A series of seventeen 1,8-naphthyridine derivatives (5a-5q) conjugated at N 1 to various substituted phenyl rings were designed and synthesized as potential topoisomerase II (Topo II) inhibitors. The antiproliferative activity of the target compounds against three cancer cell lines showed that compounds 5g and 5p had the highest antiproliferative activity. In addition, 5p and 5g displayed a high selectivity index (SI) for cancer cells when tested on WI38 normal cells, whereby compound 5p showed the highest SI. Furthermore, 5g and 5p induced cell cycle arrest at the S and G1/S phases, respectively, triggering apoptosis in HepG-2 cells.The in vitro Topo II inhibitory effect (plasmid-based) of both compounds revealed that 5p had better inhibition of Topo II. In addition, 5p displayed potent topoisomerase IIβ inhibitory effect when compared to known topoisomerase inhibitors (doxorubicin and topotecan). Molecular docking proposed a unique binding pattern of 5p in the etoposide binding pocket of topoisomerase IIβ, endorsing its potential role as a Topo II poison. Accordingly, 5p was chosen for radioiodination to study the degree of tumor localization following administration in solid tumor-bearing mice. The radioiodinated 5p showed a selective localization at the tumor site, which further confirmed the value of 5p as a lead 1,8-naphthyridine anticancer agent.

This review focuses on the potential of 1,8-Naphthyridine derivativesinchemotherapeuticcancer treatment and highlights significant recent progress in the synthetic development of 1,8-naphthyridines as antitumor agents. The present review provides the classical (Skraup, Doebner-Von-Miller, Gould-Jacob, Meth-Cohn, Friedlander, Pfitzinger, Knorr and Conard Limpach, Combes, Niementowski and Pictet-Spengler)and green approaches (metal free ionic liquid mediated reactions, microwave irradiation reactions) for 1,8-naphthyridines synthesis. Their derivatives which exert their anticancer activity via several mechanismslike apoptosis-inducing agents, cell cycle arrest, topoisomerase I and II inhibitors, tubulin polymerization inhibitors, protein kinase inhibitors, intercalation with DNA, angiogenesis inhibitors, Ras protein inhibitors and telomerase inhibitors, are highlighted with proper synthetic methods, SAR studies and molecular docking of these derivatives.

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