The Experts below are selected from a list of 3033 Experts worldwide ranked by ideXlab platform
Jia Zhou - One of the best experts on this subject based on the ideXlab platform.
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abstract 2668 regio and stereospecific synthesis of oridonin d ring aziridinated analogues for the treatment of triple negative breast cancer via mediated irreversible covalent Warheads
Cancer Research, 2018Co-Authors: Ye Ding, Chunyong Ding, Haiying Chen, Zhiqing Liu, Eric A Wold, Mark A White, Qiang Shen, Jia ZhouAbstract:The covalent drugs dramatically resurge in recent years due to the comprehensive optimization of the structure-activity relationship (SAR) and structure-reactivity relationship (SRR). Natural product oridonin with an impressive pharmacological profile through its covalent enone Warhead on the D-ring has attracted substantial SAR studies to appreciate its potential in the development of new molecular entities for the treatment of various human cancers and inflammation. Herein, for the first time we report the excessive reactivity of this covalent Warhead and mediation of the covalent binding capability through a Rh2(esp)2-catalyzed mild and concise regio- and stereospecific aziridination approach. Intriguingly, new analogue YD0514 with a more drug-like irreversible covalent Warhead has been identified to significantly induce apoptosis and inhibit colony formation against triple-negative breast cancer with comparable to enhanced antitumor effects in vitro and in vivo, while displaying lower toxicity to normal human mammary epithelial cells in comparison with oridonin. Citation Format: Ye Ding, Dengfeng Li, Chunyong Ding, Zhiqing Liu, Eric A. Wold, Na Ye, Haiying Chen, Mark A. White, Qiang Shen, Jia Zhou. Regio- and stereospecific synthesis of oridonin D-ring aziridinated analogues for the treatment of triple-negative breast cancer via mediated irreversible covalent Warheads [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2668.
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regio and stereospecific synthesis of oridonin d ring aziridinated analogues for the treatment of triple negative breast cancer via mediated irreversible covalent Warheads
Journal of Medicinal Chemistry, 2018Co-Authors: Ye Ding, Chunyong Ding, Haiying Chen, Zhiqing Liu, Eric A Wold, Mark A White, Qiang Shen, Pingyuan Wang, Jia ZhouAbstract:Covalent drug discovery has undergone a resurgence in recent years due to comprehensive optimization of the structure–activity relationship (SAR) and the structure–reactivity relationship (SRR) for covalent drug candidates. The natural product oridonin maintains an impressive pharmacological profile through its covalent enone Warhead on the D-ring and has attracted substantial SAR studies to characterize its potential in the development of new molecular entities for the treatment of various human cancers and inflammation. Herein, for the first time, we report the excessive reactivity of this covalent Warhead and mediation of the covalent binding capability through a Rh2(esp)2-catalyzed mild and concise regio- and stereospecific aziridination approach. Importantly, aziridonin 44 (YD0514), with a more-druglike irreversible covalent Warhead, has been identified to significantly induce apoptosis and inhibit colony formation against triple-negative breast cancer with enhanced antitumor effects in vitro and in ...
Areg Danagoulian - One of the best experts on this subject based on the ideXlab platform.
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a physically cryptographic Warhead verification system using neutron induced nuclear resonances
Nature Communications, 2019Co-Authors: Ezra M Engel, Areg DanagoulianAbstract:Arms control treaties are necessary to reduce the large stockpiles of the nuclear weapons that constitute one of the biggest dangers to the world. However, an impactful treaty hinges on effective inspection exercises to verify the participants' compliance to the treaty terms. Such procedures would require verification of the authenticity of a Warhead undergoing dismantlement. Previously proposed solutions lacked the combination of isotopic sensitivity and information security. Here we present the experimental feasibility proof of a technique that uses neutron induced nuclear resonances and is sensitive to the combination of isotopics and geometry. The information is physically encrypted to prevent the leakage of sensitive information. Our approach can significantly increase the trustworthiness of future arms control treaties while expanding their scope to include the verified dismantlement of nuclear Warheads themselves.
