The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Larry K Keefer - One of the best experts on this subject based on the ideXlab platform.
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analysis of the hno and no donating properties of alicyclic amine Diazeniumdiolates
Nitric Oxide, 2014Co-Authors: Gaurav Bharadwaj, Larry K Keefer, Patricia G Z Benini, Debashree Basudhar, Cyf Ramoscolon, Gail M Johnson, Marti Larriva, Daniela Andrei, Katrina M MirandaAbstract:Nitroxyl (HNO) donors have been shown to elicit a variety of pharmacological responses, ranging from tumoricidal effects to treatment of heart failure. Isopropylamine-based Diazeniumdiolates have been shown to produce HNO on decomposition under physiological conditions. Herein, we report the synthesis and HNO release profiles of primary alicyclic amine-based Diazeniumdiolates. These compounds extend the range of known diazeniumdiolate-based HNO donors. Acetoxymethyl ester-protected Diazeniumdiolates were also synthesized to improve purification and cellular uptake. The acetoxymethyl derivative of cyclopentylamine diazeniumdiolate not only showed higher cytotoxicity toward cancer cells as compared to the parent anion but was also effective in combination with tamoxifen for targeting estrogen receptor α-negative breast cancer cells.
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direct reaction of amides with nitric oxide to form Diazeniumdiolates
Journal of Organic Chemistry, 2014Co-Authors: Ryan J Holland, Larry K Keefer, John R Klose, Zhao Cao, Jeffrey R Deschamps, Joseph E SaavedraAbstract:We report the apparently unprecedented direct reaction of nitric oxide (NO) with amides to generate ions of structure R(C═O)NH–N(O)═NO–, with examples including R = Me (1a) or 3-pyridyl (1b). The sodium salts of both released NO in pH 7.4 buffer, with 37 °C half-lives of 1–3 min. As NO-releasing drug candidates, diazeniumdiolated amides would have the advantage of generating only 1 equiv of base on hydrolyzing exhaustively to NO, in contrast to their amine counterparts, which generate 2 equiv of base.
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decoding nitric oxide release rates of amine based Diazeniumdiolates
Journal of Physical Chemistry A, 2013Co-Authors: Yanni Wang, Larry K Keefer, Jack R Collins, Ryan J Holland, Joseph IvanicAbstract:Amine-based Diazeniumdiolates (NONOates) have garnered widespread use as nitric oxide (NO) donors, and their potential for nitroxyl (HNO) release has more recently been realized. While NO release r...
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Stereochemical Origins of Chromophore Extension in O^2-Substituted Diazeniumdiolates, Prodrugs of Nitric Oxide
Journal of Chemical Crystallography, 2013Co-Authors: Jeffrey R Deschamps, Joseph E Saavedra, Larry K Keefer, Zhao Cao, Harinath ChakrapaniAbstract:Ultraviolet spectral data for nitric oxide prodrugs of structure R_2NN(O)=NOR′ tend to fall into two classes: those in which R_2N is pyrrolidinyl have λ_max near 255 nm when R′ is a simple alkyl substituent, while those in which R_2N is not pyrrolidinyl display λ_max around 230 nm. To test the hypothesis that this spectral difference might reflect an electronic interaction large enough to affect key bond lengths and the configuration at the R_2N nitrogen, we have compared the crystal structures of two compounds in which R′ was β- d -glucopyranosyl tetraacetate and R_2N was pyrrolidinyl versus diethylamino. The X-ray studies revealed a pyramidyl R_2N nitrogen for the diethylamino derivative while the pyrrolidine derivative’s R_2N approached planarity, consistent with substantial electronic interaction between the N(O)=NOR′ chromophore and pyrrolidine’s (but not diethylamine’s) nitrogen atom. Compensatory changes in key bond lengths were also seen. These findings indicate that overlap between the pyrrolidine nitrogen’s p orbital and the N(O)=NOR′ chromophore can be an important determinant of structure and electron distribution in the diazeniumdiolate series. Graphical Abstract Ultraviolet spectral data for nitric oxide prodrugs of structure R_2NN(O)=NOR′ tend to fall into two classes and the wavelength of the ultraviolet absorbance maximum is a convenient and rather sensitive indicator of the tetrahedral versus planar steric arrangement at the R_2N^3 nitrogen.
