Vai ai contenuti. | Spostati sulla navigazione | Spostati sulla ricerca | Vai al menu | Contatti | Accessibilità

| Crea un account

Basili, Serena (2009) Computational Approaches for the Rational Design of Novel Topoisomerase I Poisons as Potential Anticancer Drugs. [Tesi di dottorato]

Full text disponibile come:

[img]Documento PDF
Tesi non accessible per motivi correlati alla proprietà intellettuale.
Visibile a: nessuno

10Mb

Abstract (inglese)

Topoisomerase I (TopoI) is an essential DNA-targeting enzyme which alters the supercoiling of DNA through a concerted process of breaking and rejoining of a DNA strand, thereby controlling the DNA topology required for replication and transcription. TopoI mediates relaxation of supercoiled DNA by creating a transient single-strand break in the DNA duplex that originates from a transesterification reaction involving a nucleophilic attack by the active-site tyrosine (Tyr723) hydroxyl group on a DNA phosphodiester bond situated at the site of cleavage. The resulting 3'-phosphotyrosine enzyme-DNA complex (“covalent binary complex” or “cleavable complex”) is then reversed, after DNA relaxation through strand passage, when the released 5'-OH of the nicked strand reattacks the phosphotyrosine intermediate in a second transesterification reaction. These events result in the relaxation of the DNA structure, which is required during transcription or replication.
TopoI is a specific target for the pentacyclic alkaloid Camptothecin (CPT), which was first isolated in 1966 from extracts of Camptotheca Acuminata, and its derivatives, known as TopoI poisons.
These molecules block DNA religation, thus converting TopoI into a DNA-damaging agent. In the presence of a TopoI poison a ternary complex between DNA, an intercalator and topoisomerase is formed. Such a ternary complex is more stable than the DNA-TopoI associate, which may lead to an enhanced lifetime of the initially cleaved DNA. As a consequence of the misalignment of the free 5-hydroxyl group and the scissile tyrosine-DNA bond due to the presence of the drug, the religation of the broken strand cannot take place, i.e. the strand break persists. This activates a complex sequence of intacellular responses, that ultimately lead to cell death by apoptosis. Therefore, molecules which form such stabilized ternary complexes with DNA and TopoI exhibit a high potential as DNA-targeting anticancer drugs.
Camptothecin was early shown to be clinically problematic because, in addition to its negligible water solubility, its active “ring-closed” ?-hydroxylactone form is rapidly converted under physiological conditions to the open carboxylate form, which is inactive and readily binds to human serum albumin, making it inaccessible for cellular uptake.
To date, only two semisynthetic analogs of Camptothecin (Topotecan and Irinotecan) have been approved by FDA for the clinical treatment of the ovarian, small cell-lung and colon cancers.
Solving crystal structures of Top1 in complex both with Camptothecin and Topotecan and with structurally different molecules (indolocarbazoles and indoloquinolines) has significantly increased the amount of structural information about the interaction between the Top1-DNA binary complex and the poison molecule. This encouraged the application of structure-based drug design to investigate
and rationalize the activity of Top1 poisons and to rationally design new potential anticancer drugs. Thus, we considered the possibility to find a new pharmacophore exploiting all the available crystal structures to find the set of structural features which are in common to all of the five TopoI poisons.
In order to obtain new derivatives easier to be synthesized while maintaining the pharmacophoric features required for the formation of a stable TopoI-DNA-poison ternary complex, the synthesis of simplified CPT derivatives was proposed. It is possible to suppose that a pentacyclic scaffold is not necessarily required for a molecule to effectively bind the TopoI-DNA binary complex, providing that it maintains an aromatic planar system for the intercalation and appropriate functional groups to interact with specific residues of TopoI. On the basis of this assumption, several scaffolds were designed and docking studies with different search algorithms were performed to predict the ability of simplified analogs to form stable ternary complex with TopoI and DNA.
Moreover, we performed a molecular docking analysis on a series of new 5-substituted CPT derivatives to achieve more insight into the interactions of the new compounds with the binary TopoI-DNA complex. The introduction of substituents in position 5 of the CPT scaffold results in derivatives with reduced cytotoxic potency compared with the reference drugs. In general, the presence of a small lipophilic substituent is well tolerated while the modification with hydrophilic groups results in reduced affinity for the binding site. The presence of bulky groups is detrimental for cytotoxic potency because of the loss of important stabilizing interactions. Computational results indicated as a general feature that the 5-?-epimer is better tolerated in the binding site compared to the 5-?-epimer, resulting in higher biological activity.
Recently, a new series of 16a-thio-CPT derivatives has been synthesized. Biological assays for this class of compounds revealed that 16a-thio-CPT derivatives have higher anticancer activity compared to their oxo-analogs, both in vitro and in vivo, and are potent TopoI inhibitors. In order to find a rational explanation to their remarkable activity, a computational analysis was performed, both for predicting elements of their pharmacokinetic behavior and for describing their binding mode through a docking analysis. Docking results did not reveal striking differences between thio- and oxo-derivatives in terms of binding mode and docking score. On the contrary, the predicted values for features such as lipophilicity, water solubility and cell permeability indicated that these properties may be responsible for a significantly different pharmacokinetic profile for the two classes of compounds.
For the docking analysis of 5-substituted and 16a-thio CPT derivatives we used the quantum mechanics (QM)-polarized ligand docking (QPLD) protocol (Schrödinger software suite) with an aim to improve accuracy in docking calculations. Traditional docking methods employ an approximated physical chemistry-based representation of protein-ligand interactions, obtaining charges from a molecular mechanics force-field. The QPLD protocol uses an ab initio methodology to calculate ligand charges within the protein environment, thus taking into account the charge polarization induced by the protein environment.
The work on 5-substituted and 16a-thio CPT derivative was sponsored by the pharmaceutical company Indena S.p.A., Milano, Italy. The work was carried out in collaboration with the group of Professor Arturo Battaglia (Centro Nazionale Richerche Bologna, Italy) for the synthesis of the compounds, and with the group of Professor Franco Zunino (Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy), that was concerned with biological assays.

