2,2′-Dihydroxybenzophenones and their carbonyl N-analogues as inhibitor scaffolds for MDR-involved human glutathione transferase isoenzyme A1-1
Abstract The MDR-involved human GSTA1-1, an important isoenzyme overexpressed in several tumors leading to chemotherapeutic-resistant tumour cells, has been targeted by 2,2′-dihydroxybenzophenones and some of their carbonyl N-analogues, as its potential inhibitors. A structure-based library of the l...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Perperopoulou, Fereniki D. [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2014transfer abstract |
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| Schlagwörter: |
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| Umfang: |
14 |
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| Übergeordnetes Werk: |
Enthalten in: A theoretical model of cyberchondria development: Antecedents and intermediate processes - Zheng, Han ELSEVIER, 2021, a Tetrahedron publication for the rapid dissemination of full original research papers and critical reviews on bioorganic chemistry, medicinal chemistry, bioinorganic chemistry and related disciplines, Amsterdam [u.a.] |
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| Übergeordnetes Werk: |
volume:22 ; year:2014 ; number:15 ; day:1 ; month:08 ; pages:3957-3970 ; extent:14 |
| Links: |
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| DOI / URN: |
10.1016/j.bmc.2014.06.007 |
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ELV017786487 |
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| 245 | 1 | 0 | |a 2,2′-Dihydroxybenzophenones and their carbonyl N-analogues as inhibitor scaffolds for MDR-involved human glutathione transferase isoenzyme A1-1 |
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| 520 | |a Abstract The MDR-involved human GSTA1-1, an important isoenzyme overexpressed in several tumors leading to chemotherapeutic-resistant tumour cells, has been targeted by 2,2′-dihydroxybenzophenones and some of their carbonyl N-analogues, as its potential inhibitors. A structure-based library of the latter was built-up by a nucleophilic cleavage of suitably substituted xanthones to 2,2′-dihydroxy-benzophenones (5–9) and subsequent formation of their N-derivatives (oximes 11–13 and N-acyl hydrazones 14–16). Screening against hGSTA1-1 led to benzophenones 6 and 8, and hydrazones 14 and 16, having the highest inhibition potency (IC50 values in the range 0.18±0.02 to 1.77±0.10μM). Enzyme inhibition kinetics, molecular modeling and docking studies showed that they interact primarily at the CDNB-binding catalytic site of the enzyme. In addition, the results from cytotoxicity studies with human colon adenocarcinoma cells showed low LC50 values for benzophenone 6 and its N-acyl hydrazone analogue 14 (31.4±0.4μM and 87±1.9μM, respectively), in addition to the strong enzyme inhibition profile (IC50( 6 ) =1,77±0.10μM; IC50( 14 ) =0.33±0.05μM). These structures may serve as leads for the design of new potent mono- and bi-functional inhibitors and pro-drugs against human GTSs. | ||
| 520 | |a Abstract The MDR-involved human GSTA1-1, an important isoenzyme overexpressed in several tumors leading to chemotherapeutic-resistant tumour cells, has been targeted by 2,2′-dihydroxybenzophenones and some of their carbonyl N-analogues, as its potential inhibitors. A structure-based library of the latter was built-up by a nucleophilic cleavage of suitably substituted xanthones to 2,2′-dihydroxy-benzophenones (5–9) and subsequent formation of their N-derivatives (oximes 11–13 and N-acyl hydrazones 14–16). Screening against hGSTA1-1 led to benzophenones 6 and 8, and hydrazones 14 and 16, having the highest inhibition potency (IC50 values in the range 0.18±0.02 to 1.77±0.10μM). Enzyme inhibition kinetics, molecular modeling and docking studies showed that they interact primarily at the CDNB-binding catalytic site of the enzyme. In addition, the results from cytotoxicity studies with human colon adenocarcinoma cells showed low LC50 values for benzophenone 6 and its N-acyl hydrazone analogue 14 (31.4±0.4μM and 87±1.9μM, respectively), in addition to the strong enzyme inhibition profile (IC50( 6 ) =1,77±0.10μM; IC50( 14 ) =0.33±0.05μM). These structures may serve as leads for the design of new potent mono- and bi-functional inhibitors and pro-drugs against human GTSs. | ||