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Nitric oxide-releasing prodrug triggers cancer cell death through deregulation of cellular redox balance
Elsevier, 2013Co-Authors: Anna E Maciag, Joseph E Saavedra, Ryan J Holland, Y.-s. Robert Cheng, Luis G. Rodriguez, Lucy M. Anderson, Larry K KeeferAbstract:JS-K is a nitric oxide (NO)-releasing prodrug of the O2-arylated diazeniumdiolate family that has demonstrated pronounced cytotoxicity and antitumor properties in a variety of cancer models both in vitro and in vivo. The current study of the metabolic actions of JS-K was undertaken to investigate mechanisms of its cytotoxicity. Consistent with model chemical reactions, the activating step in the metabolism of JS-K in the cell is the dearylation of the diazeniumdiolate by glutathione (GSH) via a nucleophilic aromatic substitution reaction. The resulting product (CEP/NO anion) spontaneously hydrolyzes, releasing two equivalents of NO. The GSH/GSSG redox couple is considered to be the major redox buffer of the cell, helping maintain a reducing environment under basal conditions. We have quantified the effects of JS-K on cellular GSH content, and show that JS-K markedly depletes GSH, due to JS-K's rapid uptake and cascading release of NO and reactive nitrogen species. The depletion of GSH results in alterations in the redox potential of the cellular environment, initiating MAPK stress signaling pathways, and inducing apoptosis. Microarray analysis confirmed signaling gene changes at the transcriptional level and revealed alteration in the expression of several genes crucial for maintenance of cellular redox homeostasis, as well as cell proliferation and survival, including MYC. Pre-treating cells with the known GSH precursor and nucleophilic reducing agent N-acetylcysteine prevented the signaling events that lead to apoptosis. These data indicate that multiplicative depletion of the reduced glutathione pool and deregulation of intracellular redox balance are important initial steps in the mechanism of JS-K's cytotoxic action
Zhangjian Huang - One of the best experts on this subject based on the ideXlab platform.
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o 2 3 aminopropyl Diazeniumdiolates suppress the progression of highly metastatic triple negative breast cancer by inhibition of microvesicle formation via nitric oxide based epigenetic regulation
Chemical Science, 2018Co-Authors: Fenghua Kang, Yihua Zhang, Jiayi Zhu, Hua Xiang, Jide Tian, Zhangjian HuangAbstract:Currently, there is no effective therapy for the treatment of highly metastatic triple-negative breast cancer (TNBC). Microvesicle (MV) formation is crucial for the metastasis of TNBC. Here we report a novel strategy to inhibit the generation of MVs for the intervention of TNBC. O2-3-Aminopropyl Diazeniumdiolates 3a–f are designed and synthesized, which can be activated by lysyloxidase over-expressed in TNBC cells. The most active compound 3f is able to selectively release high levels of NO in TNBC cells, inhibit the cell proliferation, and reduce the adhesion, invasion and migration of TNBC cells in vitro. Furthermore, 3f significantly suppresses the growth and metastasis of implanted TNBC in vivo through attenuating MV formation by an epigenetic modification of miR-203/RAB22A expression in an NO-dependent manner, providing the first evidence of NO donor(s) acting as epigenetic modulators to fight highly metastatic TNBC.
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synthesis and evaluation of o2 derived Diazeniumdiolates activatable via bioorthogonal chemistry reactions in living cells
Organic Letters, 2018Co-Authors: Fenghua Kang, Yihua Zhang, Tingting Wang, Boheng Wan, Zhangjian HuangAbstract:A class of O2-alkyl derived Diazeniumdiolates 3a-f and 4a-c were designed and synthesized as new bioorthogonal NO precursors, which can be effectively uncaged in the presence of a palladium catalyst via bioorthogonal bond cleavage reactions to generate NO in living cancer cells, eliciting potent antiproliferative activity.