Abstract (italiano)

La Topoisomerasi I eucariotica (TopoI) è un enzima essenziale che modifica il grado di superavvolgimento del DNA mediante un processo di rottura e successiva ricongiunzione di uno dei due filamenti del DNA, regolandone lo stato topologico richiesto nei processi di replicazione e di trascrizione.
Il rilassamento del DNA superavvolto indotto dalla TopoI avviene attraverso la rottura transitoria di un filamento per mezzo di una reazione di transesterificazione. Quest'ultima coinvolge l'attacco nucleo lo da parte del gruppo ossidrilico di un residuo di tirosina (Tyr723) del sito attivo dell'enzima ad un legame fosfodiesterico del DNA a livello del sito di taglio, con formazione di un complesso covalente 3'-fosfotirosina TopoI-DNA (noto anche come cleavable complex). La rotazione del filamento tagliato intorno a quello intatto rende possibile il rilassamento della molecola di DNA. Il complesso binario covalente subisce in seguito un attacco nucleofilo a livello della fosfotirosina da parte dell'estremità libera 5'-OH del lamento rotto, che permette la riformazione del legame fosfodiesterico.
La TopoI è il target specifico dell'alcaloide pentaciclico Camptotecina (CPT), isolato per la prima volta nel 1966 dalla corteccia di Camptotheca Acuminata, e dei suoi derivati, noti come veleni di TopoI.
Queste molecole bloccano il processo di ricongiunzione del filamento di DNA tagliato, convertendo la TopoI in un agente dannoso per il DNA stesso. Queste molecole si intercalano tra le basi del DNA a livello del sito di taglio dando luogo alla formazione di un complesso ternario con la TopoI e il DNA. La maggiore stabilità del complesso ternario rispetto al complesso binario TopoI-DNA risulta in un aumento del tempo di vita del DNA tagliato. Poiché la presenza del veleno induce il disallineamento dell'estremità libera 5'-OH del filamento rotto con il legame fosfotirosinico, il processo di ricongiunzione non può avvenire. Questo porta all'attivazione di una serie complessa di segnali intracellulari, il cui risultato ultimo è la morte della cellula per apoptosi. Di conseguenza, le molecole in grado di formare complessi ternari stabili hanno attività antitumorale.
L'utilizzo clinico della CPT è ostacolato sia dalla sua scarsissima idrosolubilità, sia perchè la sua forma attiva lattonica “chiusa” è rapidamente convertita, in condizioni fisiologiche, nella forma carbossilica “aperta”, che è inattiva e si lega in elevata percentuale all'albumina serica.
Attualmente solo due derivati semisintetici della CPT (Topotecan ed Irinotecan) sono utilizzati nella pratica clinica per il trattamento di cancro ovarico, polmonare e colo-rettale.
La recente risoluzione, mediante cristallografia a raggi X, della struttura tridimensionale di TopoI in complesso sia con la Camptotecina e il Topotecan che con derivati strutturalmente diversi (indolocarbazolici ed isochinolinici), ha fornito chiarimenti sulle caratteristiche dell'interazione enzima-inibitore. Tali informazioni costituiscono elementi molto utili nello studio dei veleni di TopoI con un approccio di tipo computazionale il cui scopo è comprendere in che modo queste molecole interagiscono con il loro target e progettare nuovi nuovi derivati come potenziali farmaci ad attività antitumorale. È stato quindi possibile individuare un nuovo farmacoforo sfruttando le cinque strutture cristallogra che disponibili, al fine di rintracciare un set di caratteristiche strutturali comuni a tutti i veleni di TopoI.
Con lo scopo di disporre di nuovi derivati più semplici da ottenere dal punto di vista della sintesi ma che mantengano tutte le caratteristiche farmacoforiche richieste per la formazione di complessi ternari stabili con TopoI e DNA, è stata proposta la sintesi di analoghi “semplificati” della CPT. Si può infatti ipotizzare che una molecola non debba necessariamente possedere uno scaffold
pentaciclico per legarsi al complesso binario TopoI-DNA, purchè mantenga un sistema planare aromatico per intercalare il DNA e opportuni gruppi funzionali in grado di interagire con specifici aminoacidi dell'enzima. Sulla base di questa assunzione, diversi possibili scaffold sono stati disegnati e sottoposti a studi di docking con diversi protocolli di ricerca per predire la loro capacità di formare stabili complessi ternari con TopoI e DNA.
È stato inoltre condotto uno studio di docking molecolare per una serie di nuovi derivati della CPT sostituiti in posizione 5 (5-derivati) per descrivere la loro modalità di interazione con il complesso TopoI-DNA. In generale, l'introduzione di sostituenti in posizione 5 ha come risultato una diminuzione dell'attività citotossica rispetto alla CPT. La presenza di sostituenti lipofili di piccole dimensioni sembra essere tollerata all'interno del sito di binding, mentre l'introduzione di gruppi idro lici dà luogo ad una diminuzione dell'affinità. L'introduzione di gruppi stericamente ingombranti provoca la perdita di importanti interazioni al'interno del sito di legame. I risultati computazionali indicano come caratteristica generale che l'epimero ? dei 5-derivati ha un'affinità maggiore per il sito di binding rispetto all'epimero ?.
Recentemente sono stati sintetizzati una serie di 16a-tio-CPT analoghi. I saggi biologici condotti su questi composti hanno rivelato che i tio-derivati sono potenti inibitori della TopoI ed hanno attività antitumorale maggiore rispetto ai loro oxo-analoghi, sia in vitro che in vivo. Al fine di razionalizzare la maggiore attività dei tio-analoghi rispetto ai derivati tradizionali, è stato eseguito
uno studio computazionale volto sia a predire proprietá chimico-fisiche rilevanti per la descrizione del possibile profilo farmacocinetico delle nuove molecole, sia a descriverne la modalità di legame
nel sito del complesso binario TopoI-DNA tramite studi di docking.
I risultati di docking non hanno messo in evidenza differenze di rilievo tra i tio- e gli oxo-derivati in termini di modalità di binding e di docking score. Al contrario, i valori predetti per proprietà come la lipofilicità, la solubilità in acqua e la permeabilità cellulare indicano che il profilo farmacocinetico delle due classi di composti potrebbe essere significativamente diverso.
Per le simulazioni di docking condotte sui 5-CPT-derivati e sui tio-CPT-derivati è stato utilizzato il protocollo quantum mechanics (QM)-polarized ligand docking (QPLD) (implementato nella suite Schrödinger) con lo scopo di aumentare l'accuratezza dei calcoli di docking. I metodi tradizionali utilizzati per il docking molecolare utilizzano una rappresentazione chimico-fisica approssimata delle interazioni proteina-ligando, dove le cariche atomiche sono calcolate in base al campo di forza. Il protocollo QPLD utilizza invece una metodologia ab initio per il calcolo delle cariche del ligando all'interno della cavità della proteina, tenendo in considerazione la polarizzazione di carica indotta dagli aminoacidi del sito di legame sul ligando.
Il lavoro relativo ai 5-CPT-derivati e ai tio-CPT-derivati à stato supportato dall'azienda farmaceutica Indena S.p.A., Milano, Italia. Il lavoro è stato condotto in collaborazione con il gruppo del Professor Arturo Battaglia (Centro Nazionale Richerche Bologna) per la sintesi dei composti e con il gruppo del Professor Franco Zunino (Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano) per i saggi biologici.