| 650 | 7 | |a hGSTA1-1 |2 Elsevier | |
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| 650 | 7 | |a MDR |2 Elsevier | |
| 650 | 7 | |a SM |2 Elsevier | |
| 650 | 7 | |a GSH |2 Elsevier | |
| 700 | 1 | |a Tsoungas, Petros G. |4 oth | |
| 700 | 1 | |a Thireou, Trias N. |4 oth | |
| 700 | 1 | |a Rinotas, Vagelis E. |4 oth | |
| 700 | 1 | |a Douni, Eleni K. |4 oth | |
| 700 | 1 | |a Eliopoulos, Elias E. |4 oth | |
| 700 | 1 | |a Labrou, Nikolaos E. |4 oth | |
| 700 | 1 | |a Clonis, Yannis D. |4 oth | |
| 773 | 0 | 8 | |i Enthalten in |n Elsevier |a Zheng, Han ELSEVIER |t A theoretical model of cyberchondria development: Antecedents and intermediate processes |d 2021 |d a Tetrahedron publication for the rapid dissemination of full original research papers and critical reviews on bioorganic chemistry, medicinal chemistry, bioinorganic chemistry and related disciplines |g Amsterdam [u.a.] |w (DE-627)ELV006510728 |
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10.1016/j.bmc.2014.06.007 doi GBVA2014016000015.pica (DE-627)ELV017786487 (ELSEVIER)S0968-0896(14)00453-2 DE-627 ger DE-627 rakwb eng 540 610 540 DE-600 610 DE-600 004 VZ 53.70 bkl 05.42 bkl 53.76 bkl 54.00 bkl Perperopoulou, Fereniki D. verfasserin aut 2,2′-Dihydroxybenzophenones and their carbonyl N-analogues as inhibitor scaffolds for MDR-involved human glutathione transferase isoenzyme A1-1 2014transfer abstract 14 nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Abstract The MDR-involved human GSTA1-1, an important isoenzyme overexpressed in several tumors leading to chemotherapeutic-resistant tumour cells, has been targeted by 2,2′-dihydroxybenzophenones and some of their carbonyl N-analogues, as its potential inhibitors. A structure-based library of the latter was built-up by a nucleophilic cleavage of suitably substituted xanthones to 2,2′-dihydroxy-benzophenones (5–9) and subsequent formation of their N-derivatives (oximes 11–13 and N-acyl hydrazones 14–16). Screening against hGSTA1-1 led to benzophenones 6 and 8, and hydrazones 14 and 16, having the highest inhibition potency (IC50 values in the range 0.18±0.02 to 1.77±0.10μM). Enzyme inhibition kinetics, molecular modeling and docking studies showed that they interact primarily at the CDNB-binding catalytic site of the enzyme. In addition, the results from cytotoxicity studies with human colon adenocarcinoma cells showed low LC50 values for benzophenone 6 and its N-acyl hydrazone analogue 14 (31.4±0.4μM and 87±1.9μM, respectively), in addition to the strong enzyme inhibition profile (IC50( 6 ) =1,77±0.10μM; IC50( 14 ) =0.33±0.05μM). These structures may serve as leads for the design of new potent mono- and bi-functional inhibitors and pro-drugs against human GTSs. Abstract The MDR-involved human GSTA1-1, an important isoenzyme overexpressed in several tumors leading to chemotherapeutic-resistant tumour cells, has been targeted by 2,2′-dihydroxybenzophenones and some of their carbonyl N-analogues, as its potential inhibitors. A structure-based library of the latter was built-up by a nucleophilic cleavage of suitably substituted xanthones to 2,2′-dihydroxy-benzophenones (5–9) and subsequent formation of their N-derivatives (oximes 11–13 and N-acyl hydrazones 14–16). Screening