1043 ISSN: 0887-2333 [Articolo in rivista (262) - Articolo su rivista]
Abstract

A simple and rapid in vitro toxicological assay, utilizing submitochondrial particles (SMP), has been used to evaluate the toxic effects of fifteen herbicides belonging to the phenol and phenoxyalkanoic acid chemical classes. The SMP assay allows the quantitative evaluation of the toxicity of compounds with different mechanisms of action: uncouplers, inhibitors of the enzyme complexes involved in reverse electron transfer and in oxidative phosphorylation and chemicals that alter the membrane structure. The two groups of herbicides showed different levels of toxicity. For phenol derivatives, EC50 values ranged from 0.16 μM (ioxynil) to 6.7 μM (2,4-dinitrophenol), whereas for phenoxy herbicides EC50 values ranged from 21 μM (2,4,5-trichlorophenoxyacetic acid, 2,4,5-T) to 110 μM (4-chloro-2- methylphenoxyacetic acid, MCPA). On the average, the toxicity of phenolic compounds is greater than that of phenoxyalkanoic acids by two orders of magnitude. Quantitative structure-activity relationships (QSAR) were developed between EC50 values and various molecular descriptors. The results suggest the existence of different mechanisms of action for the two classes of compounds. The findings obtained for phenolic herbicides are consistent with a protonophoric uncoupling mechanism, whereas for phenoxy herbicides a non-specific mode of action at membrane level can be hypothesized. © 2005 Elsevier Ltd. All rights reserved.

Borsato, Giuseppe; Brussolo, Stefania; Crisma, Marco; De Lucchi, Ottorino; Lucchini, Vittorio; Zambon, Alfonso ( 2005 ) - Tris-annelated benzenes selectively perfunctionalized on one side only: Hexachlorobenzotrinorbornadiene as a versatile scaffold for the construction of molecular domes - SYNLETT - pp. da 1125 a 1128 ISSN: 0936-5214 [Articolo in rivista (262) - Articolo su rivista]
Abstract

Well-defined, rigid molecular domes are obtained via substitution of the chlorine atoms of hexachlorobenzotrinorbornadiene syn-3, efficiently synthesized in 1:2 ratio along with its antiisomer by CuTC-promoted cyclotrimerization of 3-bromo-2-tri-methylstannylnorbornadiene 8. The three dichlorovinyl functions at the edge of syn-3 are displaced by sulfur nucleophiles and Grignard reagents with Ni(II)Cl2dppe as catalyst, gaining the persubstituted vinyl sulfides 9 and 10, and persubstituted methyl 12 and phenylethynyl 13.

Borsato, Giuseppe; Della Negra, Federico; Gasparrini, Francesco; Misiti, Domenico; Lucchini, Vittorio; Possamai, Giorgia; Villani, Claudio; Zambon, Alfonso ( 2004 ) - Internal motions in a fulleropyrrolidine tertiary amide with axial chirality - JOURNAL OF ORGANIC CHEMISTRY - n. volume 69 - pp. da 5785 a 5788 ISSN: 0022-3263 [Articolo in rivista (262) - Articolo su rivista]
Abstract

The kinetic parameters for topomerization around the N-CO bond and enantiomerization around the C-CO bond in N-1-naphthoyl fulleropyrrolidine 1 and N-1-naphthoyl pyrrolidine 2 have been determined by dynamic NMR (line shape simulation and selective inversion transfer). The ΔS ≠ values are negligible. The ΔH # value for topomerization of 1 is smaller with respect to that of 2 by 4.3 kcal mol -1 (explained by the electron-withdrawing effect of fullerene) and the value for enantiomerization is greater by 1.4 kcal mol -1 (explained by the greater rigidity of the fulleropyrrolidine ring, as confirmed by ab initio analyses).