Aggiungi a RefWorks
Tipo di EPrint:Tesi di dottorato
Relatore:Moro, Stefano
Dottorato (corsi e scuole):Ciclo 21 > Scuole per il 21simo ciclo > SCIENZE MOLECOLARI > SCIENZE FARMACEUTICHE
Data di deposito della tesi:30 Gennaio 2009
Anno di Pubblicazione:Gennaio 2009
Parole chiave (italiano / inglese):topoisomerase I, camptothecin, DNA, molecular mechanics, molecular docking, QM-polarized ligand docking, 5-substituted camptothecin derivatives, thio-camptothecin derivatives
Settori scientifico-disciplinari MIUR:Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Scienze Farmaceutiche
Codice ID:1782
Depositato il:30 Gen 2009
Simple Metadata
Full Metadata
EndNote Format

Bibliografia

I riferimenti della bibliografia possono essere cercati con Cerca la citazione di AIRE, copiando il titolo dell'articolo (o del libro) e la rivista (se presente) nei campi appositi di "Cerca la Citazione di AIRE".
Le url contenute in alcuni riferimenti sono raggiungibili cliccando sul link alla fine della citazione (Vai!) e tramite Google (Ricerca con Google). Il risultato dipende dalla formattazione della citazione.

Y. Pommier. Topoisomerase I inhibitors: camptothecins and beyond. Nat. Rev. Cancer, 6:789802, Oct 2006. Cerca con Google

J.F. Pizzolato and L.B. Saltz. The camptothecins. Lancet, 361:22352242, Jun 2003. Cerca con Google

Monroe E. Wall, M. C. Wani, C. E. Cook, Keith H. Palmer, A. T. McPhail, and G. A. Sim. Plant antitumor agents. i. the isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from camptotheca acuminata1,2. Journal of the American Chemical Society, 88(16):38883890, 1966. Cerca con Google

J.A. Gottlieb, A.M. Guarino, J.B. Call, V.T. Oliverio, and J.B. Block. Preliminary pharmacologic and clinical evaluation of camptothecin sodium (NSC-100880). Cancer Chemother Rep, 54:461470, Dec 1970. Cerca con Google

P.J. Creaven and L.M. Allen. Renal clearance of camptothecin (NSC-100880): eect of urine volume. Cancer Chemother Rep, 57:175184, Apr 1973. Cerca con Google

Y.H. Hsiang, R. Hertzberg, S. Hecht, and L.F. Liu. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J. Biol. Chem., 260:1487314878, Nov 1985. Cerca con Google

W.D. Kingsbury, J.C. Boehm, D.R. Jakas, K.G. Holden, S.M. Hecht, G. Gallagher, M.J. Caranfa, F.L. McCabe, L.F. Faucette, and R.K. Johnson. Synthesis of water-soluble (aminoalkyl)camptothecin analogues: inhibition of topoisomerase I and antitumor activity. J. Med. Chem., 34:98107, Jan 1991. Cerca con Google

S. Sawada, S. Okajima, R. Aiyama, K. Nokata, T. Furuta, T. Yokokura, E. Sugino, K. Yamaguchi, and T. Miyasaka. Synthesis and antitumor activity of 20(S)-camptothecin derivatives: carbamate-linked, water-soluble derivatives of 7-ethyl-10-hydroxycamptothecin. Chem. Pharm. Bull., 39:14461450, Jun 1991. Cerca con Google

T. Kunimoto, K. Nitta, T. Tanaka, N. Uehara, H. Baba, M. Takeuchi, T. Yokokura, S. Sawada, T. Miyasaka, and M. Mutai. Antitumor activity of 7-ethyl-10-[4-(1- piperidino)-1-piperidino]carbonyloxy-camptothec in, a novel water-soluble derivative of camptothecin, against murine tumors. Cancer Res., 47:59445947, Nov 1987. Cerca con Google

Y. Kawato, M. Aonuma, Y. Hirota, H. Kuga, and K. Sato. Intracellular roles of SN-38, a metabolite of the camptothecin derivative CPT-11, in the antitumor eect of CPT-11. Can- cer Res., 51:41874191, Aug 1991. Cerca con Google

S. K. Ahn, N. S. Choi, B. S. Jeong, K. K. Kim, D. J. Journ, and J. K. Kim. Practical synthesis of (s)-7- Cerca con Google

(2-isopropylamino)ethylcamptothecin hydrocloryde, potent topoisomerase i inhibitor. Heterocycl Chem, 2000. Cerca con Google

S. Basili and S. Moro. Novel camptothecin derivatives as topoisomerase i inhibitors. Expert Opinion on Therapeutic Patents, 2009, in press. Cerca con Google

M.C. Wani, A.W. Nicholas, and M.E. Wall. Plant antitumor agents. 28. Resolution of a key tricyclic synthon, 5'(RS)-1,5-dioxo-5'-ethyl-5'-hydroxy-2'H,5'H,6'H- 6'-oxopyrano[3' ,4'- f]delta 6,8-tetrahydro-indolizine: total synthesis and antitumor activity of 20(S)- and 20(R)- camptothecin. J. Med. Chem., 30:23172319, Dec 1987. Cerca con Google

