AbstractsBiology & Animal Science

Chemotherapy is still one of the primary modalities for the treatment of cancer. However, the application of free anticancer drugs has several drawbacks due to the high toxicity, the lack of selectivity and the low bioavailability. The main objective of the current PhD thesis was to improve the activity mainly of antiproliferative drugs but also of other drugs and bioactive compounds. To achieve this, two axes were followed:a) Design, synthesis and biological evaluation of bioconjugates for selective drug delivery and tumour targeting: Two antiproliferative drugs were studied gemcitabine and sunitinib. Selective drug delivery was achieved by the conjugation of these drugs to gonadotropin-releasing hormone (GnRH) peptide in order to target the GnRH receptor, which is found to over express in different tumor cells. First the chemistry of drug-peptide conjugation was studied and more specific the oxime bonds, the carboxylic acid ester bonds and the carbamate bonds in chemical linkers. Then the biological evaluation of bioconjugates was tested in androgen-independent CaP cell lines followed by the pharmacokinetic study in mice. The results showed that the bioconjugates showed better anticancer activity or stability than the parent drugs. In this way, effective concentration of drugs at target can be achieved by selecting the linker with specific bonds according to required condition of particular drug.b) Molecular hybrids: In the synthesis of molecular hybrids, gemcitabine (anticancer) and quercetin (antioxidant/anticancer) were studied. The hybrid product of gemcitabine with lipoic acid (prooxidant) showed better anticancer and prooxidant activity than the parent compounds. About quercetin: Synthesis of the different hybrids for different purposes were presented. First, quercetin-aminoacids hybrids are useful for improving biological availability by improving aqueous solubility (quercetin-glutamic acid) of quercetin, which was the major cause of quercetin low bioavailability. Second, quercetin used for conjugation with the Losartan and Captopril drugs, which are used for antihypertension. As we know lowering blood pressure is the only treatment available for hypertensive patients, and therefore lowering blood pressure causes oxidative stress in vascular level in hypertension treatment. Therefore our molecular hybrid Quercetin-Losartan and Quercetin-Cprotpil will help to minimize hypertension as well as generated oxidative stress. Η χημειοθεραπεία αποτελεί ακόμα μία από τις κύριες μεθόδους αντιμετώπισης του καρκίνου. Ωστόσο η εφαρμογή των αντικαρκινικών φαρμάκων σε ελεύθερη μορφή έχει πολλά μειονεκτήματα λόγω, της υψηλής τοξικότητας, της έλλειψης επιλεκτικότητας και της χαμηλής βιοδιαθεσιμότητας των φαρμάκων αυτών. Ο κυρίως στόχος της παρούσας διατριβής ήταν η βελτίωση της δραστικότητας φαρμάκων (κυρίως αντικαρκινικών) καθώς και άλλων βιοδραστικών ενώσεων. Για το σκοπό αυτό ακολουθήθηκαν δύο άξονες: α) Σχεδιασμός, σύνθεση και βιολογική αξιολόγηση βιοσυζυγών για την εκλεκτική απελευθέρωση φαρμάκου και στόχευση όγκων.…