Synthesis and Optimization of New 3,6-Disubstitutedindole Derivatives and Their Evaluation as Anticancer Agents Targeting the MDM2/MDMx Complex.

Twelve derivatives of the general formula 3-substituted-6-chloroindoles were synthesized and tested for their growth inhibitory effects versus p53(+/+) colorectal cancer HCT116 and its p53 knockout isogenic cells; colorectal cancer cell p53(-/-) SW480; the lung cancer cell line p53(-/-) H1299; mouse embryonic fibroblasts (MEF) p53(+/+) and its p53 knockout isogenic cells. The compounds were also evaluated for their ability to induce p53 nuclear translocation and binding to murine double minute 2 (MDM2) and murine double minute 4 (MDM4). Of these, compound 5a was the most active in inhibiting the growth of cells, with selectivity towards the p53(+/+) cell lines, and it showed stronger binding to MDM4 rather than MDM2. The activity profile of compound 5a is strongly similar to that of Nutlin-3.

Modulating the cyclic guanosine monophosphate substrate selectivity of the phosphodiesterase 3 inhibitors by pyridine, pyrido[2,3-d]pyrimidine derivatives and their effects upon the growth of HT-29 cancer cell line.

Analogues with the scaffolds of 3-cyano-4-alkoxyphenyl-6-bromoaryl-2-pyridone and 2-amino-3-cyano-4-alkoxyphenyl-6-bromoarylpyridine were synthesized. Cyclization of the 2-amino derivatives with formic acid and formamide gave the corresponding pyrido[2,3-d]pyrimidin-4(3H)-one and the pyrido[2,3-d]-pyrimidin-4-amine derivatives, respectively. Active phosphodiesterase 3 (PDE3) inhibitors were identified from each of the four aforementioned scaffolds. This is the first report that pyrido[2,3-d]pyrimidin-4(3H)-one and pyrido[2,3-d]pyrimidin-4-amine derivatives can inhibit PDE3. The analogues with the pyridone and pyrido[2,3-d]pyrimidin-4(3H)-one scaffolds inhibited both cAMP and cyclic guanosine monophosphate (cGMP) hydrolysis by PDE3, while the amine containing scaffolds were more selective for cGMP hydrolysis. This observation may set the base for substrate-selective pharmacological modulation of this important class of drug targets and with less side effects, particularly tachcardia. The dual inhibitors of PDE3 were more potent inhibitor towards the growth of HT-29 cancer cell lines.