Dissertation committee:
Πουλή Νικολαΐς Καθηγήτρια ΕΚΠΑ (επιβλέπουσα), Μαράκος Παναγιώτης Καθηγητής ΕΚΠΑ, Μικρός Εμμανουήλ Καθηγητής ΕΚΠΑ
Summary:
The present Thesis deals with the design and synthesis of new substituted
pyrazolo[3,4-c] pyridines, and their pharmacological evaluation as cytotoxic
agents, as well as potential inhibitors of protein kinases.
The compounds can be divided into three groups: the first includes derivatives
of pyrazolo[3,4-c] pyridine which bear 7-arylamino substitution, as well as
5-chloro, 5-cyano-, 5-arylaminomethyl, or 5-alkylaminomethyl substituents. The
other two groups include the corresponding 3-phenyl- and 3-isopropylderivatives.
The synthesis of the first group derivatives was accomplished using either
N-(2-chloro-4-methylpyridin-3-yl)acetamide or
N-(2-chloro-4-methylpyridin-5-yl)acetamide, which have been prepared using
commercially available picolines. The 5-chloro-analogues were obtained through
intramolecular cyclization of the above mentioned 3-acetamide, N-oxidation of
the intermediate pyrazol[3,4-c]pyridine and metathesis to the corresponding
5,7-dichlorocompound. The 7-chloro-group was substituted by suitable arylamides
and the 5-chloro group was then reduced. The 5-cyanopyrazolopyridines were
prepared through N-oxide metathesis of the suitable picoline-5-acetamide,
followed by intramolecular cyclization to result in the
5-cyano-7-chloropyrazolopyridine. Upon introduction of 7-arylamino substituents
and reductive amination the 5-aryl- or alkylaminomethyl-derivatives were
obtained.
The target substituted 3-phenylpyrazolopyridines were synthesized through
Suzuki coupling of 5-chloro-3-iodopyrazolopyridine. The 5-cyano-group was then
inserted to the resulting 5-chloro-3-phenylderivative through palladium
coupling.
Finally, the 3-isopropylpyrazolopyridines were prepared using suitably
substituted pyridinacetamides, which were obtained through Lithium mediated
introduction of the isopropyl group to protected 2-amino-4-picoline. The target
compounds have resulted using an analogous synthetic procedure.
The new compounds have been evaluated for their cytotoxic activity against ten
human cancer cell lines. A number of the derivatives proved to be active,
showing IC50 values within the range of 0.38-12 μΜ, whereas the most potent
analogues proved to belong to the 3-phenylpyrazolopyridine series. Preliminary
experiments concerning the evaluation of the inhibitory activity of the
synthesized derivates against PI3 Kinase, showed that a number of the most
cytotoxic compounds were potent inhibitors of the enzyme as well.
Keywords:
Design, Synthesis, Pyrazolopyridines, Inhibitors, Kinases