Borsato, G; Lucchini, V; Modena, G; Pasquato, L; Zambon, A ( 2003 ) - Nucleophilic reactions at the ring carbons of thiiranium and thiirenium ions. An experimental and theoretical comparison of the S(N)2 and S(N)2-Vin mechanisms - ARKIVOC - pp. da 38 a 55 ISSN: 1551-7012 [Articolo in rivista (262) - Articolo su rivista]
Abstract

Generally, the bimolecular nucleophilic substitution at the saturated carbon (S(N)2) and the mechanistically similar substitution at the vinyl carbon (S(N)2-Vin) cannot be quantitatively compared, because of the many interfering steric and electronic factors. The cis and trans rearrangements of trans c-2, t-3-di-tert-butyl-r-1-methylthiiranium ion 5a into thietanium ions 6a and 6b and that of 2,3-di-tert-butyl-1-methylthiirenium ion 7 into thietium ion 8 can be be compared both experimentally and computationally. They occur with intramolecular S(N)2 and S(N)2-Vin mechanisms respectively and are both almost exclusively governed by the nucleofugality of the sulfonium leaving group.

Borsato, G. and De Lucchi; and Fabris, O.; and Lucchini, F.; and Pasqualotti, V.; and Zambon, M. ( 2003 ) - Synthesis of the syn and anti isomer of 1,4,5,8,9,12-hexahydro-2,3,6,7,10,11-hexamethylidene-1,4 : 5,8 : 9,12-trimethanotriphenylene and Diels-Alder reactivity of the syn isomer - TETRAHEDRON LETTERS - pp. da 561 a 563 ISSN: 0040-4039 [Articolo in rivista (262) - Articolo su rivista]
Abstract

The title compounds, new members in the class of tris-annelated benzenes with [2.2.1] bicyclic rings, were obtained in high yields by coupling of 2-bromo-3-trimethyltin-5,6-dimethylenenorborn-2-ene with copper(I) 2-thiophenecarboxylate (CuTC). The syn isomer was reacted with 3 equiv. of the dienophiles TCNE, DMAD, PTAD and norbornadiene to afford the corresponding cycloadducts.

Borsato, G.; De Lucchi, O; Fabris, F.; Lucchini, V.; Frascella, P.; Zambon, A. ( 2003 ) - Synthesis and evaluation of new chiral diols based on the dicyclopentadiene skeleton - TETRAHEDRON LETTERS - pp. da 3517 a 3520 ISSN: 0040-4039 [Articolo in rivista (262) - Articolo su rivista]
Abstract

The resolution by Lipase PS of rac-5 (from reduction of ketone 6, obtained from dicyclopentadiene with a new environment-friendly synthesis) gives (2S)-5, which was further reduced to the endo (2R)-1a alcohol. The endo (2S)-1b alcohol was obtained from camphor with a multistep synthesis. Pinacol couplings of 3a,b, carried out with Mg/Hg or Corey's general procedure respectively, afforded with high diastereoselectivity the C2 symmetry diols (2R,2′R)-2a and (2S,2′S)-2b, with endo oriented OH functions. The enantiogenic power of the endo alcohol (2R)-1a and (2S)-1b and of the diols (2R,2′R)-2a and (2S,2′S)-2b was tested towards the LiAlH4 reduction of acetophenone. The C2 symmetry appears to play a fundamental role.

Argese, Emanuele; Bettiol, Cinzia; Fasolo, Matteo; Zambon, Alfonso; Agnoli, Francesca ( 2002 ) - Substituted aniline interaction with submitochondrial particles and quantitative structure-activity relationships - BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES - n. volume 1558 - pp. da 151 a 160 ISSN: 0005-2736 [Articolo in rivista (262) - Articolo su rivista]
Abstract

The toxic effects of eighteen substituted anilines were determined by means of a short-term in vitro assay, using submitochondrial particles (SMP) as biosensors. The assay allows for the quantification of the effects of toxicants that act specifically on mitochondrial respiratory functions, like uncouplers and inhibitors, or non-specifically, by disturbing the structure and functioning of the inner mitochondrial membrane. The obtained EC50 values range from 72.5 to 1910 μmol/l. The type and position of the substituents are of fundamental importance in determining the toxic potency. In general, the presence of electron-withdrawing substituents produces higher toxic effects, whereas electron-donating groups seem to reduce the toxicity. Quantitative structure-activity relationships (QSAR) showed that toxicity values were correlated with the Hammett σ constant and with hydrogen bonding capacity descriptors, such as ELUMO, EHOMO and Q+. The results indicate that toxicity increases with increasing the hydrogen bonding donor capacity of the NH2 group and support the hypothesis of a mechanism of action based on hydrogen bonding formation between the amino group of anilines and polar groups at the membrane/water interface. Such an interaction would cause a derangement of the membrane structure and, as a consequence, a disturbance of its functioning. © 2002 Elsevier Science B.V. All rights reserved.

