Academic literature on the topic 'Pyrroloazepine'

Chapter one; “(-)-Rhazinilam and (-)-Rhazinal: Alkaloids with Anti-mitotic Properties Derived from Kopsia teoi”, provides the background information behind the motives that initiated this research project. The plant alkaloid (-)-rhazinilam [(-)-1] and its naturally-occurring derivative (-)-rhazinal [(-)-13] both exhibit potent anti-mitotic activities and, as such, are interesting targets for total synthesis. Chapter one is a review of the literature regarding these two compounds and discusses the occurrence, proposed biosynthetic origins, structural elucidation and biological activites of compound (-)-1 and that of its analogues including alkaloid (-)-13. Previous total syntheses of these two compounds are then examined, concluding with the only reported total synthesis of compound (-)-13. Developed within the Banwell research group, this total synthesis produced the racemic modification of alkaloid (-)-13 due to a lack of any stereocontrol in the key intramolecular Michael addition step. This unprecedented key step, involving cyclisation of the C2 of pyrrole onto an N-tethered and ?,?-disubstituted acrylate to produce a quaternary-carbon stereogenic centre, would be of greatly enhanced utility if it could be achieved in a catalytic-enantioselective fashion. The realisation of this goal is the central aim of the research conducted within this thesis. ¶ Chapter two; “Investigating Asymmetric Induction in the Intramolecular Michael Addition of pyrrole to N-Tethered Acrylates and Related Species”, introduces the model study used to direct research towards achieving the goal of asymmetric induction in the title process. The model is a somewhat simplified version of the original process used in the total synthesis of compound (-)-13 involving cyclisation of the C2 of pyrrole onto an N-tethered and ?-monosubstituted Michael acceptor, to produce a tertiary-carbon stereogenic centre. This simplification allows the rapid synthesis of a broad range of potential substrates for use in the title process, thus enabling the investigation of various different approaches to inducing asymmetry therein. High levels of asymmetric induction are observed with the use of chiral substrates or catalysts, facilitating the synthesis of both 6- and 7-membered rings annulated to pyrrole with construction of the relevant tertiary-carbon stereogenic centre in enantio-enriched form. For the reactions producing a 6-membered ring annulated to pyrrole, unambiguous proof of the absolute sense of asymmetric induction observed in the intramolecular Michael addition event is established using a chemical correlation study involving elaboration of a key indolizine-type cyclisation product, to the plant alkaloid of known absolute stereochemistry, (-)-tashiromine [(-)-75]. For the reaction producing a 7-membered ring annulated to pyrrole, the same information is obtained via X-ray crystallographic analyses of a dibrominated derivative of a key pyrroloazepine-type cyclisation product. ¶ Chapter three “An Enantioselective Total Synthesis of the Alkaloid (-)-Rhazinal: An Anti-mitotic Agent Isolated from Kopsia teoi.”, focuses on the application of methodology developed in the previous chapter, to the original goal of inducing asymmetry in the intramolecular Michael addition reaction, involving cyclisation of the C2 of pyrrole onto an N-tethered and ?,?-disubstituted acrylate to produce a quaternary-carbon stereogenic centre. This is ultimately achieved in a catalytic-enantioselective fashion, resulting in the first such total synthesis of the anti-mitotic alkaloid (-)-rhazinal [(-)-13]. ¶ Chapter four “Extending the Reaction Manifold to the Syntheses of Related Natural Products: A Formal Total Synthesis of (+)-Aspidospermidine and Syntheses of (-)-Rhazinilam and (-)-Leuconolam from (-)-Rhazinal”, describes three extensions to the reaction manifold used in the enantioselective total synthesis of alkaloid (-)-13: The acquisition in an enantioselective manner, of an intermediate previously obtained in racemic form, en route to the racemic modification of the natural product (±)-aspidospermidine [(±)-134], constitutes a formal and enantioselective total synthesis of (+)-aspidospermidine [(+)-134]. The direct deformylation of (-)-rhazinal [(-)-13], is carried out, to produce the parent alkaloid (-)-rhazinilam [(-)-1]. The pyrrole ring present in (-)-rhazinilam [(-)-1] is oxidised, to produce the related natural product (-)-Leuconolam [(-)-12] which has not, hitherto, been prepared by total synthesis. ¶Chapter five contains the experimental procedures and characterisation data associated with compounds described in chapters two to four.