R.P. Hertzberg, M.J. Caranfa, K.G. Holden, D.R. Jakas, G. Gallagher, M.R. Mattern, S.M. Mong, J.O. Bartus, R.K. Johnson, and W.D. Kingsbury. Modication of the hydroxy lactone ring of camptothecin: inhibition of mammalian topoisomerase I and biological activity. J. Med. Chem., 32:715 720, Mar 1989. Cerca con Google

M.C. Wani, A.W. Nicholas, and M.E. Wall. Plant antitumor agents. 23. Synthesis and antileukemic activity of camptothecin analogues. J. Med. Chem., 29:23582363, Nov 1986. Cerca con Google

E. Raymond, M. Campone, R. Stupp, J. Menten, P. Chollet, T. Lesimple, R. Fety-Deporte, D. Lacombe, X. Paoletti, and P. Fumoleau. Multicentre phase II and pharmacokinetic study of RFS2000 (9-nitro-camptothecin) administered orally 5 days a week in patients with glioblastoma multiforme. Eur. J. Cancer, 38:13481350, Jul 2002. Cerca con Google

P. Schoski, A. Herr, J. B. Vermorken, J. Van den Brande, J. H. Beijnen, H. Rosing, J. Volk, A. Ganser, S. Adank, H. J. Botma, and J. Wanders. Clinical phase II study and pharmacological evaluation of rubitecan in non-pretreated patients with metastatic colorectal cancer-signicant eect of food intake on the bioavailability of the oral camptothecin analogue. Eur. J. Cancer, 38:807813, Apr 2002. [18] B. C. Giovanella, J. S. Stehlin, H. R. Hinz, A. J. Kozielski, N. J. Harris, and D. M. Vardeman. Preclinical evaluation of the anticancer activity and toxicity of 9-nitro-20(S)- camptothecin (Rubitecan). Int. J. Oncol., 20:8188, Jan 2002. Cerca con Google

S. T. Liew and L. X. Yang. Design, synthesis and development of novel camptothecin drugs. Curr. Pharm. Des., 14:10781097, 2008. Cerca con Google

M. J. Luzzio, J. M. Besterman, D. L. Emerson, M. G. Evans, K. Lackey, P. L. Leitner, G. McIntyre, B. Morton, P. L. Myers, and M. Peel. Synthesis and antitumor activity of novel water soluble derivatives of camptothecin as specic inhibitors of topoisomerase I. J. Med. Chem., 38:395401, Feb 1995. Cerca con Google

L. Paz-Ares, R. Kunka, D. DeMaria, J. Cassidy, M. Alden, P. Beranek, S. Kaye, D. Littleeld, D. Reilly, S. Depee, P. Wissel, C. Twelves, and P. O'Dwyer. A phase I clinical and pharmacokinetic study of the new topoisomerase inhibitor GI147211 given as a 72-h continuous infusion. Br. J. Cancer, 78:13291336, Nov 1998. Cerca con Google

J. P. Stevenson, D. DeMaria, J. Sludden, S. B. Kaye, L. Paz- Ares, L. B. Grochow, A. McDonald, K. Selinger, P. Wissel, P. J. O'Dwyer, and C. Twelves. Phase I/pharmacokinetic study of the topoisomerase I inhibitor GG211 administered as a 21-day continuous infusion. Ann. Oncol., 10:339344, Mar 1999. Cerca con Google

T. Gamucci, R. Paridaens, B. Heinrich, J. H. Schellens, N. Pavlidis, J. Verweij, C. Sessa, S. Kaye, M. Roelvink, J. Wanders, and A. Hanauske. Activity and toxicity of GI147211 in breast, colorectal and non-small-cell lung cancer patients: an EORTC-ECSG phase II clinical study. Ann. Oncol., 11:793797, Jul 2000. Cerca con Google

K. Gelmon, H. Hirte, B. Fisher, W. Walsh, M. Ptaszynski, M. Hamilton, N. Onetto, and E. Eisenhauer. A phase 1 study of OSI-211 given as an intravenous infusion days 1, 2, and 3 every three weeks in patients with solid cancers. Invest New Drugs, 22:263275, Aug 2004. Cerca con Google

F. J. Giles, M. S. Tallman, G. Garcia-Manero, J. E. Cortes, D. A. Thomas, W. G. Wierda, S. Verstovsek, M. Hamilton, E. Barrett, M. Albitar, and H. M. Kantarjian. Phase I and pharmacokinetic study of a low-clearance, unilamellar liposomal formulation of lurtotecan, a topoisomerase 1 inhibitor, in patients with advanced leukemia. Cancer, 100:14491458, Apr 2004. Cerca con Google

I. Mitsui, E. Kumazawa, Y. Hirota, M. Aonuma, M. Sugimori, S. Ohsuki, K. Uoto, A. Ejima, H. Terasawa, and K. Sato. A new water-soluble camptothecin derivative, DX- 8951f, exhibits potent antitumor activity against human tumors in vitro and in vivo. Jpn. J. Cancer Res., 86:776782, Aug 1995. Cerca con Google

G. K. Abou-Alfa, R. Letourneau, G. Harker, M. Modiano, H. Hurwitz, N. S. Tchekmedyian, K. Feit, J. Ackerman, R. L. De Jager, S. G. Eckhardt, and E. M. O'Reilly. Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer. J. Clin. Oncol., 24:44414447, Sep 2006. Cerca con Google

E. K. Rowinsky, T. R. Johnson, C. E. Geyer, L. A. Hammond, S. G. Eckhardt, R. Drengler, L. Smetzer, J. Coyle, J. Rizzo, G. Schwartz, A. Tolcher, D. D. Von Ho, and R. L. De Jager. DX-8951f, a hexacyclic camptothecin analog, on a daily-times-ve schedule: a phase I and pharmacokinetic study in patients with advanced solid malignancies. J. Clin. Oncol., 18:31513163, Sep 2000. Cerca con Google