Canovese, Luciano; Lucchini, Vittorio; Santo, Claudio; Visentin, Fabiano; Zambon, Alfonso ( 2002 ) - A novel mechanism for the fluxional behaviour of [Pd(η2-tetramethylethylenetetracarboxylate)(2-methylthiomethylpyridine)] - JOURNAL OF ORGANOMETALLIC CHEMISTRY - n. volume 642 - pp. da 58 a 63 ISSN: 0022-328X [Articolo in rivista (262) - Articolo su rivista]
Abstract

The fluxional behaviour of [Pd(η2-tmetc)(NSMe)] (tmetc=tetramethylethylenetetracarboxylate, NSMe=2-methylthiomethylpyridine) in CD2Cl2 is governed by two mechanisms: (i) the concentration independent inversion at sulfur which averages the methylenic signals and collapses the four methyl signals of tmetc to two; (ii) the concentration dependent mechanism occurring via a dimeric intermediate with CS symmetry which collapses the two residual tmetc signals into a singlet. The fluxional behaviour of [Pd(η2-tmetc)(NSMe)] (tmetc=tetramethylethylenetetracarboxylate, NSMe=2-methylthiomethylpyridine) in CD2Cl2 is governed by two mechanisms: (1) the concentration independent inversion at sulfur; and (2) the concentration dependent mechanism occurring via a dimeric intermediate with CS symmetry.

Canovese, L; Lucchini, V; Santo, C; Visentin, F; Zambon, A ( 2002 ) - A novel mechanism for the fluxional behaviour of [Pd(eta(2)-tetramethylethylenetetracarboxylate)(2-methylthiomethylpyridine)] - JOURNAL OF ORGANOMETALLIC CHEMISTRY - n. volume 642 - pp. da 58 a 63 ISSN: 0022-328X [Articolo in rivista (262) - Articolo su rivista]
Abstract

The fluxional behaviour of [Pd(eta(2)-tmetc)(N-SMe) (tmetc = tetramethylethylenetetracarboxylate, N-SMe = 2-methylthiomethylpyridine) in CD2Cl2 is governed by two mechanisms: (i) the concentration independent inversion at sulfur which averages the methylenic signals and collapses the four methyl signals of tmetc to two; (ii) the concentration dependent mechanism occurring via a dimeric intermediate with C-s symmetry which collapses the two residual tmetc signals into a singlet. (C) 2002 Elsevier Science B.V. All rights reserved.

Borsato, Giuseppe; De Lucchi, Ottorino; Fabris, Fabrizio; Groppo, Luca; Lucchini, Vittorio; Zambon, Alfonso ( 2002 ) - Efficient cyclotrimerization of bicyclic vic-bromostannylalkenes promoted by copper(I) thiophen-2-carboxylate - JOURNAL OF ORGANIC CHEMISTRY - n. volume 67 - pp. da 7894 a 7897 ISSN: 0022-3263 [Articolo in rivista (262) - Articolo su rivista]
Abstract

Copper(I) thiophen-2-carboxylate was successfully employed in the trimerization of [2.2.1] bicyclic vicbromotrimethyltin olefins (in their racemic composition), bearing different functionalities, to invariably obtain almost quantitative yields of the syn and anti tris-annelated benzenes. The two isomers come in different ratios, smaller than or equal to the statistical 1:3 ratio, depending on the steric hindrance opposed by the functionalities. In the case of enantiopure (3-bromo-4,7,7-trimethylbicyclo[2.2.1]hept-2- en-2-yl)trimethylstannane, the 1:9 ratio found with Cu(NO3)2·3H2O increases to 1:6.