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glutathione s transferase π activatable o2 sulfonylethyl derived Diazeniumdiolates potently suppress melanoma in vitro and in vivo
Journal of Medicinal Chemistry, 2018Co-Authors: Zhangjian Huang, Yu Zou, Haoliang Yuan, Yinqiu Zhang, Yue Fei, Atul Bhardwaj, Jatinder Kaur, Edward E. Knaus, Yihua ZhangAbstract:A group of glutathione S-transferase π (GSTπ) activatable O2-(sulfonylethyl derived) Diazeniumdiolates 5–12 were designed and synthesized. These compounds could be activated by GSTπ to initiate the β-elimination reaction, liberating an active vinyl sulfone-based GSH derivative and a diazeniumdiolate anion which subsequently releases NO in situ. The most active compound 6 released relatively high levels of NO and inhibited proliferation of melanoma B16 cells, superior to a diazeniumdiolate-based anticancer agent JS-K (1). Importantly, 6 had 8-fold less inhibitory activity against normal epithelial JB6 Cl 30-7b cells. The inhibitory activity of 6 could be diminished by an NO scavenger or GSTπ inhibitor. Furthermore, 6 induced nitration of mitochondrial tyrosine in B16 cells and inoculated B16 tumors in mice, which might be responsible for oxidation of protein leading to tumor suppression. Finally, 6 significantly retarded the B16 cells growth in a mouse xenograft model. These findings suggest that 6 may hav...
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Glutathione S‑Transferase π‑Activatable O2‑(Sulfonylethyl Derived) Diazeniumdiolates Potently Suppress Melanoma in Vitro and in Vivo
2018Co-Authors: Zhangjian Huang, Yu Zou, Haoliang Yuan, Yinqiu Zhang, Yue Fei, Atul Bhardwaj, Jatinder Kaur, Edward E. Knaus, Yihua ZhangAbstract:A group of glutathione S-transferase π (GSTπ) activatable O2-(sulfonylethyl derived) Diazeniumdiolates 5–12 were designed and synthesized. These compounds could be activated by GSTπ to initiate the β-elimination reaction, liberating an active vinyl sulfone-based GSH derivative and a diazeniumdiolate anion which subsequently releases NO in situ. The most active compound 6 released relatively high levels of NO and inhibited proliferation of melanoma B16 cells, superior to a diazeniumdiolate-based anticancer agent JS-K (1). Importantly, 6 had 8-fold less inhibitory activity against normal epithelial JB6 Cl 30-7b cells. The inhibitory activity of 6 could be diminished by an NO scavenger or GSTπ inhibitor. Furthermore, 6 induced nitration of mitochondrial tyrosine in B16 cells and inoculated B16 tumors in mice, which might be responsible for oxidation of protein leading to tumor suppression. Finally, 6 significantly retarded the B16 cells growth in a mouse xenograft model. These findings suggest that 6 may have a potential to treat melanoma
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synthesis and evaluation of novel o2 derived Diazeniumdiolates as photochemical and real time monitoring nitric oxide delivery agents
Organic chemistry frontiers, 2017Co-Authors: Xiaojun Luo, Yihua Zhang, Yisheng Lai, Honghua Zhang, Zhangjian HuangAbstract:A group of photochemical nitric oxide (NO) delivery agents, O2-(4-hydroxyphenacyl) Diazeniumdiolates 1–2 as well as O2-(3-(benzothiazole-2-yl)-4-hydroxyphenacyl) Diazeniumdiolates 3–4, could be triggered by ultraviolet light (365–400 nm) and visible light (≥410 nm), respectively, to produce NO in cancer cells and generate potent antitumor activity. Importantly, with the photolysis of 3 being initiated, the accompanying distinct fluorescence color change (from green to blue) may act as a qualitative real-time optical indicator for NO release in cancer cells.
Yihua Zhang - One of the best experts on this subject based on the ideXlab platform.
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o 2 3 aminopropyl Diazeniumdiolates suppress the progression of highly metastatic triple negative breast cancer by inhibition of microvesicle formation via nitric oxide based epigenetic regulation
Chemical Science, 2018Co-Authors: Fenghua Kang, Yihua Zhang, Jiayi Zhu, Hua Xiang, Jide Tian, Zhangjian HuangAbstract:Currently, there is no effective therapy for the treatment of highly metastatic triple-negative breast cancer (TNBC). Microvesicle (MV) formation is crucial for the metastasis of TNBC. Here we report a novel strategy to inhibit the generation of MVs for the intervention of TNBC. O2-3-Aminopropyl Diazeniumdiolates 3a–f are designed and synthesized, which can be activated by lysyloxidase over-expressed in TNBC cells. The most active compound 3f is able to selectively release high levels of NO in TNBC cells, inhibit the cell proliferation, and reduce the adhesion, invasion and migration of TNBC cells in vitro. Furthermore, 3f significantly suppresses the growth and metastasis of implanted TNBC in vivo through attenuating MV formation by an epigenetic modification of miR-203/RAB22A expression in an NO-dependent manner, providing the first evidence of NO donor(s) acting as epigenetic modulators to fight highly metastatic TNBC.
