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

Kang, Da Hye; Kim, Jung Sook; Jung, Mi Ja; Lee, Eung Seok; Jahng, Yurngdong; Kwon, Young Joo; Na, Younghwa

doi:10.1016/j.bmcl.2007.12.053

Cited by 49 publications

(12 citation statements)

References 16 publications

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“…The experiments were performed as described previously [24]. The cancer cells were cultured according to the supplier's instructions.…”

Section: Biological Assaysmentioning

confidence: 99%

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Synthesis, biological evaluation, and molecular docking study of 3-(3′-heteroatom substituted-2′-hydroxy-1′-propyloxy) xanthone analogues as novel topoisomerase IIα catalytic inhibitor

Jun¹,

Lee²,

Jung³

et al. 2011

European Journal of Medicinal Chemistry

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“…The experiments were performed as described previously [24]. The cancer cells were cultured according to the supplier's instructions.…”

Section: Biological Assaysmentioning

confidence: 99%

“…The DNA topo I inhibition assay was performed as described previously with minor modifications [24]. The DNA topo I activity was determined by assessing the relaxation of supercoiled DNA pBR322.…”

Section: Biological Assaysmentioning

confidence: 99%

Synthesis, biological evaluation, and molecular docking study of 3-(3′-heteroatom substituted-2′-hydroxy-1′-propyloxy) xanthone analogues as novel topoisomerase IIα catalytic inhibitor

Jun¹,

Lee²,

Jung³

et al. 2011

European Journal of Medicinal Chemistry

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“…Cytotoxicities of compounds prepared were screened by the method previously reported (Kang et al, 2008) against selected human cancer cell lines: HeLa (human cervix tumor), HCT-116 (human colon tumor), DU-145 (human prostate tumor), MDA-MB231 (human breast tumor), and HL-60 (human myeloid leukemic tumor) cell lines. As shown in Table II, IC 50 values of compound 6 and its methylated analogues were ranged from 25.78 µM to more than 100 µM against HCT-116, DU-145, and MDA-MB231 while no cytotoxicity was observed for HeLa and HL-60 up to 100 µM.…”

Section: Cytotoxicitymentioning

confidence: 99%

2,2-dimethyl-2H-pyran-derived alkaloids I. Practical synthesis of acronycine and benzo[b]acronycine and their biological properties

et al. 2008

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The 2,2-dimethyl-2H-pyran-derived alkaloids acronycine and its demethylated congeners were prepared in three steps from anthranilic acid and phloroglucinol. The phenylboronic acid-mediated interamolecular cyclization reaction of 1,3-dihydroxyacridone and 3-methylbut-2-enal was employed as a key step, which was also applied to the synthesis of related cytotoxic benzo[b]acronycine. Inhibitory activities of the compounds prepared on topoisomerase I and II as well as their cytotoxicities were evaluated. Cytotoxicity of 2 is closely related to the strong inhibitory activity against topo II at 20 microM level.

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“…Specifically, fluoroquinophenoxazines such as A-62176 and A-85226 (Fig. 1) have been reported as antibacterial [11, 12] and anticancer [13–16] agents. For example, A-62176 exhibited good activity against several cancer cell lines with IC 50 values ranging from 0.87–4.34 µM [13].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, evaluation, and CoMFA study of fluoroquinophenoxazine derivatives as bacterial topoisomerase IA inhibitors

Zhang

Annamalai

et al. 2017

European Journal of Medicinal Chemistry

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New antibacterial agents with novel target and mechanism of action are urgently needed to combat problematic bacterial infections and mounting antibiotic resistances. Topoisomerase IA represents an attractive and underexplored antibacterial target, as such, there is a growing interest in developing selective and potent topoisomerase I inhibitors for antibacterial therapy. Based on our initial biological screening, fluoroquinophenoxazine 1 was discovered as a low micromolar inhibitor against E. coli topoisomerase IA. In the literature, fluoroquinophenoxazine analogs have been investigated as antibacterial and anticancer agents, however, their topoisomerase I inhibition was relatively underexplored and there is little structure-activity relationship (SAR) available. The good topoisomerase I inhibitory activity of 1 and the lack of SAR prompted us to design and synthesize a series of fluoroquinophenoxazine analogs to systematically evaluate the SAR and to probe the structural elements of the fluoroquinophenoxazine core toward topoisomerase I enzyme target recognition. In this study, a series of fluoroquinophenoxazine analogs was designed, synthesized, and evaluated as topoisomerase I inhibitors and antibacterial agents. Target-based assays revealed that the fluoroquinophenoxazine derivatives with 9-NH2 and/or 6-substituted amine functionalities generally exhibited good to excellent inhibitory activities against topoisomerase I with IC50s ranging from 0.24–3.9 µM. Notably, 11a bearing the 6-methylpiperazinyl and 9-amino motifs was identified as one of the most potent topoisomerase I inhibitors (IC50 = 0.48 µM), and showed broad spectrum antibacterial activity (MICs = 0.78–7.6 µM) against all the bacteria strains tested. Compound 11g with the 6-bipiperidinyl lipophilic side chain exhibited the most potent antituberculosis activity (MIC = 2.5 µM, SI = 9.8). In addition, CoMFA analysis was performed to investigate the 3D-QSAR of this class of fluoroquinophenoxazine derivatives. The constructed CoMFA model produced reasonable statistics (q2 = 0.688 and r2 = 0.806). The predictive power of the developed model was obtained using a test set of 7 compounds, giving a predictive correlation coefficient r2pred of 0.767. Collectively, these promising data demonstrated that fluoroquinophenoxazine derivatives have the potential to be developed as a new chemotype of potent topoisomerase IA inhibitors with antibacterial therapeutic potential.

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

Cited by 49 publications

References 16 publications

Synthesis, biological evaluation, and molecular docking study of 3-(3′-heteroatom substituted-2′-hydroxy-1′-propyloxy) xanthone analogues as novel topoisomerase IIα catalytic inhibitor

Synthesis, biological evaluation, and molecular docking study of 3-(3′-heteroatom substituted-2′-hydroxy-1′-propyloxy) xanthone analogues as novel topoisomerase IIα catalytic inhibitor

2,2-dimethyl-2H-pyran-derived alkaloids I. Practical synthesis of acronycine and benzo[b]acronycine and their biological properties

Synthesis, evaluation, and CoMFA study of fluoroquinophenoxazine derivatives as bacterial topoisomerase IA inhibitors

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