O. Soepenberg, M. J. de Jonge, A. Sparreboom, P. de Bruin, F. A. Eskens, G. de Heus, J. Wanders, P. Cheverton, M. P. 1 Ducharme, and J. Verweij. Phase I and pharmacokinetic study of DE-310 in patients with advanced solid tumors. Clin. Cancer Res., 11:703711, Jan 2005. Cerca con Google

I. F. Pollack, M. Er, D. Bom, T. G. Burke, J. T. Strode, and D. P. Curran. Potent topoisomerase I inhibition by novel silatecans eliminates glioma proliferation in vitro and in vivo. Cancer Res., 59:48984905, Oct 1999. Cerca con Google

A. H. Van Hattum, H. M. SchlÃ1 4per, F. H. Hausheer, H. M. Pinedo, and E. Boven. Novel camptothecin derivative BNP1350 in experimental human ovarian cancer: determination of ecacy and possible mechanisms of resistance. Int. J. Cancer, 100:2229, Jul 2002. Cerca con Google

J. L. Nitiss and K. C. Nitiss. Gimatecan (sigma-tau industrie farmaceutiche riunite/novartis). IDrugs, 8:578588, Jul 2005. Cerca con Google

C. Sessa, S. Cresta, T. Cerny, J. Baselga, E. Rota Caremoli, A. Malossi, D. Hess, J. Trigo, M. Zucchetti, M. D'Incalci, A. Zaniboni, G. Capri, B. Gatti, P. Carminati, C. Zanna, S. Marsoni, and L. Gianni. Concerted escalation of dose and dosing duration in a phase I study of the oral camptothecin gimatecan (ST1481) in patients with advanced solid tumors. Ann. Oncol., 18:561568, Mar 2007. Cerca con Google

M. De Cesare, G. Pratesi, P. Perego, N. Carenini, S. Tinelli, L. Merlini, S. Penco, C. Pisano, F. Bucci, L. Vesci, S. Pace, F. Capocasa, P. Carminati, and F. Zunino. Potent antitumor activity and improved pharmacological prole of ST1481, a novel 7-substituted camptothecin. Cancer Res., 61:7189 7195, Oct 2001. Cerca con Google

S. Dallavalle, A. Ferrari, B. Biasotti, L. Merlini, S. Penco, G. Gallo, M. Marzi, M. O. Tinti, R. Martinelli, C. Pisano, P. Carminati, N. Carenini, G. Beretta, P. Perego, M. De Cesare, G. Pratesi, and F. Zunino. Novel 7-oxyiminomethyl derivatives of camptothecin with potent in vitro and in vivo antitumor activity. J. Med. Chem., 44:32643274, Sep 2001. Cerca con Google

A. Chatterjee, R. Digumarti, K. Katneni, V.V. Upreti, R.N. Mamidi, R. Mullangi, A. Surath, M.L. Srinivas, S. Uppalapati, S. Jiwatani, and N.R. Srinivas. Safety, tolerability, and pharmacokinetics of a capsule formulation of DRF-1042, a novel camptothecin analog, in refractory cancer patients in a bridging phase I study. J Clin Pharmacol, 45:453460, Apr 2005. Cerca con Google

L. Lesueur-Ginot, D. Demarquay, R. Kiss, P. G. Kasprzyk, L. Dassonneville, C. Bailly, J. Camara, O. Lavergne, and D. C. Bigg. Homocamptothecin, an E-ring modied camptothecin with enhanced lactone stability, retains topoisomerase I-targeted activity and antitumor properties. Cancer Res., 59:29392943, Jun 1999. Cerca con Google

O. Lavergne, L. Lesueur-Ginot, F. Pla Rodas, P. G. Kasprzyk, J. Pommier, D. Demarquay, G. Prà c vost, G. Ulibarri, A. Rolland, A. M. Schiano-Liberatore, J. Harnett, D. Pons, J. Camara, and D. C. Bigg. Homocamptothecins: synthesis and antitumor activity of novel E-ringmodi ed camptothecin analogues. J. Med. Chem., 41:5410 5419, Dec 1998. Cerca con Google

A. K. Larsen, C. Gilbert, G. Chyzak, S. Y. Plisov, I. Naguibneva, O. Lavergne, L. Lesueur-Ginot, and D. C. Bigg. Unusual potency of BN 80915, a novel uorinated E-ring modi- ed camptothecin, toward human colon carcinoma cells. Can- cer Res., 61:29612967, Apr 2001. Cerca con Google

I. F. Troc􀀀øniz, M. J. Garrido, C. Segura, J. M. Cendrøs, P. Principe, C. Peraire, and R. Obach. Phase I dose-nding study and a pharmacokinetic/pharmacodynamic analysis of the neutropenic response of intravenous diomotecan in patients with advanced malignant tumours. Cancer Chemother. Pharmacol., 57:727735, Jun 2006. Cerca con Google

L. Scott, O. Soepenberg, J. Verweij, M. J. de Jonge, A. S. Th Planting, D. McGovern, P. Principe, R. Obach, and C. Twelves. A multicentre phase I and pharmacokinetic study of BN80915 (diomotecan) administered daily as a 20-min intravenous infusion for 5 days every 3 weeks to patients with advanced solid tumours. Ann. Oncol., 18:569575, Mar 2007. Cerca con Google

P. Hautefaye, B. CimetiÃre, A. Pierrà c , S. Là c once, J. Hickman, W. Laine, C. Bailly, and G. Lavielle. Synthesis and pharmacological evaluation of novel non-lactone analogues of camptothecin. Bioorg. Med. Chem. Lett., 13:2731 2735, Aug 2003. Cerca con Google

A. Lansiaux, S. Là c once, L. Kraus-Berthier, C. Bal- Mahieu, R. Mazinghien, S. Didier, M. H. David-Cordonnier, P. Hautefaye, G. Lavielle, C. Bailly, J. A. Hickman, and A. Pierrà c . Novel stable camptothecin derivatives replacing the E-ring lactone by a ketone function are potent inhibitors of topoisomerase I and promising antitumor drugs. Mol. Pharmacol., 72:311319, Aug 2007. Cerca con Google

K. Takagi, T. S. Dexheimer, C. Redon, O. Sordet, K. Agama, G. Lavielle, A. Pierré, S. E. Bates, and Y. Pommier. Novel E-ring camptothecin keto analogues (S38809 and S39625) are stable, potent, and selective topoisomerase I inhibitors without being substrates of drug eux transporters. Mol. Cancer Ther., 6:32293238, Dec 2007. Cerca con Google