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synthesis and evaluation of o2 derived Diazeniumdiolates activatable via bioorthogonal chemistry reactions in living cells
Organic Letters, 2018Co-Authors: Fenghua Kang, Yihua Zhang, Tingting Wang, Boheng Wan, Zhangjian HuangAbstract:A class of O2-alkyl derived Diazeniumdiolates 3a-f and 4a-c were designed and synthesized as new bioorthogonal NO precursors, which can be effectively uncaged in the presence of a palladium catalyst via bioorthogonal bond cleavage reactions to generate NO in living cancer cells, eliciting potent antiproliferative activity.
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glutathione s transferase π activatable o2 sulfonylethyl derived Diazeniumdiolates potently suppress melanoma in vitro and in vivo
Journal of Medicinal Chemistry, 2018Co-Authors: Zhangjian Huang, Yu Zou, Haoliang Yuan, Yinqiu Zhang, Yue Fei, Atul Bhardwaj, Jatinder Kaur, Edward E. Knaus, Yihua ZhangAbstract:A group of glutathione S-transferase π (GSTπ) activatable O2-(sulfonylethyl derived) Diazeniumdiolates 5–12 were designed and synthesized. These compounds could be activated by GSTπ to initiate the β-elimination reaction, liberating an active vinyl sulfone-based GSH derivative and a diazeniumdiolate anion which subsequently releases NO in situ. The most active compound 6 released relatively high levels of NO and inhibited proliferation of melanoma B16 cells, superior to a diazeniumdiolate-based anticancer agent JS-K (1). Importantly, 6 had 8-fold less inhibitory activity against normal epithelial JB6 Cl 30-7b cells. The inhibitory activity of 6 could be diminished by an NO scavenger or GSTπ inhibitor. Furthermore, 6 induced nitration of mitochondrial tyrosine in B16 cells and inoculated B16 tumors in mice, which might be responsible for oxidation of protein leading to tumor suppression. Finally, 6 significantly retarded the B16 cells growth in a mouse xenograft model. These findings suggest that 6 may hav...
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Glutathione S‑Transferase π‑Activatable O2‑(Sulfonylethyl Derived) Diazeniumdiolates Potently Suppress Melanoma in Vitro and in Vivo
2018Co-Authors: Zhangjian Huang, Yu Zou, Haoliang Yuan, Yinqiu Zhang, Yue Fei, Atul Bhardwaj, Jatinder Kaur, Edward E. Knaus, Yihua ZhangAbstract:A group of glutathione S-transferase π (GSTπ) activatable O2-(sulfonylethyl derived) Diazeniumdiolates 5–12 were designed and synthesized. These compounds could be activated by GSTπ to initiate the β-elimination reaction, liberating an active vinyl sulfone-based GSH derivative and a diazeniumdiolate anion which subsequently releases NO in situ. The most active compound 6 released relatively high levels of NO and inhibited proliferation of melanoma B16 cells, superior to a diazeniumdiolate-based anticancer agent JS-K (1). Importantly, 6 had 8-fold less inhibitory activity against normal epithelial JB6 Cl 30-7b cells. The inhibitory activity of 6 could be diminished by an NO scavenger or GSTπ inhibitor. Furthermore, 6 induced nitration of mitochondrial tyrosine in B16 cells and inoculated B16 tumors in mice, which might be responsible for oxidation of protein leading to tumor suppression. Finally, 6 significantly retarded the B16 cells growth in a mouse xenograft model. These findings suggest that 6 may have a potential to treat melanoma
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synthesis and evaluation of novel o2 derived Diazeniumdiolates as photochemical and real time monitoring nitric oxide delivery agents
Organic chemistry frontiers, 2017Co-Authors: Xiaojun Luo, Yihua Zhang, Yisheng Lai, Honghua Zhang, Zhangjian HuangAbstract:A group of photochemical nitric oxide (NO) delivery agents, O2-(4-hydroxyphenacyl) Diazeniumdiolates 1–2 as well as O2-(3-(benzothiazole-2-yl)-4-hydroxyphenacyl) Diazeniumdiolates 3–4, could be triggered by ultraviolet light (365–400 nm) and visible light (≥410 nm), respectively, to produce NO in cancer cells and generate potent antitumor activity. Importantly, with the photolysis of 3 being initiated, the accompanying distinct fluorescence color change (from green to blue) may act as a qualitative real-time optical indicator for NO release in cancer cells.