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experimental demonstration of an isotope sensitive Warhead verification technique using nuclear resonance fluorescence
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Jayson R Vavrek, Brian S Henderson, Areg DanagoulianAbstract:Future nuclear arms reduction efforts will require technologies to verify that Warheads slated for dismantlement are authentic without revealing any sensitive weapons design information to international inspectors. Despite several decades of research, no technology has met these requirements simultaneously. Recent work by Kemp et al. [Kemp RS, Danagoulian A, Macdonald RR, Vavrek JR (2016) Proc Natl Acad Sci USA 113:8618–8623] has produced a novel physical cryptographic verification protocol that approaches this treaty verification problem by exploiting the isotope-specific nature of nuclear resonance fluorescence (NRF) measurements to verify the authenticity of a Warhead. To protect sensitive information, the NRF signal from the Warhead is convolved with that of an encryption foil that contains key Warhead isotopes in amounts unknown to the inspector. The convolved spectrum from a candidate Warhead is statistically compared against that from an authenticated template Warhead to determine whether the candidate itself is authentic. Here we report on recent proof-of-concept Warhead verification experiments conducted at the Massachusetts Institute of Technology. Using high-purity germanium (HPGe) detectors, we measured NRF spectra from the interrogation of proxy “genuine” and “hoax” objects by a 2.52 MeV endpoint bremsstrahlung beam. The observed differences in NRF intensities near 2.2 MeV indicate that the physical cryptographic protocol can distinguish between proxy genuine and hoax objects with high confidence in realistic measurement times.
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Nuclear disarmament verification via resonant phenomena
Nature Publishing Group, 2018Co-Authors: Jake J. Hecla, Areg DanagoulianAbstract:Authenticating a nuclear Warhead without revealing its design is a challenge. Here the authors discuss a nuclear disarmament verification method based on neutron resonance analysis which is sensitive to the isotopic composition of the materials used in Warheads
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physical cryptographic verification of nuclear Warheads
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Scott R Kemp, Areg Danagoulian, Ruaridh R Macdonald, Jayson R VavrekAbstract:How does one prove a claim about a highly sensitive object such as a nuclear weapon without revealing information about the object? This paradox has challenged nuclear arms control for more than five decades. We present a mechanism in the form of an interactive proof system that can validate the structure and composition of an object, such as a nuclear Warhead, to arbitrary precision without revealing either its structure or composition. We introduce a tomographic method that simultaneously resolves both the geometric and isotopic makeup of an object. We also introduce a method of protecting information using a provably secure cryptographic hash that does not rely on electronics or software. These techniques, when combined with a suitable protocol, constitute an interactive proof system that could reject hoax items and clear authentic Warheads with excellent sensitivity in reasonably short measurement times.
Ye Ding - One of the best experts on this subject based on the ideXlab platform.
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abstract 2668 regio and stereospecific synthesis of oridonin d ring aziridinated analogues for the treatment of triple negative breast cancer via mediated irreversible covalent Warheads
Cancer Research, 2018Co-Authors: Ye Ding, Chunyong Ding, Haiying Chen, Zhiqing Liu, Eric A Wold, Mark A White, Qiang Shen, Jia ZhouAbstract:The covalent drugs dramatically resurge in recent years due to the comprehensive optimization of the structure-activity relationship (SAR) and structure-reactivity relationship (SRR). Natural product oridonin with an impressive pharmacological profile through its covalent enone Warhead on the D-ring has attracted substantial SAR studies to appreciate its potential in the development of new molecular entities for the treatment of various human cancers and inflammation. Herein, for the first time we report the excessive reactivity of this covalent Warhead and mediation of the covalent binding capability through a Rh2(esp)2-catalyzed mild and concise regio- and stereospecific aziridination approach. Intriguingly, new analogue YD0514 with a more drug-like irreversible covalent Warhead has been identified to significantly induce apoptosis and inhibit colony formation against triple-negative breast cancer with comparable to enhanced antitumor effects in vitro and in vivo, while displaying lower toxicity to normal human mammary epithelial cells in comparison with oridonin. Citation Format: Ye Ding, Dengfeng Li, Chunyong Ding, Zhiqing Liu, Eric A. Wold, Na Ye, Haiying Chen, Mark A. White, Qiang Shen, Jia Zhou. Regio- and stereospecific synthesis of oridonin D-ring aziridinated analogues for the treatment of triple-negative breast cancer via mediated irreversible covalent Warheads [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2668.
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regio and stereospecific synthesis of oridonin d ring aziridinated analogues for the treatment of triple negative breast cancer via mediated irreversible covalent Warheads
Journal of Medicinal Chemistry, 2018Co-Authors: Ye Ding, Chunyong Ding, Haiying Chen, Zhiqing Liu, Eric A Wold, Mark A White, Qiang Shen, Pingyuan Wang, Jia ZhouAbstract:Covalent drug discovery has undergone a resurgence in recent years due to comprehensive optimization of the structure–activity relationship (SAR) and the structure–reactivity relationship (SRR) for covalent drug candidates. The natural product oridonin maintains an impressive pharmacological profile through its covalent enone Warhead on the D-ring and has attracted substantial SAR studies to characterize its potential in the development of new molecular entities for the treatment of various human cancers and inflammation. Herein, for the first time, we report the excessive reactivity of this covalent Warhead and mediation of the covalent binding capability through a Rh2(esp)2-catalyzed mild and concise regio- and stereospecific aziridination approach. Importantly, aziridonin 44 (YD0514), with a more-druglike irreversible covalent Warhead, has been identified to significantly induce apoptosis and inhibit colony formation against triple-negative breast cancer with enhanced antitumor effects in vitro and in ...