D.J. Adams, M.W. Dewhirst, J.L. Flowers, M.P. Gamcsik, O.M. Colvin, G. Manikumar, M.C. Wani, and M.E. Wall. Camptothecin analogues with enhanced antitumor activity at acidic pH. Cancer Chemother. Pharmacol., 46:263271, 2000. Cerca con Google

X.Y. Chu, Y. Kato, and Y. Sugiyama. Multiplicity of biliary excretion mechanisms for irinotecan, CPT-11, and its metabolites in rats. Cancer Res., 57:19341938, May 1997. [47] J.H. Schellens, M. Maliepaard, R.J. Scheper, G.L. Scheer, J.W. Jonker, J.W. Smit, J.H. Beijnen, and A.H. Schinkel. Transport of topoisomerase I inhibitors by the breast cancer resistance protein. Potential clinical implications. Ann. N. Y. Acad. Sci., 922:188194, 2000. Cerca con Google

C.H. Yang, E. Schneider, M.L. Kuo, E.L. Volk, E. Rocchi, and Y.C. Chen. BCRP/MXR/ABCP expression in topotecan-resistant human breast carcinoma cells. Biochem. Pharmacol., 60:831837, Sep 2000. Cerca con Google

G.L. Beretta, P. Perego, and F. Zunino. Mechanisms of cellular resistance to camptothecins. Curr. Med. Chem., 13:3291 3305, 2006. Cerca con Google

L. H. Meng, Z. Y. Liao, and Y. Pommier. Non-camptothecin DNA topoisomerase I inhibitors in cancer therapy. Curr Top Med Chem, 3:305320, 2003. Cerca con Google

Y. Yamashita, N. Fujii, C. Murakata, T. Ashizawa, M. Okabe, and H. Nakano. Induction of mammalian DNA topoisomerase I mediated DNA cleavage by antitumor indolocarbazole derivatives. Biochemistry, 31:1206912075, Dec 1992. Cerca con Google

B. H. Long, W. C. Rose, D. M. Vyas, J. A. Matson, and S. Forenza. Discovery of antitumor indolocarbazoles: rebeccamycin, NSC 655649, and uoroindolocarbazoles. Curr Med Chem Anticancer Agents, 2:255266, Mar 2002. Cerca con Google

T. K. Li, P. J. Houghton, S. D. Desai, P. Daroui, A. A. Liu, E. S. Hars, A. L. Ruchelman, E. J. LaVoie, and L. F. Liu. Characterization of ARC-111 as a novel topoisomerase I-targeting anticancer drug. Cancer Res., 63:84008407, Dec 2003. Cerca con Google

A. L. Ruchelman, S. K. Singh, X. Wu, A. Ray, J. M. Yang, T. K. Li, A. Liu, L. F. Liu, and E. J. LaVoie. Diazaand riazachrysenes: potent topoisomerase-targeting agents with exceptional antitumor activity against the human tumor xenograft, MDA-MB-435. Bioorg. Med. Chem. Lett., 12:33333336, Nov 2002. Cerca con Google

A. L. Ruchelman, S. K. Singh, A. Ray, X. H. Wu, J. M. Yang, T. K. Li, A. Liu, L. F. Liu, and E. J. LaVoie. 5HDibenzo[ Cerca con Google

c,h]1,6-naphthyridin-6-ones: novel topoisomerase Itargeting anticancer agents with potent cytotoxic activity. Cerca con Google

Bioorg. Med. Chem., 11:20612073, May 2003. Cerca con Google

A. Morrell, M. Jayaraman, M. Nagarajan, B. M. Fox, M. R. Meckley, A. Ioanoviciu, Y. Pommier, S. Antony, M. Hollingshead, and M. Cushman. Evaluation of indenoisoquinoline topoisomerase I inhibitors using a hollow ber assay. Bioorg. Med. Chem. Lett., 16:43954399, Aug 2006. Cerca con Google

S. Antony, M. Jayaraman, G. Laco, G. Kohlhagen, K. W. Kohn, M. Cushman, and Y. Pommier. Dierential induction of topoisomerase I-DNA cleavage complexes by the indenoisoquinoline MJ-III-65 (NSC 706744) and camptothecin: basesequence analysis and activity against camptothecin-resistant topoisomerases I. Cancer Res., 63:74287435, Nov 2003. Cerca con Google

S. Antony, G. Kohlhagen, K. Agama, M. Jayaraman, S. Cao, F. A. Durrani, Y. M. Rustum, M. Cushman, and Y. Pommier. Cellular topoisomerase I inhibition and antiproliferative Cerca con Google

activity by MJ-III-65 (NSC 706744), an indenoisoquinoline topoisomerase I poison. Mol. Pharmacol., 67:523530, Feb 2005. Cerca con Google

Malini Gupta, Akira Fujimori, and Yves Pommier. Eukaryotic dna topoisomerases i. Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression, 1262(1):1 14, 1995. Cerca con Google

J. T. Stivers, T. K. Harris, and A. S. Mildvan. Vaccinia DNA topoisomerase I: evidence supporting a free rotation mechanism for DNA supercoil relaxation. Biochemistry, 36:5212 5222, Apr 1997. Cerca con Google

J. J. Champoux. Mechanism of the reaction catalyzed by the DNA untwisting enzyme: attachment of the enzyme to 3'-terminus of the nicked DNA. J. Mol. Biol., 118:441446, Jan 1978. Cerca con Google

Y. H. Hsiang and L. F. Liu. Identication of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res., 48:17221726, Apr 1988. Cerca con Google

Y. P. Tsao, A. Russo, G. Nyamuswa, R. Silber, and L. F. Liu. Interaction between replication forks and topoisomerase I-DNA cleavable complexes: studies in a cell-free SV40 DNA replication system. Cancer Res., 53:59085914, Dec 1993. Cerca con Google

Y.P. Tsao, P. D'Arpa, and L.F. Liu. The involvement of active DNA synthesis in camptothecin-induced G2 arrest: altered regulation of p34cdc2/cyclin B. Cancer Res., 52:1823 1829, Apr 1992. Cerca con Google