Mark E. Meyerhoff - One of the best experts on this subject based on the ideXlab platform.
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the mediation of platelet quiescence by no releasing polymers via cgmp induced serine 239 phosphorylation of vasodilator stimulated phosphoprotein
Biomaterials, 2013Co-Authors: Terry C Major, Gail M Annich, Mark E. Meyerhoff, Hitesh Handa, Elizabeth J Brisbois, Melissa M Reynolds, Robert H BartlettAbstract:Abstract Nitric oxide (NO) releasing (NORel) materials have been shown to create localized increases in NO concentration by the release of NO from a diazeniumdiolate-containing or S -nitrosothiol-containing polymer coating and the improvement of extracorporeal circulation (ECC) hemocompatibility. However, the mechanism and, in particular, the platelet upregulation of the NO/cGMP signaling protein, vasodilator-stimulated phosphoprotein phosphorylated at serine 239 (P-VASP (ser 239)), for the improved ECC hemocompatibility via NO release still needs elucidation. In this work, two NORel polymeric coatings were evaluated in a 4 h rabbit thrombogenicity model and the anti-thrombotic mechanism investigated for rabbit platelet P-VASP upregulation. Polymer films containing 25 wt% diazeniumdiolated dibutylhexanediamine (DBHD) or 5 wt% S -nitroso- N -acetylpenicillamine (SNAP) coated on the inner walls of ECC circuits yielded significantly reduced ECC thrombus formation and maintained normal platelet aggregation compared to polymer controls after 4 h of blood exposure. Platelet P-VASP (ser 239), a useful tool to monitor NO/cGMP signaling, was upregulated after 4 h on ECC and markedly increased after ex vivo sodium nitroprusside (SNP) stimulation. Interestingly, in the rabbit platelet, NO did not upregulate the cAMP P-VASP phosphoprotein P-VASP (ser 157) as previously shown in human platelets. These results suggest that NORel polymers preserve rabbit platelet quiescence by sustaining a level of cGMP signaling as monitored by P-VASP (ser 239) upregulation. The upregulation of this NO-mediated platelet signaling mechanism in this rabbit thrombogenicity model indicates the potential for improved thromboresistance of any NORel-coated medical device.
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in vitro and in vivo study of sustained nitric oxide release coating using diazeniumdiolate doped poly vinyl chloride matrix with poly lactide co glycolide additive
Journal of Materials Chemistry B, 2013Co-Authors: Hitesh Handa, Gail M Annich, Robert H Bartlett, Elizabeth J Brisbois, Terry C Major, Lahdan Refahiyat, Kagya A Amoako, Mark E. MeyerhoffAbstract:Nitric oxide (NO) is an endogenous vasodilator as well as natural inhibitor of platelet adhesion and activation that can be released from a NO donor species, such as diazeniumdiolated dibutylhexanediamine (DBHD/N2O2) within a polymer coating. In this study, various Food and Drug Administration approved poly(lactic-co-glycolic acid) (PLGA) species were evaluated as additives to promote a prolonged NO release from DBHD/N2O2 within a plasticized poly(vinyl chloride) (PVC) matrix. When using an ester-capped PLGA additive with a slow hydrolysis time, the resulting coatings continuously release between 7 and 18 × 10−10 mol cm−2 min−1 NO for 14 days at 37 °C in PBS buffer. The corresponding pH changes within the polymer films were visualized using pH sensitive indicators and are shown to correlate with the extended NO release pattern. The optimal combined diazeniumdiolate/PLGA-doped NO release (NOrel) PVC coating was evaluated in vitro and its effect on the hemodynamics was also studied within a 4 h in vivo extracorporeal circulation (ECC) rabbit model of thrombogenicity. Four out of 7 control circuits clotted within 3 h, whereas all the NOrel coated circuits were patent after 4 h. Platelet counts on the NOrel ECC were preserved (79 ± 11% compared to 54 ± 6% controls). The NOrel coatings showed a significant decrease in the thrombus area as compared to the controls. Results suggest that by using ester-capped PLGAs as additives to a conventional plasticized PVC material containing lipophilic Diazeniumdiolates, the NO release can be prolonged for up to 2 weeks by controlling the pH within the organic phase of the coating.