Iwao Ojima - One of the best experts on this subject based on the ideXlab platform.
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design synthesis and biological evaluation of a highly potent and cancer cell selective folate taxoid conjugate
Bioorganic & Medicinal Chemistry, 2015Co-Authors: Joshua D Seitz, Jacob G Vineberg, Evan Herlihy, Bora Park, Eduard Melief, Iwao OjimaAbstract:Abstract The folate receptor (FR) has been widely recognized as an excellent target for the tumor-selective delivery of cytotoxic agents, and four folate–drug conjugates have entered clinical evaluations for the treatment of solid tumors to date. However, most of these conjugates required structural modification of the cytotoxic Warheads in order to achieve efficient drug release from the linkers. We designed and constructed a novel folate conjugate of a highly-potent next-generation taxoid, SB-T-1214, by exploiting bioorthogonal Cu-free ‘click’ chemistry. The synthesis was highly convergent and required no HPLC purification to obtain the final folate–taxoid conjugate 1. Conjugate 1 demonstrated highly FR-specific potency (IC50 2.1–3.5 nM) against a panel of cancer cell lines, with a >1000-fold decrease in cytotoxicity against normal human cells (IC50 >5000 nM). The remarkable potency and selectivity of conjugate 1 can be attributed to highly FR-specific receptor-mediated endocytosis as well as efficient release of the unmodified cytotoxic Warhead using a mechanism-based self-immolative linker.
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Design, Synthesis, and Biological Evaluations of Tumor-Targeting Dual-Warhead Conjugates for a Taxoid–Camptothecin Combination Chemotherapy
2015Co-Authors: Jacob G Vineberg, Edison S Zuniga, Anushree Kamath, Yingjen Chen, Joshua D Seitz, Iwao OjimaAbstract:Novel tumor-targeting dual-Warhead conjugates, 2 (DW-1) and 3 (DW-2), which consist of a next-generation taxoid, 1 (SB-T-1214), and camptothecin as two Warheads, self-immolative disulfide linkers for drug release, biotin as the tumor-targeting moiety, and 1,3,5-triazine as the tripod splitter module, were designed and synthesized. The potency of 2 was evaluated against MX-1, MCF-7, ID8, L1210FR (BR+, biotin receptor overexpressed) and WI38 (BR–, normal) cell lines in the absence and presence of glutathione (GSH), which is an endogenous thiol that triggers drug release inside the cancer cells. With the GSH and resuspension protocol, 2 exhibited IC50 values of 3.22–9.80 nM against all BR+ cancer cell lines, and 705 nM against WI38. Thus, there was a two orders of magnitude higher selectivity to cancer cells. Also, a clear cooperative effect was observed for the taxoid–camptothecin combination when two drugs were delivered to the cancer cells specifically in the form of a dual-Warhead conjugate
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design synthesis and biological evaluations of tumor targeting dual Warhead conjugates for a taxoid camptothecin combination chemotherapy
Journal of Medicinal Chemistry, 2014Co-Authors: Jacob G Vineberg, Edison S Zuniga, Anushree Kamath, Yingjen Chen, Joshua D Seitz, Iwao OjimaAbstract:Novel tumor-targeting dual-Warhead conjugates, 2 (DW-1) and 3 (DW-2), which consist of a next-generation taxoid, 1 (SB-T-1214), and camptothecin as two Warheads, self-immolative disulfide linkers for drug release, biotin as the tumor-targeting moiety, and 1,3,5-triazine as the tripod splitter module, were designed and synthesized. The potency of 2 was evaluated against MX-1, MCF-7, ID8, L1210FR (BR+, biotin receptor overexpressed) and WI38 (BR–, normal) cell lines in the absence and presence of glutathione (GSH), which is an endogenous thiol that triggers drug release inside the cancer cells. With the GSH and resuspension protocol, 2 exhibited IC50 values of 3.22–9.80 nM against all BR+ cancer cell lines, and 705 nM against WI38. Thus, there was a two orders of magnitude higher selectivity to cancer cells. Also, a clear cooperative effect was observed for the taxoid–camptothecin combination when two drugs were delivered to the cancer cells specifically in the form of a dual-Warhead conjugate.