S. Kharbanda, E. Rubin, H. Gunji, H. Hinz, B. Giovanella, P. Pantazis, and D. Kufe. Camptothecin and its derivatives induce expression of the c-jun protooncogene in human myeloid leukemia cells. Cancer Res., 51:66366642, Dec 1991. Cerca con Google

T.K. Li and L.F. Liu. Tumor cell death induced by topoisomerase-targeting drugs. Annu. Rev. Pharmacol. Tox- icol., 41:5377, 2001. Cerca con Google

Y. Mao, M. Sun, S.D. Desai, and L.F. Liu. SUMO-1 conjugation to topoisomerase I: A possible repair response to topoisomerase-mediated DNA damage. Proc. Natl. Acad. Sci. U.S.A., 97:40464051, Apr 2000. Cerca con Google

S.D. Desai, T.K. Li, A. Rodriguez-Bauman, E.H. Rubin, and L.F. Liu. Ubiquitin/26S proteasome-mediated degradation of topoisomerase I as a resistance mechanism to camptothecin Cerca con Google

in tumor cells. Cancer Res., 61:59265932, Aug 2001. Cerca con Google

B.A. Teicher. Next generation topoisomerase I inhibitors: Rationale and biomarker strategies. Biochem. Pharmacol., 75:12621271, Mar 2008. Cerca con Google

B.L. Staker, K. Hjerrild, M.D. Feese, C.A. Behnke, A.B. Burgin, and L. Stewart. The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc. Natl. Acad. Sci. U.S.A., 99:1538715392, Nov 2002. Cerca con Google

C. Jaxel, G. Capranico, D. Kerrigan, K. W. Kohn, and Y. Pommier. Eect of local DNA sequence on topoisomerase I cleavage in the presence or absence of camptothecin. J. Biol. Chem., 266:2041820423, Oct 1991. Cerca con Google

F. Leteurtre, M. Fesen, G. Kohlhagen, K. W. Kohn, and Y. Pommier. Specic interaction of camptothecin, a topoisomerase I inhibitor, with guanine residues of DNA detected by photoactivation at 365 nm. Biochemistry, 32:89558962, Aug 1993. Cerca con Google

A. Ioanoviciu, S. Antony, Y. Pommier, B.L. Staker, L. Stewart, and M. Cushman. Synthesis and mechanism of action studies of a series of norindenoisoquinoline topoisomerase I poisons reveal an inhibitor with a ipped orientation in the ternary DNA-enzyme-inhibitor complex as determined by Xray Cerca con Google

crystallographic analysis. J. Med. Chem., 48:48034814, Jul 2005. Cerca con Google

B.L. Staker, M.D. Feese, M. Cushman, Y. Pommier, D. Zembower, L. Stewart, and A.B. Burgin. Structures of three classes of anticancer agents bound to the human topoisomerase I-DNA covalent complex. J. Med. Chem., 48:2336 2345, Apr 2005. Cerca con Google

G. Jones, P. Willett, R.C. Glen, A.R. Leach, and R. Taylor. Development and validation of a genetic algorithm for exible docking. J. Mol. Biol., 267:727748, Apr 1997. Cerca con Google

MOE, Chemical Computing Group Inc, 1010 Sherbrooke St. West Suite 910 Montreal, Quebec H3A 2R7 Canada. Cerca con Google

Glide, version 3.5, Schrödinger, LLC, New York, NY, 2005. [78] M. D. Eldridge, C. W. Murray, T. R. Auton, G. V. Paolini, and R. P. Mee. Empirical scoring functions: I. The development of a fast empirical scoring function to estimate the binding anity of ligands in receptor complexes. J. Comput. Aided Mol. Des., 11:425445, Sep 1997. Cerca con Google

Schrödinger Suite 2007 QM-Polarized Ligand Docking protocol; Glide version 4.5, Schrödinger, LLC, New York, NY, 2005; Jaguar version 7.0, Schrödinger, LLC, New York, NY, 2005; QSite version 4.5, Schrödinger, LLC, New York, NY, 2005. Cerca con Google

[80] Jaguar version 7.0, Schrödinger, LLC, New York, NY, 2005. 115 Cerca con Google

A. E. Cho, V. Guallar, B. J. Berne, and R. Friesner. Importance of accurate charges in molecular docking: quantum mechanical/molecular mechanical (QM/MM) approach. J. Comput. Chem., 26:915931, Jul 2005. Cerca con Google

B. G. Johnson, P. M. W. Gill, and J. A. Pople. The performance of a family of density-functional methods. J. Chem. Phys., 98:56125626, 1993. Cerca con Google

C. Lee, W. Yang, and R. G. Parr. Development of the Colle- Salvetti correlation-energy formula into a functional of the electron density. Phys. Rev., B Condens. Matter, 37:785 789, Jan 1988. Cerca con Google

A. D. J. Becke. A new mixing of Hartree-Fock and local density-functional theories. J. Chem. Phys., 98:13721377, 1993. Cerca con Google

A. D. J. Becke. Density-functional thermochemistry. III. The role of exact exchange. J. Chem. Phys., 98:56485652, 1993. Cerca con Google

L. A. Curtiss, K. Raghavachari, P. C. Redfern, and J. A. J. Pople. Assessment of Gaussian-2 and density functional theories for the computation of enthalpies of formation. J. Chem. Phys., 106:10631079, 1997. Cerca con Google

C. W. Bauschlicher. A comparison of the accuracy of dierent functionals. Chem. Phys. Lett, 246:4044, 1995. Cerca con Google

Helen Berman, Kim Henrick, and Haruki Nakamura. Announcing the worldwide Protein Data Bank. Nat Struct Biol, 10(12), Dec 2003. Cerca con Google

W. D. Cornell, P. Cieplak, C. I. Bayly, I. R. Gould, K. M. Merz, D. M. Ferguson, D. C. Spellmeyer, T. Fox, J. W. Caldwell, and P. A. Kollman. A second generation force eld for the simulation of proteins, nucleic acids, and organic molecules. J. Am. Chem. Soc., 117:51795197, 1995. Cerca con Google