against hGSTA1-1 led to benzophenones 6 and 8, and hydrazones 14 and 16, having the highest inhibition potency (IC50 values in the range 0.18±0.02 to 1.77±0.10μM). Enzyme inhibition kinetics, molecular modeling and docking studies showed that they interact primarily at the CDNB-binding catalytic site of the enzyme. In addition, the results from cytotoxicity studies with human colon adenocarcinoma cells showed low LC50 values for benzophenone 6 and its N-acyl hydrazone analogue 14 (31.4±0.4μM and 87±1.9μM, respectively), in addition to the strong enzyme inhibition profile (IC50( 6 ) =1,77±0.10μM; IC50( 14 ) =0.33±0.05μM). These structures may serve as leads for the design of new potent mono- and bi-functional inhibitors and pro-drugs against human GTSs. hGSTA1-1 Elsevier Caco-2 Elsevier DMSO Elsevier IPTG Elsevier GST Elsevier CDNB Elsevier MDR Elsevier SM Elsevier GSH Elsevier Tsoungas, Petros G. oth Thireou, Trias N. oth Rinotas, Vagelis E. oth Douni, Eleni K. oth Eliopoulos, Elias E. oth Labrou, Nikolaos E. oth Clonis, Yannis D. oth Enthalten in Elsevier Zheng, Han ELSEVIER A theoretical model of cyberchondria development: Antecedents and intermediate processes 2021 a Tetrahedron publication for the rapid dissemination of full original research papers and critical reviews on bioorganic chemistry, medicinal chemistry, bioinorganic chemistry and related disciplines Amsterdam [u.a.] (DE-627)ELV006510728 volume:22 year:2014 number:15 day:1 month:08 pages:3957-3970 extent:14 https://doi.org/10.1016/j.bmc.2014.06.007 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U 53.70 Nachrichtentechnik Kommunikationstechnik: Allgemeines VZ 05.42 Telekommunikation VZ 53.76 Kommunikationsdienste Fernmeldetechnik VZ 54.00 Informatik: Allgemeines VZ AR 22 2014 15 1 0801 3957-3970 14 045F 540 |
| spelling |
10.1016/j.bmc.2014.06.007 doi GBVA2014016000015.pica (DE-627)ELV017786487 (ELSEVIER)S0968-0896(14)00453-2 DE-627 ger DE-627 rakwb eng 540 610 540 DE-600 610 DE-600 004 VZ 53.70 bkl 05.42 bkl 53.76 bkl 54.00 bkl Perperopoulou, Fereniki D. verfasserin aut 2,2′-Dihydroxybenzophenones and their carbonyl N-analogues as inhibitor scaffolds for MDR-involved human glutathione transferase isoenzyme A1-1 2014transfer abstract 14 nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Abstract The MDR-involved human GSTA1-1, an important isoenzyme overexpressed in several tumors leading to chemotherapeutic-resistant tumour cells, has been targeted by 2,2′-dihydroxybenzophenones and some of their carbonyl N-analogues, as its potential inhibitors. A structure-based library of the latter was built-up by a nucleophilic cleavage of suitably substituted xanthones to 2,2′-dihydroxy-benzophenones (5–9) and subsequent formation of their N-derivatives (oximes 11–13 and N-acyl hydrazones 14–16). Screening against hGSTA1-1 led to benzophenones 6 and 8, and hydrazones 14 and 16, having the highest inhibition potency (IC50 values in the range 0.18±0.02 to 1.77±0.10μM). Enzyme inhibition kinetics, molecular modeling and docking studies showed that they interact primarily at the CDNB-binding catalytic site of the enzyme. In addition, the results from cytotoxicity studies with human colon adenocarcinoma cells showed low LC50 values for benzophenone 6 and its N-acyl hydrazone analogue 14 (31.4±0.4μM and 87±1.9μM, respectively), in addition to the strong enzyme inhibition profile (IC50( 6 ) =1,77±0.10μM; IC50( 14 ) =0.33±0.05μM). These structures may serve as leads for the design of new potent mono- and bi-functional inhibitors and pro-drugs against human GTSs. Abstract The MDR-involved human GSTA1-1, an important isoenzyme overexpressed in several tumors leading to chemotherapeutic-resistant tumour cells, has been targeted by 2,2′-dihydroxybenzophenones and some of their carbonyl N-analogues, as