Summary:
This thesis deals with the design and synthesis of new tricyclic nucleosides as
potential antiproliferative agents. The nucleotides are the structural units of
nucleic acids and play a crutial role in many metabolic processes. The study of
their structural analogues is an important area of research within biological
sciences, and numerous derivatives possess therapeutic interest, mainly as
antiviral and anticancer drugs.
Cancer cells have the tendency to differentiate continuously and randomly and
for this reason, drugs are targeting the activation of apoptosis. The
cytokinins are plant hormones that promote cell division and differentiation.
Their physiological role has prompted the development of compounds that might
repair dysfunctions of cell division and differentiation in animal cells, as in
the case of cancer cells. It is known that their ribonucleotide derivatives,
natural and synthetic, inhibit proliferation of cancer cells through selective
activation of apoptosis and simultaneous blockade of the transition of G1 / S
cell cycle.
Based on the above mentioned considerations, a number of non-classical
adenosine derivatives have been prepared in order to study their potential
antiproliferative activity. The new molecules bear a tricyclic structure
mimicking the purine system and possess alkylamino substituents which are
present into active cytokinins. The derivatives were synthesized using as
starting material 2,6-diaminopyridine which upon acetylation, nitration,
selective deacetylation and reduction of the nitro group revealed an
intermediate o-diamine. This compound was converted to the corresponding
imidazolpyridine which was then subjected to nitration, reduction of the nitro
group and reaction with glyoxal to provide
imidazo[4',5':5.6]pyrido[2,3-b]pyrazine. Glycosylation of this molecule gave
the two possible regio-isomers. The major isomer was converted to the 9-chloro
derivative which was used for the preparation of the 9-aminosubstituted
analogues.
Keywords:
Imidazo[4’, 5’:5, 6]pyrido[2, 3-b]pyrazine, Adenosine analogues, Cytokinines, Nucleosides