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diazeniumdiolate doped poly lactic co glycolic acid based nitric oxide releasing films as antibiofilm coatings
Biomaterials, 2012Co-Authors: Wenyi Cai, Mark E. MeyerhoffAbstract:Nitric oxide (NO) releasing films with a bilayer configuration are fabricated by doping dibutyhexyldiamine diazeniumdiolate (DBHD/N2O2) in a poly(lactic-co-glycolic acid) (PLGA) layer and further encapsulating this base layer with a silicone rubber top coating. By incorporating pH sensitive dyes within the films, pH changes in the PLGA layer are visualized and correlated with the NO release profiles (flux vs. time). It is demonstrated that PLGA acts as both a promoter and controller of NO release from the coating by providing protons through its intrinsic acid residues (both end groups and monomeric acid impurities) and hydrolysis products (lactic acid and glycolic acid). Control of the pH changes within the PLGA layer can be achieved by adjusting the ratio of DBHD/N2O2 and utilizing PLGAs with different hydrolysis rates. Coatings with a variety of NO release profiles are prepared with lifetimes of up to 15 d at room temperature (23 °C) and 10 d at 37 °C. When incubated in a CDC flow bioreactor for a one week period at RT or 37 °C, all the NO releasing films exhibit considerable antibiofilm properties against gram-positive Staphylococcus aureus and gram-negative Escherichia coli. In particular, compared to the silicone rubber surface alone, an NO releasing film with a base layer of 30 wt% DBHD/N2O2 mixed with poly(lactic acid) exhibits an ∼98.4% reduction in biofilm biomass of S. aureus and ∼99.9% reduction for E. coli at 37 °C. The new diazeniumdiolate-doped PLGA-based NO releasing coatings are expected to be useful antibiofilm coatings for a variety of indwelling biomedical devices (e.g., catheters).
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intravascular glucose lactate sensors prepared with nitric oxide releasing poly lactide co glycolide based coatings for enhanced biocompatibility
Biosensors and Bioelectronics, 2011Co-Authors: Terry C Major, Robert H Bartlett, Mark E. MeyerhoffAbstract:Intravenous amperometric needle-type enzymatic glucose/lactate sensors intended for continuous monitoring are prepared with a novel nitric oxide (NO) releasing layer to improve device hemocompatibility. To create an underlying NO release coating, the sensors with immobilized enzymes (either glucose oxidase or lactate oxidase) are prepared with a thin layer of poly(lactide-co-glycolide) (PLGA) loaded with lipophilic diazeniumdiolate species that slowly release NO via a proton driven reaction. An outer thin layer (ca. 30 μm) of PurSil (polyurethane/dimethylsiloxane copolymer) limits the flux of glucose and lactate to the inner layer of enzyme, to provide the desired linear amperometric response. A 30 μm coating of PLGA containing 33 wt% of the appropriate NO donor (N-diazeniumdiolated dibutylhexanediamine, DBHD/N₂O₂) can release NO at a physiologically relevant rate > 1 × 10⁻¹⁰mol min⁻¹ cm⁻² for at least 7 days without influencing the analytical performance of the glucose/lactate sensors. In vitro, the sensors exhibit relatively stable amperometric response over a one-week period with high selectivity over interferences (e.g., ascorbic acid) required for blood monitoring applications. Glucose sensors implanted in the veins of rabbits for 8h exhibit significantly enhanced hemocompatibility for the NO release sensors vs. corresponding controls (without NO release in same animals), with greatly reduced thrombus formation on their surfaces. Further, the analytical performance of the NO release glucose sensors are superior to controls placed in the veins of the same animals, with a greater accuracy in measuring blood glucose levels as evaluated using a Clarke error grid type analysis.
