Design and synthesis of fluoroquinophenoxazines that interact with human telomeric g-quadruplexes and their biological effects

Wenhu Duan, Anupama Rangan, Hariprasad Vankayalapati, Mu Yong Kim, Qingping Zeng, Daekyu Sun, Haiyong Han, Oleg Yu Fedoroff, David Nishioka, Sun Young Rha, Elzbieta Izbicka, Daniel D. Von Hoff, Laurence Hurley

Research output: Contribution to journalArticle

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Abstract

In this study we have identified a new structural motif for a ligand with G-quadruplex interaction that results in biological effects associated with G-quadruplex-interactive compounds. Fluoroquinolones have been reported to possess weak telomerase inhibitory activity in addition to their better known bacterial gyrase poisoning. Starting with a fluoroquinobenzoxazine, which has modest potency in a human topoisomerase II assay, we have designed a more potent inhibitor of telomerase that has lost its topoisomerase II poisoning activity. This fluoroquinophenoxazine (FQP) interacts with G-quadruplex structures to inhibit the progression of Taq polymerase in a G-quadruplex polymerase stop assay. In addition, we demonstrate by 1H NMR studies that this compound interacts with telomeric G-quadruplex structures by external stacking to the G-tetrad with both the unimolecular fold-over and the parallel G-quadruplex structures. A photocleavage assay confirms the FQP interaction site, which is located off center of the external tetrad but within the loop region. Molecular modeling using simulated annealing was performed on the FQP-parallel G-quadruplex complex to determine the optimum FQP orientation and key molecular interactions with the telomeric G-quadruplex structure. On the basis of the results of these studies, two additional FQP analogues were synthesized, which were designed to test the importance of these key interactions. These analogues were evaluated in the Taq polymerase stop assay for G-quadruplex interaction. The data from this study and the biological evaluation of these three FQPs, using cytotoxicity and a sea urchin embryo system, were in accord with the predicted more potent telomeric G-quadruplex interactions of the initial lead compound and one of the analogues. On the basis of these structural and biological studies, the design of more potent and selective telomeric G-quadruplex-interactive compounds can be envisaged.

Original languageEnglish (US)
Pages (from-to)103-120
Number of pages18
JournalMolecular Cancer Therapeutics
Volume1
Issue number2
StatePublished - Dec 2001

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G-Quadruplexes
Taq Polymerase
Type II DNA Topoisomerase
Telomerase
Poisoning
Sea Urchins
Fluoroquinolones
Embryonic Structures

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Drug Discovery
  • Pharmacology

Cite this

Design and synthesis of fluoroquinophenoxazines that interact with human telomeric g-quadruplexes and their biological effects. / Duan, Wenhu; Rangan, Anupama; Vankayalapati, Hariprasad; Kim, Mu Yong; Zeng, Qingping; Sun, Daekyu; Han, Haiyong; Fedoroff, Oleg Yu; Nishioka, David; Rha, Sun Young; Izbicka, Elzbieta; Von Hoff, Daniel D.; Hurley, Laurence.

In: Molecular Cancer Therapeutics, Vol. 1, No. 2, 12.2001, p. 103-120.

Research output: Contribution to journalArticle

Duan, W, Rangan, A, Vankayalapati, H, Kim, MY, Zeng, Q, Sun, D, Han, H, Fedoroff, OY, Nishioka, D, Rha, SY, Izbicka, E, Von Hoff, DD & Hurley, L 2001, 'Design and synthesis of fluoroquinophenoxazines that interact with human telomeric g-quadruplexes and their biological effects', Molecular Cancer Therapeutics, vol. 1, no. 2, pp. 103-120.
Duan, Wenhu ; Rangan, Anupama ; Vankayalapati, Hariprasad ; Kim, Mu Yong ; Zeng, Qingping ; Sun, Daekyu ; Han, Haiyong ; Fedoroff, Oleg Yu ; Nishioka, David ; Rha, Sun Young ; Izbicka, Elzbieta ; Von Hoff, Daniel D. ; Hurley, Laurence. / Design and synthesis of fluoroquinophenoxazines that interact with human telomeric g-quadruplexes and their biological effects. In: Molecular Cancer Therapeutics. 2001 ; Vol. 1, No. 2. pp. 103-120.
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AU - Kim, Mu Yong

AU - Zeng, Qingping

AU - Sun, Daekyu

AU - Han, Haiyong

AU - Fedoroff, Oleg Yu

AU - Nishioka, David

AU - Rha, Sun Young

AU - Izbicka, Elzbieta

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AU - Hurley, Laurence

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N2 - In this study we have identified a new structural motif for a ligand with G-quadruplex interaction that results in biological effects associated with G-quadruplex-interactive compounds. Fluoroquinolones have been reported to possess weak telomerase inhibitory activity in addition to their better known bacterial gyrase poisoning. Starting with a fluoroquinobenzoxazine, which has modest potency in a human topoisomerase II assay, we have designed a more potent inhibitor of telomerase that has lost its topoisomerase II poisoning activity. This fluoroquinophenoxazine (FQP) interacts with G-quadruplex structures to inhibit the progression of Taq polymerase in a G-quadruplex polymerase stop assay. In addition, we demonstrate by 1H NMR studies that this compound interacts with telomeric G-quadruplex structures by external stacking to the G-tetrad with both the unimolecular fold-over and the parallel G-quadruplex structures. A photocleavage assay confirms the FQP interaction site, which is located off center of the external tetrad but within the loop region. Molecular modeling using simulated annealing was performed on the FQP-parallel G-quadruplex complex to determine the optimum FQP orientation and key molecular interactions with the telomeric G-quadruplex structure. On the basis of the results of these studies, two additional FQP analogues were synthesized, which were designed to test the importance of these key interactions. These analogues were evaluated in the Taq polymerase stop assay for G-quadruplex interaction. The data from this study and the biological evaluation of these three FQPs, using cytotoxicity and a sea urchin embryo system, were in accord with the predicted more potent telomeric G-quadruplex interactions of the initial lead compound and one of the analogues. On the basis of these structural and biological studies, the design of more potent and selective telomeric G-quadruplex-interactive compounds can be envisaged.

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