J. Wang, P. Cieplak, and P. A. Kollman. How well does a restrained electrostatic potential (resp) model perform in calculating conformational energies of organic and biological molecules? J. Comput. Chem., 21:10491074, 2000. Cerca con Google

Thomas A. Halgren. Merck molecular force eld. i. basis, form, scope, parameterization, and performance of mm94. Cerca con Google

Journal of Computational Chemistry, 17:490519, 1996. [92] S. Sawada, K. Nokata, T. Furuta, T. Yokokura, and T. Miyasaka. Chemical modication of an antitumor alkaloid camptothecin: synthesis and antitumor activity of 7-Csubstituted camptothecins. Chem. Pharm. Bull., 39:2574 2580, Oct 1991. Cerca con Google

H.-K. Wang, S. Y. Liu, K. M. Hwang, A. T. McPhail, and H. H. Lee. The synthesis of 5-substituted camptothecins as potential inhibitors of DNA topoisomerase I. Bioorg. Med. Chem. Lett., 5:7782, Jan 1995. Cerca con Google

D. Subrahmanyam, V. M. Sarma, A. Venkateswarlu, T. V. R. S. Sastry, A. P. Kulakarni, R. D. Srinivas, and K. V. S. R. Krishna Reddy. In vitro cytotoxicity of 5-aminosubstituted 20(S)-camptothecins. part 1. Bioorg. Med. Chem. Lett., 7:20132020, Sept 1999. Cerca con Google

M. Sugimori, A. Ejima, S. Ohsuki, K. Matsumoto, Y. Kawato, M. Yasuoka, H. Tagawa, and H. Terasawa. Antitumor agents. VI: Synthesis and antitumor activity of ring A-, ring B-, and ring C-modied derivatives of camptothecin. Heterocycles, 38:8194, 1994. Cerca con Google

D. Subrahmanyam, A. Venkateswarlu, K. R. Venkateswara, T. V. R. S. Sastry, G. Vandana, and S. A. Kumar. Novel C-ring analogues of 20(S)-camptothecin-part-2: Synthesis and cytotoxicity of 5-C-substituted 20(S)-camptothecin analogues. Bioorg. Med. Chem. Lett., 9:16331638, June 1999. Cerca con Google

D. Subrahmanyam, V. M. Sarma, A. Venkateswarlu, T. V. R. S. Sastry, S. S. V. Akella, A. S. S. V. Srinivas, C. V. Krishna, D. S. Deevi, S. A. Kumar, Babu M. J., and N. K. Damodaran. Novel C-ring analogues of 20(S)-camptothecin. Part 3: synthesis and their in vitro cytotoxicity of A-, B- and Cerca con Google

C-ring analogues. Bioorg. Med. Chem. Lett., 10:369371, Feb 2000. Cerca con Google

J. Torregrossa, G. J. Bubley, and G. B. Jones. Microwave expedited synthesis of 5-aminocamptothecin analogs: Inhibitors of hypoxia inducible factor HIF-1. Bioorg. Med.Chem. Lett., 16:60826085, Dec 2006. Cerca con Google

C. Samorì, A. Guerrini, G. Varchi, G. Fontana, E. Bombardelli, S. Tinelli, G.L. Beretta, S. Basili, S. Moro, F. Zunino, and A. Battaglia. Semi-synthesis, biological activity and molecular modeling studies of c-ring modied camptothecins. J. Med. Chem., 2009, in press. Cerca con Google

R. Marchesini, A. Colombo, C. Caserini, P. Perego, R. Supino, G. Capranico, M. Tronconi, and F. Zunino. Interaction of ionizing radiation with topotecan in two human tumor cell lines. Int. J. Cancer, 66:342346, May 1996. Cerca con Google

G. L. Beretta, M. Binaschi, E. Zagni, L. Capuani, and G. Capranico. Tethering a type IB topoisomerase to a DNA site by enzyme fusion to a heterologous site-selective DNAbinding protein domain. Cancer Res., 59:36893697, Aug 1999. Cerca con Google

A. W. Nicholas, M. C. Wani, G. Manikumar, M. E. Wall, K. W. Kohn, and Y. Pommier. Plant antitumor agents. 29.Synthesis and biological activity of ring D and ring E modi- ed analogues of camptothecin. J. Med. Chem., 33:972978, Mar 1990. Cerca con Google

J. E. Chrencik, B. L. Staker, A. B. Burgin, P. Pourquier, Y. Pommier, L. Stewart, and M. R. Redinbo. Mechanisms f camptothecin resistance by human topoisomerase I mutations. . Mol. Biol., 339:773784, Jun 2004. Cerca con Google

O. Keskin, I. Bahar, R. L. Jernigan, J. A. Beutler, R. H. Shoemaker, E. A. Sausville, and D. G. Covell. Characterization of anticancer agents by their growth inhibitory activity and relationships to mechanism of action and structure. An- ticancer Drug Des., 15:7998, Apr 2000. Cerca con Google

Samuel J. Danishefsky, William G. Bornmann, Wang Shen, and Craig A. Coburn. Methods of preparation of camptothecin analogs. US Patent Number 5391745, February 1995. Cerca con Google

M. A. Elban, W. Sun, B. M. Eisenhauer, R. Gao, and S. M. Hecht. Synthesis and biological evaluation of 10,11- methylenedioxy-14-azacamptothecin. Org. Lett., 8:3513 3516, Aug 2006. Cerca con Google

C. Samorì, A. Guerrini, G. Varchi, F. Zunino, G. L. Beretta, C. Femoni, E. Bombardelli, G. Fontana, and A. Battaglia. Thiocamptothecin. J. Med. Chem., 51:30403044, May 2008. Cerca con Google

E. Bombardelli, G. Fontana, C. Manzotti, A. Battaglia, and C. Samorì. Camptothecin derivatives with antitumor activity. International Patent Number 08011994, January 2008. Cerca con Google

C. Samorì, A. Guerrini, G. Varchi, G. Fontana, E. Bombardelli, S. Tinelli, G.L. Beretta, S. Basili, S. Moro, F. Zunino, and A. Battaglia. Manuscript in preparation. Cerca con Google

Solo per lo Staff dell Archivio: Modifica questo record