DNA and RNA Building Blocks: Useful Scaffolds for the Synthesis of New Phosphodiesterase Type 3 Inhibitor Hybrid Compounds

Phosphodiesterases (PDEs) are characterized based on their affinities for cAMP and cGMP, their sensitivities to specific inhibitors, their biochemical and physical properties and their biological regulatory pathways.1 Impaired cAMP and/or cGMP generation upon overexpression of PDE isoforms have been described in various cancer pathologies.2 Selective inhibition of PDE isoforms, which raises the levels of intracellular cAMP and/or cGMP, may regulate the tumor microenvironment and induce apoptosis and cell cycle arrest in a broad spectrum of tumor cells. Therefore, development and clinical application of inhibitors specific for individual PDE isoenzymes may selectively restore normal intracellular signaling and provide antitumor therapy with reduced adverse effects.3 Recent studies have shown that PDE3, PDE4 and PDE5 are overexpressed in cancer cells. In addition, inhibition of PDE3 along with other PDEs may lead to inhibition of tumor cell growth and angiogenesis.4 Herein, inspired by the chemical structure of Cilostazol, a commercially available PDE3 inhibitor that is used as a medicine for the treatment of heart failures, some hybrid structures of nucleobases and tetrazole were synthesized. The cytotoxic effects of synthesized compounds on HeLa and MCF-7 cell lines were determined using MTT assay. PDE3 inhibitory effect of synthesized compounds was analyzed using an IMAP TR-FRET phosphodiesterase assay kit and cAMP as the substrate.

Keywords:

nucleobase , molecular hybridization , phosphodiesterase type 3 , anticancer agent