Cytotoxic Metal Complexes With N-Heterocyclic Carbenes Containing 1,2,4-Oxadiazole Substituents

Abstract

The work presented in this PhD thesis dealt with the synthesis and antitumor evaluation of both 1,2,4-oxadiazole ligands and their related NHC complexes. Compounds with various steric and electronic properties were designed, isolated and characterised by IR, 1H, 13C NMR, MS (HR-ESI) and X-ray diffraction. Majority of the prepared 1,2,4-oxadiazole derivatives were tested for their antitumor activity in a monolayer cell survival and proliferation assay using human tumor cell lines of different origin/histotype. Six of the novel gold(I) N-heterocyclic carbenes (NHC) linked to 1,2,4-oxadiazol derivatives compounds revealed impressive potency (mean IC50 < 0.1 µM) and tumor selectivity. In order to diversify and increase this library, the substituents were further modified under the aspect of obtaining a better biological activity. The target was to obtain 1,2,4-oxadiazoles with substituents which were not accessible by direct coupling (carboxylic acid, hydrazine, vinyl, hydroxylamine, thioamide). The synthetic plan also included the implementation of further heterocycles in order to increase the biological activity. In this direction, a series of 1,2,4-oxadiazoles incorporating a succinimide, maleimide, thiazole, oxazole, imidazole, pyrazole and pyrazol-pyrimidine core were designed, synthesized and investigated for antitumor activity. Starting from 3-tert-butyl-5-(4-amino)-phenyl-1,2,4-oxadiazole and the imidazole derivative therefrom, it was possible to generate a library of ten new imidazolium salts that were used as precursors for NHC complexes. The imidazole containing derivative served as a starting compound for the 1,2,4-oxadiazole-derived imidazolium salts, designed mostly unsymmetrically in order to introduce a second substituent of choice. The majority of these substituents are biologically active organic moieties. Some of them are exotic (anthracene, 2-pyridine, 2,3,4,5-tetra-O-acetyl-D-glucopyranose) and others are quite unique (indole, quincorine (QCI) and quincoridine (QCD)) since no other examples are reported in the literature. The sugar derivative and the two quinuclidine derivatives are rare examples of chiral imidazolium salts. In conclusion, the synthesised imidazolium salts were used as NHC ligands in order to generate gold (I), silver (I) and rhodium (I) complexes with very strong antitumor activity.