Novel substituted 1,8‐naphthyridines: Design, synthesis, radiolabeling, and evaluation of apoptosis and topoisomerase II inhibition

• Published in: Archiv der Pharmazie (Weinheim) Vol. 356; no. 7; pp. e2300035 - n/a
• Main Authors: Abuzahra, Manar M., Ahmed, Nesreen S., Sarhan, Mona O., Mahgoub, Shahenda, Abdelhameed, Ahmed, Zaghary, Wafaa A.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01-07-2023
• Subjects: Animals; Antineoplastic Agents - chemistry; Apoptosis; biodistribution; Cell cycle; cell cycle arrest; Cell Line, Tumor; cytotoxic agents; DNA Topoisomerases, Type II - metabolism; docking; Drug Design; Iodine Radioisotopes - pharmacology; Localization; Mice; Molecular Docking Simulation; Molecular Structure; Naphthyridines - pharmacology; radiolabelling; Structure-Activity Relationship; Topoisomerase II Inhibitors; docking; cytotoxic agents; biodistribution; radiolabelling; cell cycle arrest
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.202300035

A series of seventeen 1,8‐naphthyridine derivatives (5a‐5q) conjugated at N1 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.
Among various N1‐substituted‐1,8‐naphthyridine derivatives, compounds 5g and 5p showed the highest cytotoxicity on cancer cells, with low toxicity on normal cells. 5g and 5p arrested the cell cycle with subsequent apoptosis and good inhibition of topoisomerase II. Furthermore, 131I‐5p showed high tumor localization when injected in solid tumor‐bearing mice.