Heat shock protein 90 (Hsp90 – proteina dello shock termico 90), una delle più abbondanti proteine nelle cellule eucariote, è un chaperone ATP dipendente che gioca un ruolo centrale regolando la stabilizzazione, l’attivazione e la degradazione di una gamma di proteine [97]. Queste proteine “clienti” includono proteine riconosciute come sovra-espresse o mutanti oncogeniche come C-RAF, B-RAF, ERBB2, AKT, telomerasi ed il gene p53. Alcune di queste proteine sono associate con le sei caratteristiche dei tumori [98-99], e perciò Hsp90 è emersa come un bersaglio molto attraente per i nuovi agenti terapeutici contro il cancro. Il progresso in quest’area è stato ampiamente revisionato negl’ultimi cinque anni. Specifici inibitori delle Hsp90 sono ora entrati negli studi clinici. Un lavoro interessante sugli inibitori di Hsp90 è stato fatto con due prodotti naturali: il radicicol e la
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geldanamicina, che si legano entrambi alla tasca di legame dell’ATP
nel dominio N-terminale delle proteine [100 a,b].
Radicicol
La struttura che si lega con le proteine sia del radicicol che della geldanamicina è stata studiata attraverso cristallografia a raggi X [101] e in soluzione con spettroscopia NMR [102].
Se radicicol fu originariamente isolato da funghi Monocillum Nordinii più di 50 anni fa, e successivamente da Nectria Radicicola e dalla pianta associata al fungo Chaetomium Chiversii [97]; ha attirato l’interesse di chimici sintetici ed è stato il soggetto di tre sintesi totali [103 a,b,c,d,e,g]. E’ uno dei più potenti inibitori di Hsp90 in vitro, mentre ha una scarsa attività in vivo, ed è un membro della più vasta classe di prodotti naturali conosciuti come lattoni dell’acido resorcilico, molti dei quali presentano una potente attività biologica. La perdita dell’attività in vivo di radicicol è presumibilmente il risultato del suo epossido reattivo e della porzione dienonica, anche se il suo derivato ossimico potrebbe avere una piccola attività in vivo [104]. In una ricerca su altri analoghi biologicamente attivi, Danishefsky e collaboratori hanno sviluppato una nuova serie di inibitori basati sul ciclopropanradicicol [105], compreso il triazol-ciclopropanradicicol descritto recentemente [106].
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Triazol-ciclopropanradicicol NP261
E’ stato riportato uno studio sulla struttura del legame del radicicol legato nella tasca dell’ATP nel dominio N-terminale di Hsp90 di lievito (Figura 10) [97]. Nella stessa pubblicazione è stat riportata l’attività biologica di alcuni analoghi del radicicol, e di una serie di nuovi macrolattoni resorcilici con anelli e conformazioni diverse.
Figura 10. Interazioni di legame del radicicol con Hsp90 di lievito.
Uno di questi analoghi, NP261, non solo ha mostrato di essere un importante inibitore di Hsp90 che si lega al dominio N-terminale della proteina, che è deplezione delle proteine clienti con up-regulation di Hsp70, ma il suo legame con le proteine avviene in maniera del tutto
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simile a quella del prodotto naturale strutturalmente più complesso (Figura 11).
Figura 11. Interazioni di legame di NP261, un lattone a 14 membri, con Hsp90 di lievito.
In questo modo entrambi i composti adottano una simile conformazione ripiegata con le stesse interazioni di legame a idrogeno che coinvolgono l’estere salicilico e gruppi i fenolici, il carbossilato della catena laterale di Asp79, il gruppo ammidico della catena principale della Gly83, l’ossidrile della catena laterale di Thr171, il carbossile della catena principale di Leu34, e conservate molecole di acqua (figure ab e aab). Sebbene la struttura del radicicol mostri chiaramente il coinvolgimento dell’ossigeno epossidico nel legame a idrogeno con il gruppo ε- amminico della catena laterale di Lys44, la perdita relativamente minima del doppio dell’attività in vitro dell’analogo NP261, suggerisce che questa interazione, sebbene utile, non è essenziale [97]. Da questo studio è stato possibile ottenere utili informazioni per la progettazione e per la sintesi di nuovi macrlolattoni resorcilici, nei quali la presenza di eteroatomi potrebbero essere importanti per un potenziale legame con la
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catena laterale di Lys44, in modo tale da incrementare la potenza degli inibitori.
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RINGRAZIAMENTI
E’ difficile salutare e, soprattutto, menzionare tutti dopo un’esperienza così bella e lunga allo stesso tempo…inizierei ringraziando la prof.ssa Lapucci, nonché mia relatrice, che mi ha seguito durante tutti i miei studi, supportandomi ed aiutandomi nello svolgimento della tesi; ringrazierei i ragazzi con cui sono stato qui il primo