The Experts below are selected from a list of 273 Experts worldwide ranked by ideXlab platform
Xiaohua Peng - One of the best experts on this subject based on the ideXlab platform.
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Substituents Have a Large Effect on Photochemical Generation of Benzyl Cations and DNA Cross-Linking.
Chemistry (Weinheim an der Bergstrasse Germany), 2018Co-Authors: Heli Fan, Huabing Sun, Xiaohua PengAbstract:Photoactivated DNA interstrand Cross-Linking agents have a wide range of biological applications. Recently, several aryl boronates have been reported to induce DNA interstrand Cross-link (ICL) formation via carbocations upon photoirradiation. Herein, we synthesized a series of new bifunctional phenyl compounds to test the generality of such a mechanism, and to understand how the chemical structure influences carbocation formation and the DNA Cross-Linking process. These compounds efficiently form DNA ICLs via generated benzyl cations upon 350 nm irradiation. The DNA Cross-Linking efficiency and the pathway for carbocation generation depend on both the aromatic substituents and the leaving groups. Bromine as a leaving group facilitates the DNA Cross-Linking process in comparison with trimethyl ammonium salt. Both electron-donating and -withdrawing substituents induce bathochromic shifts, which favor photoinduced DNA ICL formation. For the bromides, the benzyl cation intermediates were generated through oxidation of the corresponding benzyl radicals. However, for the ammonia salts, the benzyl cations were formed through two pathways: either through oxidation of the benzyl radicals or by direct heterolysis of the C-N bond. Photoinduced C-N homolysis to form benzyl radicals occurred with compounds having donating substituents, whereas direct heterolysis of the C-N bond occurred with those bearing withdrawing substituents. The adducts formed between 1 a and four natural nucleosides were characterized, indicating that the alkylation sites for the photogenerated benzyl cations are dG, dA, and dC.
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Reactive Oxygen Species (ROS) Inducible DNA Cross-Linking Agents and Their Effect on Cancer Cells and Normal Lymphocytes
2016Co-Authors: Xiaohua PengAbstract:ABSTRACT: Reducing host toxicity is one of the main challenges of cancer chemotherapy. Many tumor cells contain high levels of ROS that make them distinctively different from normal cells. We report a series of ROS-activated aromatic nitrogen mustards that selectively kill chronic lymphocytic leukemia (CLL) over normal lymphocytes. These agents showed powerful DNA Cross-Linking abilities when coupled with H2O2, one of the most common ROS in cancer cells, whereas little DNA Cross-Linking was detected without H2O2. Consistent with chemistry observation, in vitro cytotoxicity assay demonstrated that these agents induced 40−80 % apoptosis in primary leukemic lymphocytes isolated from CLL patients but less than 25 % cell death to normal lymphocytes from healthy donors. The IC50 for the most potent compound (2) was ∼5 μM in CLL cells, while the IC50 was not achieved in normal lymphocytes. Collectively, these data provide utility and selectivity of these agents that will inspire further and effective applications. Making use of the unique property of cancer cells is one of the most important avenues to design targeted anticancer drugs. Many types of cancer cells are under oxidative stress because of their disturbed intracellular redox balance, which makes the
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Chapter Six – Novel DNA Cross-Linking Reagents
Advances in Molecular Toxicology, 2016Co-Authors: Xiaohua PengAbstract:Abstract DNA interstrand Cross-links (ICLs) are the sources of the cytotoxicity of many anticancer agents. DNA Cross-Linking agents are used as anticancer agents, for DNA damage and repair study, for nucleic acid detection, and for construction of DNA nanomaterials. This chapter summarizes various novel methods and chemical reagents recently developed for inducing DNA ICL formation, the mechanisms involved for DNA Cross-Linking, and their applications. It starts by presenting photoinduced DNA ICL formation via [2+2] cycloaddition reaction, quinone methide, or carbocation formation. It then discusses novel DNA Cross-Linking agents activated by various chemical agents, including the arylboronate or boronic acid derivatives activated by hydrogen peroxide, silyl-protected bifunctional phenol derivatives triggered by fluoride, and phenyl selenides or furan analogs activated by oxidation reagents. General mechanisms involved formation of alkylating species, including quinone methide, nitrogen mustard, methide analogs, and enal formation. Enzyme-activated DNA Cross-Linking agents and their application for targeting cancer cells are also explained. By the end of the chapter, DNA ICL formation induced by “click” chemistry is highlighted.