its potential inhibitors. A structure-based library of the latter was built-up by a nucleophilic cleavage of suitably substituted xanthones to 2,2′-dihydroxy-benzophenones (5–9) and subsequent formation of their N-derivatives (oximes 11–13 and N-acyl hydrazones 14–16). Screening against hGSTA1-1 led to benzophenones 6 and 8, and hydrazones 14 and 16, having the highest inhibition potency (IC50 values in the range 0.18±0.02 to 1.77±0.10μM). Enzyme inhibition kinetics, molecular modeling and docking studies showed that they interact primarily at the CDNB-binding catalytic site of the enzyme. In addition, the results from cytotoxicity studies with human colon adenocarcinoma cells showed low LC50 values for benzophenone 6 and its N-acyl hydrazone analogue 14 (31.4±0.4μM and 87±1.9μM, respectively), in addition to the strong enzyme inhibition profile (IC50( 6 ) =1,77±0.10μM; IC50( 14 ) =0.33±0.05μM). These structures may serve as leads for the design of new potent mono- and bi-functional inhibitors and pro-drugs against human GTSs. hGSTA1-1 Elsevier Caco-2 Elsevier DMSO Elsevier IPTG Elsevier GST Elsevier CDNB Elsevier MDR Elsevier SM Elsevier GSH Elsevier Tsoungas, Petros G. oth Thireou, Trias N. oth Rinotas, Vagelis E. oth Douni, Eleni K. oth Eliopoulos, Elias E. oth Labrou, Nikolaos E. oth Clonis, Yannis D. oth Enthalten in Elsevier Zheng, Han ELSEVIER A theoretical model of cyberchondria development: Antecedents and intermediate processes 2021 a Tetrahedron publication for the rapid dissemination of full original research papers and critical reviews on bioorganic chemistry, medicinal chemistry, bioinorganic chemistry and related disciplines Amsterdam [u.a.] (DE-627)ELV006510728 volume:22 year:2014 number:15 day:1 month:08 pages:3957-3970 extent:14 https://doi.org/10.1016/j.bmc.2014.06.007 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U 53.70 Nachrichtentechnik Kommunikationstechnik: Allgemeines VZ 05.42 Telekommunikation VZ 53.76 Kommunikationsdienste Fernmeldetechnik VZ 54.00 Informatik: Allgemeines VZ AR 22 2014 15 1 0801 3957-3970 14 045F 540 |
| allfields_unstemmed |
10.1016/j.bmc.2014.06.007 doi GBVA2014016000015.pica (DE-627)ELV017786487 (ELSEVIER)S0968-0896(14)00453-2 DE-627 ger DE-627 rakwb eng 540 610 540 DE-600 610 DE-600 004 VZ 53.70 bkl 05.42 bkl 53.76 bkl 54.00 bkl Perperopoulou, Fereniki D. verfasserin aut 2,2′-Dihydroxybenzophenones and their carbonyl N-analogues as inhibitor scaffolds for MDR-involved human glutathione transferase isoenzyme A1-1 2014transfer abstract 14 nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Abstract The MDR-involved human GSTA1-1, an important isoenzyme overexpressed in several tumors leading to chemotherapeutic-resistant tumour cells, has been targeted by 2,2′-dihydroxybenzophenones and some of their carbonyl N-analogues, as its potential inhibitors. A structure-based library of the latter was built-up by a nucleophilic cleavage of suitably substituted xanthones to 2,2′-dihydroxy-benzophenones (5–9) and subsequent formation of their N-derivatives (oximes 11–13 and N-acyl hydrazones 14–16). Screening against hGSTA1-1 led to benzophenones 6 and 8, and hydrazones 14 and 16, having the highest inhibition potency (IC50 values in the range 0.18±0.02 to 1.77±0.10μM). Enzyme inhibition kinetics, molecular modeling and docking studies showed that they interact primarily at the CDNB-binding catalytic site of the enzyme. In addition, the results from cytotoxicity studies with human colon adenocarcinoma cells showed low LC50 values for benzophenone 6 and its N-acyl hydrazone analogue 14 (31.4±0.4μM and 87±1.9μM, respectively), in addition to the strong enzyme inhibition profile (IC50( 6 ) =1,77±0.10μM; IC50( 14 ) =0.33±0.05μM). These structures may serve as leads for the design of new potent mono- and bi-functional