Unit:
Τομέας ΦΑΡΜΑΚΕΥΤΙΚΗΣ ΤΕΧΝΟΛΟΓΙΑΣLibrary of the School of Science
Author:
Χρυσανθακόπουλος Μάριος
Dissertation committee:
Καθηγήτρια Α. Τσαντίλη-Κακουλίδου (επιβλέπουσα), Καθηγήτρια Β. Δημόπουλος, Αναπλ. Καθηγήτρια Ε. Παντέρη
Original Title:
Αξιολόγηση πειραματικών/υπολογιστικών παραμέτρων λιποφιλίας σε Ποσοτικές Σχέσεις Δομής-Δράσης και εκτίμηση φαρμακοκινητικών διεργασιών στη βάση βιοχρωματογραφικών δεικτών. Εφαρμογή σε όξινα παράγωγα του πυρρολίου, αναστολείς της Αναγωγάσης της Αλδόζης
Summary:
In the first section of the thesis, a detailed investigation of the
lipophilicity series of substituted pyrrolyl-acetic acid derivatives,
inhibitors of aldose reductase, was conducted using calculation systems and
experimental techniques e.g. direct partitioning in the octanol-water system
and reversed-phase chromatography (RP-HPLC, RP-TLC) at pH 3.0 and 7.4. The
addition of n-octanol in the mobile phase for better simulation of the
chromatographic indices with logP and logD values was examined. The reliability
of calculated values to predict logP and logD and as parameters for correlation
with biological activity was evaluated. The experimental values proved to be
more suitable in all cases.
The second section focused on biomimetic chromatography and affinity
chromatography using IAM, HSA and AGP stationary phases.
IAM chromatographic indices were compared to conventional lipophilicity
parameters and individual correlations were established. The retention/pH
profile in IAM column (in the range from 2.5 to 7.4) was investigated and
compared with the corresponding profiles obtained in reverse phase
chromatography and octanol-water system. logkwIAM values were used to extract
model equations for estimating the intestinal absorption in combination with
hydrogen bond basicity and protonated molecular fraction. HSA chromatography
was implemented in a series of structurally diverse compounds. The most
suitable conditions for the simulation of protein binding to serum albumin was
examined resulting in the establishment of a model equation. A similar effort
for the AGP chromatography and binding to the alpha-acid glycoprotein did not
lead to satisfactory results, but provided useful information on the mechanism
of retention.
Keywords:
Lipophilicity, Quantitative Structure Activity Relationships, Reversed phase Chromatography, Biomimetic Chromatography, Aldose Reductase Inhibitors
Number of references:
304