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fluorine containing taxoid anticancer agents and their tumor targeted drug delivery
Journal of Fluorine Chemistry, 2013Co-Authors: Joshua D Seitz, Jacob G Vineberg, Edison S Zuniga, Iwao OjimaAbstract:Abstract A long-standing problem of conventional chemotherapy is the lack of tumor-specific treatments. Traditional chemotherapy relies on the premise that rapidly proliferating cancer cells are more likely to be killed by a cytotoxic agent. In reality, however, cytotoxic agents have very little or no specificity, which leads to systemic toxicity, causing undesirable severe side effects. Consequently, various “molecularly targeted cancer therapies” have been developed for use in specific cancers, including tumor-targeted drug delivery systems. In general, such a drug delivery system consists of a tumor recognition moiety and a cytotoxic “Warhead” connected through a “smart” linker to form a conjugate. When a multi-functionalized nanomaterial is used as the vehicle, a “Trojan Horse” approach can be used for mass delivery of cytotoxic “Warheads” to maximize the efficacy. Exploitation of the special properties of fluorine has proven successful in the development of new and effective biochemical tools as well as therapeutic agents. Fluorinated congeners can also serve as excellent probes for the investigation of biochemical mechanisms. 19 F NMR can provide unique and powerful tools for mechanistic investigations in chemical biology. This account presents our recent progress, in perspective, on the molecular approaches to the design and development of novel tumor-targeted drug delivery systems for new generation chemotherapy by exploiting the unique nature of fluorine.
Qiang Shen - One of the best experts on this subject based on the ideXlab platform.
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abstract 2668 regio and stereospecific synthesis of oridonin d ring aziridinated analogues for the treatment of triple negative breast cancer via mediated irreversible covalent Warheads
Cancer Research, 2018Co-Authors: Ye Ding, Chunyong Ding, Haiying Chen, Zhiqing Liu, Eric A Wold, Mark A White, Qiang Shen, Jia ZhouAbstract:The covalent drugs dramatically resurge in recent years due to the comprehensive optimization of the structure-activity relationship (SAR) and structure-reactivity relationship (SRR). Natural product oridonin with an impressive pharmacological profile through its covalent enone Warhead on the D-ring has attracted substantial SAR studies to appreciate its potential in the development of new molecular entities for the treatment of various human cancers and inflammation. Herein, for the first time we report the excessive reactivity of this covalent Warhead and mediation of the covalent binding capability through a Rh2(esp)2-catalyzed mild and concise regio- and stereospecific aziridination approach. Intriguingly, new analogue YD0514 with a more drug-like irreversible covalent Warhead has been identified to significantly induce apoptosis and inhibit colony formation against triple-negative breast cancer with comparable to enhanced antitumor effects in vitro and in vivo, while displaying lower toxicity to normal human mammary epithelial cells in comparison with oridonin. Citation Format: Ye Ding, Dengfeng Li, Chunyong Ding, Zhiqing Liu, Eric A. Wold, Na Ye, Haiying Chen, Mark A. White, Qiang Shen, Jia Zhou. Regio- and stereospecific synthesis of oridonin D-ring aziridinated analogues for the treatment of triple-negative breast cancer via mediated irreversible covalent Warheads [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2668.
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regio and stereospecific synthesis of oridonin d ring aziridinated analogues for the treatment of triple negative breast cancer via mediated irreversible covalent Warheads
Journal of Medicinal Chemistry, 2018Co-Authors: Ye Ding, Chunyong Ding, Haiying Chen, Zhiqing Liu, Eric A Wold, Mark A White, Qiang Shen, Pingyuan Wang, Jia ZhouAbstract:Covalent drug discovery has undergone a resurgence in recent years due to comprehensive optimization of the structure–activity relationship (SAR) and the structure–reactivity relationship (SRR) for covalent drug candidates. The natural product oridonin maintains an impressive pharmacological profile through its covalent enone Warhead on the D-ring and has attracted substantial SAR studies to characterize its potential in the development of new molecular entities for the treatment of various human cancers and inflammation. Herein, for the first time, we report the excessive reactivity of this covalent Warhead and mediation of the covalent binding capability through a Rh2(esp)2-catalyzed mild and concise regio- and stereospecific aziridination approach. Importantly, aziridonin 44 (YD0514), with a more-druglike irreversible covalent Warhead, has been identified to significantly induce apoptosis and inhibit colony formation against triple-negative breast cancer with enhanced antitumor effects in vitro and in ...
