Unit:
Department of ChemistryLibrary of the School of Science
Author:
Andreadelis Ioannis
Dissertation committee:
Θωμάς Μαυρομούστακος, Καθηγητής, Τμήμα Χημείας ΕΚΠΑ (Επιβλέπων Καθηγητής)
Γεώργιος Κόκοτος, Καθηγητής, Τμήμα Χημείας ΕΚΠΑ
Μάνθος Παπαδόπουλος, Ερευνητής Α΄, Εθνικό Ίδρυμα Ερευνών
Γεωργία Βαλσαμή, Αναπληρώτρια Καθηγήτρια, Τμήμα Φαρμακευτικής ΕΚΠΑ
Νικόλαος Θωμαΐδης, Καθηγητής, Τμήμα Χημείας ΕΚΠΑ
Ανδρέας Τζάκος, Αναπληρωτής Καθηγητής, Τμήμα Χημείας Ιωαννίνων
Γεωργία Μελαγράκη, Επίκουρη Καθηγήτρια, Στρατιωτική Σχολή Ευελπίδων
Original Title:
Χρήση μοριακής δυναμικής σε συνδυασμό με φασματοσκοπία NMR για την πρόταση σύνθεσης βιοδραστικών μοριών και συστημάτων μεταφοράς τους
Translated title:
The use of molecular dynamics and NMR spectroscopy for the synthesis of bioactive compounds and their carrier systems
Summary:
In this thesis, the role of complexing natural and pharmaceutical molecules with proven beneficial health properties with 2-hydroxylpropyl-β-cyclodextrin (HP-β-CD) was studied.
In the first part of the thesis, the molecular interactions between caffeic and rosmarinic acid in hydroxypropyl-β-cyclodextrin were studied using a combination of NMR spectroscopy and molecular modeling. Changes in the chemical shifts of carbon (13C CP/MAS) and hydrogen spectroscopy as well as intermolecular within the complex NOEs have clarified the orientation and conformations of the natural products into the cyclodextrin. Molecular dynamics and Isothermal Calorimetry (ITC) experiments were also conducted to investigate the stability and degree of substitution of the cyclodextrin.
In the second part of the thesis, complexes of candesartan and candesartan cilexetil with HP-β-CD were characterized using ESI QTQF HRMS and solid state NMR and in particular CP/MAS spectroscopy. The 13C CP/MAS results showed broad peaks especially in the aromatic region, thus confirming the strong interactions between cyclodextrin and drugs. This experimental evidence was in accordance with MD simulations and quantum mechanical calculations. The synthesized and characterized complexes were evaluated biologically in vitro. It was shown that as a result of CAN’s complexation, CAN exerts higher antagonistic activity than CC. This intriguing result agrees with binding free energy calculations, which predicted efficient binding with CC while CAN binding was not favored. Thus, CC cannot be released easily from HP-β-CD and as a result is not suggested as a new pharmaceutical formulation. The opposite holds truth for CAN complex which could be used as a novel antihypertensive pharmaceutical formulation.
Main subject category:
Science
Keywords:
caffeic acid, rormarinic acid, candesartan, candesartan cilexetil, molecular dynamics.
Number of references:
236