Οι κυκλινοεξαρτώμενες κινάσες (Cdks) είναι μια κατηγορία των πρωτεϊνικών κινασών, οι οποίες ενεργοποιούνται μέσω σύνδεσης με την κατάλληλη κυκλίνη και εμπλέκονται στη ρύθμιση του κυτταρικού κύκλου. Η ενεργοποίηση συγκεκριμένων συμπλόκων Cdks-κυκλινών επιτρέπει την ομαλή μετάβαση από την μία στην επόμενη φάση του κύκλου. Ωστόσο, η υπερλειτουργία των Cdks οδηγεί σε ανεξέλεγκτο κυτταρικό πολλαπλασιασμό, με αποτέλεσμα την εμφάνιση διαφόρων ασθενειών, όπως είναι ο καρκίνος, η νόσος του Alzheimer και ο διαβήτης. Λόγω αυτού, οι Cdks αποτελούν υποψήφιους μοριακούς στόχους για την θεραπευτική αντιμετώπιση αυτών των ασθενειών. Πολλά μικρά χημικά μόρια έχουν αποδειχθεί αναστολείς των CDKs. Κάποιοι από αυτούς έχουν προχωρήσει σε κλινικές δοκιμές φάσης Ι και ΙΙ, ωστόσο κανένας δεν έχει λάβει έγκριση για κυκλοφορία. Πρόσφατα, ο Cdk αναστολέας Dinaciclib εισήλθε σε κλινικές δοκιμές φάσης ΙΙΙ. Τα θαλάσσια σφουγγάρια αποτελούν πλούσια πηγή φυσικών προϊόντων με ανασταλτική δράση έναντι πλήθους κινασών. Η Hymenialdisine (HMD) είναι ένα φυσικό προϊόν, το οποίο έχει απομονωθεί από διάφορα είδη θαλάσσιων σφουγγαριών και εμφανίζει ανασταλτική δράση έναντι πολλών πρωτεϊνικών κινασών, μεταξύ των οποίων και οι CDKs. Στα πλαίσια της παρούσας μελέτης σχεδιάσθηκαν και συντέθηκαν νέα σπειρανικά ανάλογα της HMD με σκοπό να εμφανίσουν ισχυρότερη και εκλεκτικότερη ανασταλτική δράση από αυτήν έναντι πρωτεϊνικών κινασών. Οι νέες ενώσεις φέρουν δομικά χαρακτηριστικά της HMD, όπως έναν πυρρολο[2,3-c]αζεπινονικό δακτύλιο που έχει αποδειχθεί κρίσιμος για την ανάπτυξη δεσμών υδρογόνου με τη θέση πρόσδεσης του ATP. Ωστόσο, ο γλυκοκυαμιδινικός δακτύλιος της HMD έχει αντικατασταθεί στα νέα ανάλογα από έναν εξαμελή λακταμικό σπειρανικό δακτύλιο. Η συνθετική προσέγγιση που ακολουθήθηκε για την σύνθεση των νέων ενώσεων περιελάμβανε αρχικά την ανοικοδόμηση του πυρρολο[2,3-c]αζεπινο-4,8-διονικού δακτυλίου και στην συνέχεια την μετατροπή της 4-κετο-ομάδας αυτού σε ένα αμινο-υποκατεστημένο στερεογονικό κέντρο. Για τον σκοπό αυτό, χρησιμοποιήθηκε μια κλασσική μεθοδολογία, η οποία περιελάμβανε συμπύκνωση του παραπάνω δακτυλίου με χειρόμορφα t-βουτυλοσουλφινυλαμίδια και νουκλεόφιλη προσβολή των ενδιάμεσων σουλφινυλιμινών που προέκυψαν με οργανομεταλλικά αντιδραστήρια Grignard. Η συνθετική προσέγγιση που ακολουθήθηκε επέτρεψε την σύνθεση εναντιομερών σπειρανικών αναλόγων της HMD. Η αποτίμηση της βιολογικής δράσης των νέων ενώσεων αναμένεται σύντομα.
Cyclin-dependent kinases (Cdks) are protein kinases and their enzymatic activity requires the binding of a regulatory cyclin subunit. Cdks are implicated in the regulation of the cell cycle. The activation of different Cdks-cyclin complexes drives the transition of cell through the distinct phases of the cell cycle. However, overactivation of Cdks results in uncontrolled cell proliferation and hence, in many diseases such as cancer, Alzheimer’s disease and diabetes. Cdks represent candidate molecular targets for the treatment of these diseases. Many small molecules have been proved potent Cdks inhibitors. Many of them, are in phase I or II of clinical trials. Recently, Dinaciclib became the first Cdk inhibitor which entered in phase III of clinical trials. The sea sponges are a rich source of natural products which present inhibitory activities against protein kinases. Hymenialdisine (HMD) is a natural product, which has been isolated from many sea sponges and inhibits many kinases, such as Cdks. In this research work, new spiro analogues of HMD were designed and synthesized, aimining at the discovery of new compounds with enhanced inhibitory activity and selectivity against to protein kinases. These new compounds bear structural characteristics of HMD, like a pyrrolo[2,3-c]azepinone ring, which is crucial for the binding of HMD to the ATP-binding site of the enzyme. The glycocyamidine ring of the HMD has been replaced by a six-membered lactam spiro-ring. The synthetis of new compounds involves the formation of the pyrrolo[2,3-c]azepino-4,8-dione and subsequently the introduction of a new amino-substituted stereogenic center. Key-step to this approach is the substitution of the intermediate chiral t-butanesulfinylimines by organometallic reagents. The synthetic approach provides access to different stereoisomers. The biological evaluation of the new compound is in progress.