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Chapter Six - Novel DNA Cross-Linking Reagents
Advances in Molecular Toxicology, 2016Co-Authors: Heli Fan, Xiaohua PengAbstract:Abstract DNA interstrand Cross-links (ICLs) are the sources of the cytotoxicity of many anticancer agents. DNA Cross-Linking agents are used as anticancer agents, for DNA damage and repair study, for nucleic acid detection, and for construction of DNA nanomaterials. This chapter summarizes various novel methods and chemical reagents recently developed for inducing DNA ICL formation, the mechanisms involved for DNA Cross-Linking, and their applications. It starts by presenting photoinduced DNA ICL formation via [2+2] cycloaddition reaction, quinone methide, or carbocation formation. It then discusses novel DNA Cross-Linking agents activated by various chemical agents, including the arylboronate or boronic acid derivatives activated by hydrogen peroxide, silyl-protected bifunctional phenol derivatives triggered by fluoride, and phenyl selenides or furan analogs activated by oxidation reagents. General mechanisms involved formation of alkylating species, including quinone methide, nitrogen mustard, methide analogs, and enal formation. Enzyme-activated DNA Cross-Linking agents and their application for targeting cancer cells are also explained. By the end of the chapter, DNA ICL formation induced by “click” chemistry is highlighted.
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Reactive Oxygen Species (ROS) Inducible DNA Cross-Linking Agents and Their Effect on Cancer Cells and Normal Lymphocytes
2015Co-Authors: Wenbing Chen, Kumudha Balakrishnan, Yunyan Kuang, Yanyan Han, Varsha Gandhi, Xiaohua PengAbstract:Reducing host toxicity is one of the main challenges of cancer chemotherapy. Many tumor cells contain high levels of ROS that make them distinctively different from normal cells. We report a series of ROS-activated aromatic nitrogen mustards that selectively kill chronic lymphocytic leukemia (CLL) over normal lymphocytes. These agents showed powerful DNA Cross-Linking abilities when coupled with H2O2, one of the most common ROS in cancer cells, whereas little DNA Cross-Linking was detected without H2O2. Consistent with chemistry observation, in vitro cytotoxicity assay demonstrated that these agents induced 40–80% apoptosis in primary leukemic lymphocytes isolated from CLL patients but less than 25% cell death to normal lymphocytes from healthy donors. The IC50 for the most potent compound (2) was ∼5 μM in CLL cells, while the IC50 was not achieved in normal lymphocytes. Collectively, these data provide utility and selectivity of these agents that will inspire further and effective applications
Tad H. Koch - One of the best experts on this subject based on the ideXlab platform.
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Correlation of in Situ Oxazolidine Formation with Highly Synergistic Cytotoxicity and DNA Cross-Linking in Cancer Cells from Combinations of Doxorubicin and Formaldehyde
Journal of medicinal chemistry, 2016Co-Authors: Benjamin L Barthel, Erin L. Mooz, Laura Elizabeth Wiener, Gary G. Koch, Tad H. KochAbstract:Anthracyclines are a class of antitumor compounds that are successful and widely used but suffer from cardiotoxicity and acquired tumor resistance. Formaldehyde interacts with anthracyclines to enhance antitumor efficacy, bypass resistance mechanisms, improve the therapeutic profile, and change the mechanism of action from a topoisomerase II poison to a DNA Cross-linker. Contrary to current dogma, we show that both efficient DNA Cross-Linking and potent synergy in combination with formaldehyde correlate with the anthracycline's ability to form cyclic formaldehyde conjugates as oxazolidine moieties and that the cyclic conjugates are better Cross-Linking agents and cytotoxins than acyclic conjugates. We also provide evidence that suggests that the oxazolidine forms in situ, since cotreatment with doxorubicin and formaldehyde is highly cytotoxic to dox-resistant tumor cell lines, and that this benefit is absent in combinations of formaldehyde and epirubicin, which cannot form stable oxazolidines. These results have potential clinical implications in the active field of anthracycline prodrug design and development.