inhibitors and pro-drugs against human GTSs. Abstract The MDR-involved human GSTA1-1, an important isoenzyme overexpressed in several tumors leading to chemotherapeutic-resistant tumour cells, has been targeted by 2,2′-dihydroxybenzophenones and some of their carbonyl N-analogues, as its potential inhibitors. A structure-based library of the latter was built-up by a nucleophilic cleavage of suitably substituted xanthones to 2,2′-dihydroxy-benzophenones (5–9) and subsequent formation of their N-derivatives (oximes 11–13 and N-acyl hydrazones 14–16). Screening against hGSTA1-1 led to benzophenones 6 and 8, and hydrazones 14 and 16, having the highest inhibition potency (IC50 values in the range 0.18±0.02 to 1.77±0.10μM). Enzyme inhibition kinetics, molecular modeling and docking studies showed that they interact primarily at the CDNB-binding catalytic site of the enzyme. In addition, the results from cytotoxicity studies with human colon adenocarcinoma cells showed low LC50 values for benzophenone 6 and its N-acyl hydrazone analogue 14 (31.4±0.4μM and 87±1.9μM, respectively), in addition to the strong enzyme inhibition profile (IC50( 6 ) =1,77±0.10μM; IC50( 14 ) =0.33±0.05μM). These structures may serve as leads for the design of new potent mono- and bi-functional inhibitors and pro-drugs against human GTSs. hGSTA1-1 Elsevier Caco-2 Elsevier DMSO Elsevier IPTG Elsevier GST Elsevier CDNB Elsevier MDR Elsevier SM Elsevier GSH Elsevier Tsoungas, Petros G. oth Thireou, Trias N. oth Rinotas, Vagelis E. oth Douni, Eleni K. oth Eliopoulos, Elias E. oth Labrou, Nikolaos E. oth Clonis, Yannis D. oth Enthalten in Elsevier Zheng, Han ELSEVIER A theoretical model of cyberchondria development: Antecedents and intermediate processes 2021 a Tetrahedron publication for the rapid dissemination of full original research papers and critical reviews on bioorganic chemistry, medicinal chemistry, bioinorganic chemistry and related disciplines Amsterdam [u.a.] (DE-627)ELV006510728 volume:22 year:2014 number:15 day:1 month:08 pages:3957-3970 extent:14 https://doi.org/10.1016/j.bmc.2014.06.007 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U 53.70 Nachrichtentechnik Kommunikationstechnik: Allgemeines VZ 05.42 Telekommunikation VZ 53.76 Kommunikationsdienste Fernmeldetechnik VZ 54.00 Informatik: Allgemeines VZ AR 22 2014 15 1 0801 3957-3970 14 045F 540 |
| allfieldsGer |
10.1016/j.bmc.2014.06.007 doi GBVA2014016000015.pica (DE-627)ELV017786487 (ELSEVIER)S0968-0896(14)00453-2 DE-627 ger DE-627 rakwb eng 540 610 540 DE-600 610 DE-600 004 VZ 53.70 bkl 05.42 bkl 53.76 bkl 54.00 bkl Perperopoulou, Fereniki D. verfasserin aut 2,2′-Dihydroxybenzophenones and their carbonyl N-analogues as inhibitor scaffolds for MDR-involved human glutathione transferase isoenzyme A1-1 2014transfer abstract 14 nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Abstract The MDR-involved human GSTA1-1, an important isoenzyme overexpressed in several tumors leading to chemotherapeutic-resistant tumour cells, has been targeted by 2,2′-dihydroxybenzophenones and some of their carbonyl N-analogues, as its potential inhibitors. A structure-based library of the latter was built-up by a nucleophilic cleavage of suitably substituted xanthones to 2,2′-dihydroxy-benzophenones (5–9) and subsequent formation of their N-derivatives (oximes 11–13 and N-acyl hydrazones 14–16). Screening against hGSTA1-1 led to benzophenones 6 and 8, and hydrazones 14 and 16, having the highest inhibition potency (IC50 values in the range 0.18±0.02 to 1.77±0.10μM). Enzyme inhibition kinetics, molecular modeling and docking studies showed that they interact primarily at the CDNB-binding catalytic site of the enzyme. In addition, the results from cytotoxicity studies with human colon adenocarcinoma cells showed low LC50 values