HER2 overexpression is observed in ∼6-35% of all gastric cancers, while co-amplification of topoisomerase IIα occurs in ∼32-90% of all cancers with HER2 amplification. The present study reports that HER2 expression is down-regulated by A-62176, a fluoroquinophenoxazine derivative that we previously demonstrated to inhibit topoisomerase I and IIα. The results suggest that A-62176 inhibits the interaction between the ESX, an ets transcription factor, and its co-activator Sur2, leading to the attenuation of HER2-mediated phosphorylation of MAPK/Akt. A-62176 arrests the cell cycle in the G1 phase via the down-regulation of cyclin D1 and the up-regulation of p27(Kip1) in NCI-N87 gastric cancer cells. The combination of A-62176 with doxorubicin provides a strong synergistic activity. We propose that A-62176 is a dual inhibitor that impairs the expression of HER2 and restrains the activity of topoisomerase IIα. Our results may lead to the rational design of anticancer molecules targeting a subgroup of gastric cancer cells overexpressing both HER2 and topoisomerase IIα.

01 Feb 2008·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

New insight for fluoroquinophenoxazine derivatives as possibly new potent topoisomerase I inhibitor

Q4 · MEDICINE

Article

Author: Younghwa Na ; Jung Sook Kim ; Da Hye Kang ; Mi Ja Jung ; Yurngdong Jahng ; Youngjoo Kwon ; Eung Seok Lee

Fluoroquinolones, represented by ciproxacin and norfloxacin, are well-known clinical antimicrobial agents, and their phenyl ring expanded quinophenoxazines are reported as possible antitumor active compounds. These quinophenoxazines are known to inhibit DNA topoisomerase II essential for cell replication cycle. But there were no reports for topoisomerase I inhibition study for these compounds. In this report, we have prepared a few quinophenoxazine analogues and tested their topoisomerases I and II inhibitory activities and cytotoxicity. From the result, we found that quinophenoxazine analogues possessed strong topoisomerase I inhibitory capacity as well as topoisomerase II inhibition. Among the compounds prepared, A-62176 analogues showed strong topoisomerases I and II inhibitory activities. Interestingly, compound 8 missing the 3-aminopyrrolidine moiety at C2 position has similar potent inhibitory capacity against topoisomerases I and II at higher concentrations (20 and 10 microM, respectively). But compound 8 inhibited topoisomerase I function more selectively at lower concentration, 2 microM. Our observation might strongly implicate that fluoroquinophenoxazines can be developed as efficient topoisomerase I inhibitor with the elaborate modification.

01 Jan 2006·Chemical and Pharmaceutical BulletinQ4 · MEDICINE

Study on the Synthesis and Cytotoxicity of New Quinophenoxazine Derivatives

Q4 · MEDICINE

Article

Author: Kwon, Youngjoo ; Na, Younghwa

We have synthesized several new quinophenoxazine analogues and tested their cytotoxicity activities. The results showed that the compounds, 4a and 4b, possessing phenyl ring in the structure have almost same pharmacological capacity with A-62176. This finding suggests that the phenyl ring portion is important to this series of compounds for the activity expression.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Discovery	US	Abbott Laboratories (Philippines), Inc.	-

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