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correlation of in situ oxazolidine formation with highly synergistic cytotoxicity and DNA Cross Linking in cancer cells from combinations of doxorubicin and formaldehyde
Journal of Medicinal Chemistry, 2016Co-Authors: Benjamin L Barthel, Erin L. Mooz, Laura Elizabeth Wiener, Gary G. Koch, Tad H. KochAbstract:Anthracyclines are a class of antitumor compounds that are successful and widely used but suffer from cardiotoxicity and acquired tumor resistance. Formaldehyde interacts with anthracyclines to enhance antitumor efficacy, bypass resistance mechanisms, improve the therapeutic profile, and change the mechanism of action from a topoisomerase II poison to a DNA Cross-linker. Contrary to current dogma, we show that both efficient DNA Cross-Linking and potent synergy in combination with formaldehyde correlate with the anthracycline’s ability to form cyclic formaldehyde conjugates as oxazolidine moieties and that the cyclic conjugates are better Cross-Linking agents and cytotoxins than acyclic conjugates. We also provide evidence that suggests that the oxazolidine forms in situ, since cotreatment with doxorubicin and formaldehyde is highly cytotoxic to dox-resistant tumor cell lines, and that this benefit is absent in combinations of formaldehyde and epirubicin, which cannot form stable oxazolidines. These resul...
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Correlation of in Situ Oxazolidine Formation with Highly Synergistic Cytotoxicity and DNA Cross-Linking in Cancer Cells from Combinations of Doxorubicin and Formaldehyde
2016Co-Authors: Benjamin L. Barthel, Erin L. Mooz, Laura Elizabeth Wiener, Gary G. Koch, Tad H. KochAbstract:Anthracyclines are a class of antitumor compounds that are successful and widely used but suffer from cardiotoxicity and acquired tumor resistance. Formaldehyde interacts with anthracyclines to enhance antitumor efficacy, bypass resistance mechanisms, improve the therapeutic profile, and change the mechanism of action from a topoisomerase II poison to a DNA Cross-linker. Contrary to current dogma, we show that both efficient DNA Cross-Linking and potent synergy in combination with formaldehyde correlate with the anthracycline’s ability to form cyclic formaldehyde conjugates as oxazolidine moieties and that the cyclic conjugates are better Cross-Linking agents and cytotoxins than acyclic conjugates. We also provide evidence that suggests that the oxazolidine forms in situ, since cotreatment with doxorubicin and formaldehyde is highly cytotoxic to dox-resistant tumor cell lines, and that this benefit is absent in combinations of formaldehyde and epirubicin, which cannot form stable oxazolidines. These results have potential clinical implications in the active field of anthracycline prodrug design and development
John A Hartley - One of the best experts on this subject based on the ideXlab platform.
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γ h2ax foci formation as a pharmacodynamic marker of DNA damage produced by DNA Cross Linking agents results from 2 phase i clinical trials of sjg 136 sg2000
Clinical Cancer Research, 2013Co-Authors: Peter H Clingen, Victoria J Spanswick, Maria Mellinasgomez, Tim Meyer, Igor Puzanov, Duncan I Jodrell, Daniel Hochhauser, John A HartleyAbstract:Purpose: To evaluate γ-H2AX foci as a pharmacodynamic marker for DNA damage induced by DNA interstrand Cross-Linking drugs. Experimental Design: γ-H2AX foci formation was validated preclinically in comparison with the Comet assay, and evaluated pharmacodynamically in two phase I studies of different dosing schedules of the novel Cross-Linking agent SJG-136 (SG2000). Results: The measurement of γ-H2AX foci in human fibroblasts and lymphocytes in vitro was more than 10-fold more sensitive than Comet assay measurement of Cross-Linking, with peak γ-H2AX response 24 hours after the peak of Cross-Linking. In lymphocytes from a phase I study (every three week schedule), γ-H2AX foci were detectable 1 hour following the end of administration, and in all patients, maximum response was observed at 24 hours. Significant levels of foci were still evident at days 8 and 15 consistent with the known persistence of the DNA damage produced by this agent. In two tumor biopsy samples, foci were detected 4 hours postinfusion with levels higher than in lymphocytes. Extensive foci formation was also observed before the third dose in cycle 1 in lymphocytes from a second phase I study (daily × 3 schedule). These foci also persisted with a significant level evident before the second cycle (day 21). An increased γ-H2AX response was observed during the second cycle consistent with a cumulative pharmacodynamic effect. No clear relationship between foci formation and administered drug dose was observed. Conclusion: This is the first use of γ-H2AX as a pharmacodynamic response to a DNA Cross-Linking agent in a clinical trial setting. Clin Cancer Res; 19(3); 721–30. ©2012 AACR .