for benzophenone 6 and its N-acyl hydrazone analogue 14 (31.4±0.4μM and 87±1.9μM, respectively), in addition to the strong enzyme inhibition profile (IC50( 6 ) =1,77±0.10μM; IC50( 14 ) =0.33±0.05μM). These structures may serve as leads for the design of new potent mono- and bi-functional inhibitors and pro-drugs against human GTSs. Abstract The MDR-involved human GSTA1-1, an important isoenzyme overexpressed in several tumors leading to chemotherapeutic-resistant tumour cells, has been targeted by 2,2′-dihydroxybenzophenones and some of their carbonyl N-analogues, as its potential inhibitors. A structure-based library of the latter was built-up by a nucleophilic cleavage of suitably substituted xanthones to 2,2′-dihydroxy-benzophenones (5–9) and subsequent formation of their N-derivatives (oximes 11–13 and N-acyl hydrazones 14–16). Screening against hGSTA1-1 led to benzophenones 6 and 8, and hydrazones 14 and 16, having the highest inhibition potency (IC50 values in the range 0.18±0.02 to 1.77±0.10μM). Enzyme inhibition kinetics, molecular modeling and docking studies showed that they interact primarily at the CDNB-binding catalytic site of the enzyme. In addition, the results from cytotoxicity studies with human colon adenocarcinoma cells showed low LC50 values for benzophenone 6 and its N-acyl hydrazone analogue 14 (31.4±0.4μM and 87±1.9μM, respectively), in addition to the strong enzyme inhibition profile (IC50( 6 ) =1,77±0.10μM; IC50( 14 ) =0.33±0.05μM). These structures may serve as leads for the design of new potent mono- and bi-functional inhibitors and pro-drugs against human GTSs. hGSTA1-1 Elsevier Caco-2 Elsevier DMSO Elsevier IPTG Elsevier GST Elsevier CDNB Elsevier MDR Elsevier SM Elsevier GSH Elsevier Tsoungas, Petros G. oth Thireou, Trias N. oth Rinotas, Vagelis E. oth Douni, Eleni K. oth Eliopoulos, Elias E. oth Labrou, Nikolaos E. oth Clonis, Yannis D. oth Enthalten in Elsevier Zheng, Han ELSEVIER A theoretical model of cyberchondria development: Antecedents and intermediate processes 2021 a Tetrahedron publication for the rapid dissemination of full original research papers and critical reviews on bioorganic chemistry, medicinal chemistry, bioinorganic chemistry and related disciplines Amsterdam [u.a.] (DE-627)ELV006510728 volume:22 year:2014 number:15 day:1 month:08 pages:3957-3970 extent:14 https://doi.org/10.1016/j.bmc.2014.06.007 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U 53.70 Nachrichtentechnik Kommunikationstechnik: Allgemeines VZ 05.42 Telekommunikation VZ 53.76 Kommunikationsdienste Fernmeldetechnik VZ 54.00 Informatik: Allgemeines VZ AR 22 2014 15 1 0801 3957-3970 14 045F 540 |
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2,2′-Dihydroxybenzophenones and their carbonyl N-analogues as inhibitor scaffolds for MDR-involved human glutathione transferase isoenzyme A1-1 |
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Abstract The MDR-involved human GSTA1-1, an important isoenzyme overexpressed in several tumors leading to chemotherapeutic-resistant tumour cells, has been targeted by 2,2′-dihydroxybenzophenones and some of their carbonyl N-analogues, as its potential inhibitors. A structure-based library of the latter was built-up by a nucleophilic cleavage of suitably substituted xanthones to 2,2′-dihydroxy-benzophenones (5–9) and subsequent formation of their N-derivatives (oximes 11–13 and N-acyl hydrazones 14–16). Screening against hGSTA1-1 led to benzophenones 6 and 8, and hydrazones 14 and 16, having the highest inhibition potency (IC50 values in the range 0.18±0.02 to 1.77±0.10μM). Enzyme inhibition kinetics, molecular modeling and docking studies showed that they interact primarily at the CDNB-binding catalytic site of the enzyme. In addition, the results from cytotoxicity studies with human colon adenocarcinoma cells showed low LC50 values for benzophenone 6 and its N-acyl hydrazone analogue 14 (31.4±0.4μM and 87±1.9μM, respectively), in addition to the strong enzyme inhibition profile (IC50( 6 ) =1,77±0.10μM; IC50( 14 ) =0.33±0.05μM). These structures may serve as leads for the design of new potent mono- and bi-functional inhibitors and pro-drugs against human GTSs. |