Kordatos, K.; Bosi, S.; Da Ros, T.; Zambon, A.; Lucchini, V.; Prato, M ( 2001 ) - Isolation and characterization of all eight bisadducts of fulleropyrrolidine derivatives - JOURNAL OF ORGANIC CHEMISTRY - n. volume 66 - pp. da 2802 a 2808 ISSN: 0022-3263 [Articolo in rivista (262) - Articolo su rivista]
Abstract

We report the isolation and characterization of bisadducts of fulleropyrrolidine derivatives. The compounds were characterized by means of a variety of spectroscopic techniques, including ESMS, UV-vis, 1H NMR, and 13C NMR. The whole series of bisadducts was separated for the first time in the case of the bispyrrolidines, and the determination of their structure was obtained by NMR spectroscopy with the help of HMQC and HMBC techniques.

Argese, E; Bettiol, C; Agnoli, F; Zambon, A; Mazzola, M; Ghirardini, Av ( 2001 ) - Assessment of chloroaniline toxicity by the submitochondrial particle assay - ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY - n. volume 20 - pp. da 826 a 832 ISSN: 0730-7268 [Articolo in rivista (262) - Articolo su rivista]
Abstract

The effects on mitochondrial respiration of 15 chloroanilines were recorded by using the in vitro response of submitochondrial particles (SMP) from beef heart mitochondria. The bioassay procedure for SMP is based on the process of reverse electron transfer, which can be negatively affected by inhibitors of electron transport, by uncouplers, and by chemicals that impair membrane integrity. The EC50 values, determined for the tested chloroanilines, indicate a general tendency of increasing toxicity with increasing chlorine substitution. In order to validate the results obtained and to evaluate the capability of the SMP assay to reproduce the toxic effects of the examined compounds on different freshwater species, the EC50 values were compared with literature data from other biological assays regarding both in vitro systems and whole organisms. A good correlation was found in particular with two widely used testing systems, the Microtox((R)) and the Tetrahymena assays. In addition, quantitative structure-activity relationships (QSARs) were established between the EC50 values and various molecular descriptors for hydrophobic, steric, and electronic interactions. The results obtained were utilized to elucidate the mechanism of toxic action of chloroanilines, which are commonly reported to act by the polar narcosis mode of action. Moreover, they confirmed that the SMP assay can be a useful tool for studying the toxicity of chemicals that act nonspecifically by impairing membrane structure and functions.

Trombetta, M. and Busca; and Storaro, G.; and Lenarda, L.; and Casagrande, M.; and Zambon, A. ( 2000 ) - Surface acidity modifications induced by thermal treatments and acid leaching on microcrystalline H-BEA zeolite. A FTIR, XRD and MAS-NMR study - PHYSICAL CHEMISTRY CHEMICAL PHYSICS - pp. da 3529 a 3537 ISSN: 1463-9084 [Articolo in rivista (262) - Articolo su rivista]
Abstract

Samples of beta-zeolite thermally treated at di†erent temperatures and acid leached with diluted hydrochloric acid solution have been investigated by XRD, 27Al MAS-NMR spectroscopy and FTIR spectroscopy. The results have been used to interpret the behaviour of the samples as catalysts for the acylation of 2-methoxynaphthalene. It has been shown that the as prepared sample presents two types of extraframework species. These are identiÐed as Al hydroxo-ions highly dispersed in the internal zeolite channels and Al oxide nanoparticles. Calcination causes dealumination of the framework and progressive conversion of the Al hydroxo-ions into Al oxide nanoparticles that reduce the zeolite channels practicability, modifying the shape selectivity e†ect. The acid sites present in the sinusoidal channels cm BrÔnsted (l ~1) can be OH \ 3608 distinguished from those located in the larger ones cm (l ~1), due to the inability of the bulky OH \ 3620È3612 probe molecule pivalonitrile to enter the former. However, internal terminal silanols cm (l ~1) also OH \ 3735 apparently display a signiÐcant acidity, deÐnitely higher than the acidity of those absorbing at 3747 BrÔnsted cm~1, thought to be located at the external crystal surface. The strongest Lewis acidity is displayed by the aluminum hydroxo-ions, while that of alumina nanoparticles is a little weaker. Acid-leached beta-zeolite also displays a medium strength Lewis acidity, likely due to framework Al cations. Thus a partial reinterpretation of the real structure of beta-zeolite and a partial reassignment of the bands due to the surface hydroxy groups are proposed.