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γ h2ax foci formation as a pharmacodynamic marker of DNA damage produced by DNA Cross Linking agents results from 2 phase i clinical trials of sjg 136 sg2000
Clinical Cancer Research, 2013Co-Authors: Jenny Wu, Peter H Clingen, Victoria J Spanswick, Maria Mellinasgomez, Tim Meyer, Igor Puzanov, Duncan I Jodrell, Daniel Hochhauser, John A HartleyAbstract:PURPOSE: To evaluate γ-H2AX foci as a pharmacodynamic marker for DNA damage induced by DNA interstrand Cross-Linking drugs. EXPERIMENTAL DESIGN: γ-H2AX foci formation was validated preclinically in comparison with the Comet assay, and evaluated pharmacodynamically in two phase I studies of different dosing schedules of the novel Cross-Linking agent SJG-136 (SG2000). RESULTS: The measurement of γ-H2AX foci in human fibroblasts and lymphocytes in vitro was more than 10-fold more sensitive than Comet assay measurement of Cross-Linking, with peak γ-H2AX response 24 hours after the peak of Cross-Linking. In lymphocytes from a phase I study (every three week schedule), γ-H2AX foci were detectable 1 hour following the end of administration, and in all patients, maximum response was observed at 24 hours. Significant levels of foci were still evident at days 8 and 15 consistent with the known persistence of the DNA damage produced by this agent. In two tumor biopsy samples, foci were detected 4 hours postinfusion with levels higher than in lymphocytes. Extensive foci formation was also observed before the third dose in cycle 1 in lymphocytes from a second phase I study (daily × 3 schedule). These foci also persisted with a significant level evident before the second cycle (day 21). An increased γ-H2AX response was observed during the second cycle consistent with a cumulative pharmacodynamic effect. No clear relationship between foci formation and administered drug dose was observed. CONCLUSION: This is the first use of γ-H2AX as a pharmacodynamic response to a DNA Cross-Linking agent in a clinical trial setting.
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linker length modulates DNA Cross Linking reactivity and cytotoxic potency of c8 c8 ether linked c2 exo unsaturated pyrrolo 2 1 c 1 4 benzodiazepine pbd dimers
Journal of Medicinal Chemistry, 2004Co-Authors: Stephen J Gregson, Terence C. Jenkins, Philip W Howard, Darren R Gullick, Anzu Hamaguchi, Kathryn E Corcoran, Natalie Brooks, John A Hartley, Sejal Patel, Matthew GuilleAbstract:A C2/C2'-exo-unsaturated pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer 4b (DRG-16) with a C8-O(CH2)nO-C8' diether linkage (n = 5) has been synthesized that shows markedly superior in vitro cytotoxic potency (e.g., >3400-fold in IGROV1 ovarian cells) and interstrand DNA Cross-Linking reactivity (>10-fold) compared to the shorter homologue 4a (SJG-136; n = 3). In contrast, for the C-ring unsubstituted series, the corresponding n = 5 dimer (3c) is generally less cytotoxic and has a lower interstrand Cross-Linking reactivity compared to its shorter n = 3 homologue (3a). Dimer 4b Cross-links DNA with >10-fold efficiency compared to 4a, and also inhibits the activity of the restriction endonuclease BamH1 more efficiently than either 3a or 4a. The C2-exo-unsaturated PBD dimers 4a,b are not only more effective than their C-ring saturated counterparts in terms of induced DeltaTm shift, but they also exert this effect more rapidly. Thus, while 3a and 3c exert 68 and 35% of their maximum effect immediately upon interaction with DNA, this level increases to 76 and 97% for 4a and 4b, respectively. Molecular modeling shows a rank order of 4b (n = 5) > 4a (n = 3) > 3a (n = 3) > 3c (n = 5) in terms of binding energy toward duplexes containing embedded target 5'-GAT(1-2)C Cross-link sequences, reflecting the superior fit of the C2-exo-unsaturated rather than saturated C-rings of the PBD dimers. A novel synthesis of core synthetic building blocks for PBD dimers via stepwise Mitsunobu reaction and nitration with Cu(NO3)2 is also reported.