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Abstract The MDR-involved human GSTA1-1, an important isoenzyme overexpressed in several tumors leading to chemotherapeutic-resistant tumour cells, has been targeted by 2,2′-dihydroxybenzophenones and some of their carbonyl N-analogues, as its potential inhibitors. A structure-based library of the latter was built-up by a nucleophilic cleavage of suitably substituted xanthones to 2,2′-dihydroxy-benzophenones (5–9) and subsequent formation of their N-derivatives (oximes 11–13 and N-acyl hydrazones 14–16). Screening against hGSTA1-1 led to benzophenones 6 and 8, and hydrazones 14 and 16, having the highest inhibition potency (IC50 values in the range 0.18±0.02 to 1.77±0.10μM). Enzyme inhibition kinetics, molecular modeling and docking studies showed that they interact primarily at the CDNB-binding catalytic site of the enzyme. In addition, the results from cytotoxicity studies with human colon adenocarcinoma cells showed low LC50 values for benzophenone 6 and its N-acyl hydrazone analogue 14 (31.4±0.4μM and 87±1.9μM, respectively), in addition to the strong enzyme inhibition profile (IC50( 6 ) =1,77±0.10μM; IC50( 14 ) =0.33±0.05μM). These structures may serve as leads for the design of new potent mono- and bi-functional inhibitors and pro-drugs against human GTSs. |
| abstract_unstemmed |
Abstract The MDR-involved human GSTA1-1, an important isoenzyme overexpressed in several tumors leading to chemotherapeutic-resistant tumour cells, has been targeted by 2,2′-dihydroxybenzophenones and some of their carbonyl N-analogues, as its potential inhibitors. A structure-based library of the latter was built-up by a nucleophilic cleavage of suitably substituted xanthones to 2,2′-dihydroxy-benzophenones (5–9) and subsequent formation of their N-derivatives (oximes 11–13 and N-acyl hydrazones 14–16). Screening against hGSTA1-1 led to benzophenones 6 and 8, and hydrazones 14 and 16, having the highest inhibition potency (IC50 values in the range 0.18±0.02 to 1.77±0.10μM). Enzyme inhibition kinetics, molecular modeling and docking studies showed that they interact primarily at the CDNB-binding catalytic site of the enzyme. In addition, the results from cytotoxicity studies with human colon adenocarcinoma cells showed low LC50 values for benzophenone 6 and its N-acyl hydrazone analogue 14 (31.4±0.4μM and 87±1.9μM, respectively), in addition to the strong enzyme inhibition profile (IC50( 6 ) =1,77±0.10μM; IC50( 14 ) =0.33±0.05μM). These structures may serve as leads for the design of new potent mono- and bi-functional inhibitors and pro-drugs against human GTSs. |
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2,2′-Dihydroxybenzophenones and their carbonyl N-analogues as inhibitor scaffolds for MDR-involved human glutathione transferase isoenzyme A1-1 |
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Tsoungas, Petros G. Thireou, Trias N. Rinotas, Vagelis E. Douni, Eleni K. Eliopoulos, Elias E. Labrou, Nikolaos E. Clonis, Yannis D. |
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Tsoungas, Petros G. Thireou, Trias N. Rinotas, Vagelis E. Douni, Eleni K. Eliopoulos, Elias E. Labrou, Nikolaos E. Clonis, Yannis D. |
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| doi_str |
10.1016/j.bmc.2014.06.007 |
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2024-07-06T17:12:33.089Z |
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