Current Drug Targets

Francis J. Castellino
Kleiderer-Pezold Professor of Biochemistry
Director, W.M. Keck Center for Transgene Research
Dean Emeritus, College of Science
230 Raclin-Carmichael Hall, University of Notre Dame
Notre Dame, IN 46556
USA

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Fused Aryl-Phenazines: Scaffold for the Development of Bioactive Molecules

Author(s): N.S. Hari Narayana Moorthy, Vijayakumari Pratheepa, Maria J. Ramos, Vitor Vasconcelos and Pedro A. Fernandes

Affiliation: REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, s/n, Rua do Campo Alegre, 4169-007 Porto, Portugal.

Keywords: Anticancer, benzo[a]phenazine, DNA intercalation, phenazine, topoisomerases.

Abstract:

Fused aryl phenazine derivatives (benzo[a]phenazine, pyrido[a]phenazine, benzo[a]phenazine diones, tetrahydropyrido[ a]phenazine (dermacozines), etc) are important heterocyclic compounds, which exhibit various pharmacological activities, prominently in cancer cell lines. These compounds significantly intercalate between DNA base pairs and inhibit the activities of topoisomerase I and II enzymes (Topo I and II). XR11576, XR5944, NC-190 and NC-182 belong to phenazine/fused aryl phenazine category and are under clinical studies. Several fused aryl phenazine dione compounds such as pyridazino[4,5-b]phenazine-5,12-diones, 6,11-dihydro-pyrido[2,3-b]phenazine-6,11-diones, 6,11-dihydrobenzo[ 2,3-b]phenazine-6,11-diones, tetrahydropyrido[a]phenazine, etc possessed anticancer activities on various cancer cell lines. Benzo[a]phenazine diimine and various other fused aryl phenazine compounds form coordination complex with the metal ions (Ru, Rh, Zn and Pt) that intercalate with the DNA and are used for the treatment of cancer. These molecules have influence on MDR cancer cells and serve as anticancer agents in MDR cancer cells. The structure activity relationship of the fused aryl phenazine derivatives revealed that the occurrence of four or more nitrogen atoms in the compounds has better anticancer activity than those molecules with less number of nitrogen atoms. Phenazine antibiotics derived from marine microbes are used for the treatment of microbial and worm diseases. Recent patents on these scaffolds showed that the benzo[a]phenazine derivatives have inhibitory activity on topoisomerase enzymes (Topo I and II) and that act as anticancer agents.

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Article Details

VOLUME: 15
ISSUE: 7
Page: [681 - 688]
Pages: 8
DOI: 10.2174/1389450115666140205152007