H. Ian Robins - One of the best experts on this subject based on the ideXlab platform.
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Hyperthermic modulation of SN-38-induced topoisomerase I DNA Cross-Linking and SN-38 cytotoxicity through altered topoisomerase I activity
International journal of cancer, 1999Co-Authors: Dörthe M. Katschinski, H. Ian RobinsAbstract:The effect of different temperatures (37-42.5 degrees C) on SN-38 (the active metabolite of CPT-11) cytotoxicity was examined in the human lung carcinoma cell lines H460 and Calu-6 as well as the murine fibrosarcoma cell line L929. The cytotoxicity of SN-38, determined by MTT cell survival assay, was significantly increased in each cell line in combination with 41.8 degrees C hyperthermia (x60-120 min); the combination of SN-38 with 40.5 degrees C and 42.5 degrees C, however, was unchanged compared to 37 degrees C. Determination of topoisomerase (Topo) I DNA Cross-Linking in Calu-6 cells and L929 cells after treatment with SN-38 showed the same temperature profile as seen in the cell-survival assays with increased Topo I DNA Cross-Linking after treatment with the combination of SN-38 and 41.8 degrees C hyperthermia and unchanged Topo I DNA Cross-Linking at 40.5 degrees C and 42.5 degrees C. To test the hypothesis that increased Topo I DNA Cross-Linking and SN-38 cytotoxicity at 41.8 degrees C is caused by hyperthermia-modulated changes in Topo I activity, catalytic activity of Topo I extracted from each cell line and of purified human Topo I was determined at 20-42.5 degrees C. Topo I activity was found to be gradually increased with rising temperatures, resulting in significantly higher activity at 41.8 degrees C compared to 37 degrees C; further increase of temperature past 41.8 degrees C decreased Topo I activity back to levels found at 37 degrees C. Our data are used to explain a series of events resulting in hyperthermic enhancement of Topo I DNA Cross-Linking and SN-38 cytotoxicity in combination with 41.8 degrees C hyperthermia via increased Topo I activity.
Benjamin L Barthel - One of the best experts on this subject based on the ideXlab platform.
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correlation of in situ oxazolidine formation with highly synergistic cytotoxicity and DNA Cross Linking in cancer cells from combinations of doxorubicin and formaldehyde
Journal of Medicinal Chemistry, 2016Co-Authors: Benjamin L Barthel, Erin L. Mooz, Laura Elizabeth Wiener, Gary G. Koch, Tad H. KochAbstract:Anthracyclines are a class of antitumor compounds that are successful and widely used but suffer from cardiotoxicity and acquired tumor resistance. Formaldehyde interacts with anthracyclines to enhance antitumor efficacy, bypass resistance mechanisms, improve the therapeutic profile, and change the mechanism of action from a topoisomerase II poison to a DNA Cross-linker. Contrary to current dogma, we show that both efficient DNA Cross-Linking and potent synergy in combination with formaldehyde correlate with the anthracycline’s ability to form cyclic formaldehyde conjugates as oxazolidine moieties and that the cyclic conjugates are better Cross-Linking agents and cytotoxins than acyclic conjugates. We also provide evidence that suggests that the oxazolidine forms in situ, since cotreatment with doxorubicin and formaldehyde is highly cytotoxic to dox-resistant tumor cell lines, and that this benefit is absent in combinations of formaldehyde and epirubicin, which cannot form stable oxazolidines. These resul...
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Correlation of in Situ Oxazolidine Formation with Highly Synergistic Cytotoxicity and DNA Cross-Linking in Cancer Cells from Combinations of Doxorubicin and Formaldehyde
Journal of medicinal chemistry, 2016Co-Authors: Benjamin L Barthel, Erin L. Mooz, Laura Elizabeth Wiener, Gary G. Koch, Tad H. KochAbstract:Anthracyclines are a class of antitumor compounds that are successful and widely used but suffer from cardiotoxicity and acquired tumor resistance. Formaldehyde interacts with anthracyclines to enhance antitumor efficacy, bypass resistance mechanisms, improve the therapeutic profile, and change the mechanism of action from a topoisomerase II poison to a DNA Cross-linker. Contrary to current dogma, we show that both efficient DNA Cross-Linking and potent synergy in combination with formaldehyde correlate with the anthracycline's ability to form cyclic formaldehyde conjugates as oxazolidine moieties and that the cyclic conjugates are better Cross-Linking agents and cytotoxins than acyclic conjugates. We also provide evidence that suggests that the oxazolidine forms in situ, since cotreatment with doxorubicin and formaldehyde is highly cytotoxic to dox-resistant tumor cell lines, and that this benefit is absent in combinations of formaldehyde and epirubicin, which cannot form stable oxazolidines. These results have potential clinical implications in the active field of anthracycline prodrug design and development.