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tailored synthesis of nitric oxide releasing polyurethanes using o2 protected diazeniumdiolated chain extenders
Journal of Materials Chemistry, 2010Co-Authors: Melissa M Reynolds, Joseph E Saavedra, Larry K Keefer, Brett M Showalter, Carlos A Valdez, Anna P Shanklin, Mark E. MeyerhoffAbstract:Nitric oxide (NO) has been shown to exhibit significant anti-platelet activity and its release from polymer matrices has been already utilized to increase the biocompatibility of various blood-contacting devices. Herein, the details of a new synthetic approach for preparing NO-releasing diazeniumdiolated polyurethanes (PUs) are described. The method's utility is demonstrated by the incorporation of methoxymethyl- or sugar-protected pre-formed diazeniumdiolate moieties directly into chain extender diols which are then incorporated into the polyurethane backbone. This approach provides the ability to control the number of diazeniumdiolate groups incorporated into the polymer backbone, and hence the surface flux of NO that can ultimately be liberated from polymeric films prepared from the new PU materials. The method provides a means of covalently attaching diazeniumdiolate groups to polyurethanes in a form that resists dissociation of NO during processing but can be activated for spontaneous NO release via hydrolysis of the carbohydrate or methoxymethyl moieties under basic and acidic conditions, respectively.
Joseph E Saavedra - One of the best experts on this subject based on the ideXlab platform.
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direct reaction of amides with nitric oxide to form Diazeniumdiolates
Journal of Organic Chemistry, 2014Co-Authors: Ryan J Holland, Larry K Keefer, John R Klose, Zhao Cao, Jeffrey R Deschamps, Joseph E SaavedraAbstract:We report the apparently unprecedented direct reaction of nitric oxide (NO) with amides to generate ions of structure R(C═O)NH–N(O)═NO–, with examples including R = Me (1a) or 3-pyridyl (1b). The sodium salts of both released NO in pH 7.4 buffer, with 37 °C half-lives of 1–3 min. As NO-releasing drug candidates, diazeniumdiolated amides would have the advantage of generating only 1 equiv of base on hydrolyzing exhaustively to NO, in contrast to their amine counterparts, which generate 2 equiv of base.
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Stereochemical Origins of Chromophore Extension in O^2-Substituted Diazeniumdiolates, Prodrugs of Nitric Oxide
Journal of Chemical Crystallography, 2013Co-Authors: Jeffrey R Deschamps, Joseph E Saavedra, Larry K Keefer, Zhao Cao, Harinath ChakrapaniAbstract:Ultraviolet spectral data for nitric oxide prodrugs of structure R_2NN(O)=NOR′ tend to fall into two classes: those in which R_2N is pyrrolidinyl have λ_max near 255 nm when R′ is a simple alkyl substituent, while those in which R_2N is not pyrrolidinyl display λ_max around 230 nm. To test the hypothesis that this spectral difference might reflect an electronic interaction large enough to affect key bond lengths and the configuration at the R_2N nitrogen, we have compared the crystal structures of two compounds in which R′ was β- d -glucopyranosyl tetraacetate and R_2N was pyrrolidinyl versus diethylamino. The X-ray studies revealed a pyramidyl R_2N nitrogen for the diethylamino derivative while the pyrrolidine derivative’s R_2N approached planarity, consistent with substantial electronic interaction between the N(O)=NOR′ chromophore and pyrrolidine’s (but not diethylamine’s) nitrogen atom. Compensatory changes in key bond lengths were also seen. These findings indicate that overlap between the pyrrolidine nitrogen’s p orbital and the N(O)=NOR′ chromophore can be an important determinant of structure and electron distribution in the diazeniumdiolate series. Graphical Abstract Ultraviolet spectral data for nitric oxide prodrugs of structure R_2NN(O)=NOR′ tend to fall into two classes and the wavelength of the ultraviolet absorbance maximum is a convenient and rather sensitive indicator of the tetrahedral versus planar steric arrangement at the R_2N^3 nitrogen.
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Nitric oxide-releasing prodrug triggers cancer cell death through deregulation of cellular redox balance
Elsevier, 2013Co-Authors: Anna E Maciag, Joseph E Saavedra, Ryan J Holland, Y.-s. Robert Cheng, Luis G. Rodriguez, Lucy M. Anderson, Larry K KeeferAbstract:JS-K is a nitric oxide (NO)-releasing prodrug of the O2-arylated diazeniumdiolate family that has demonstrated pronounced cytotoxicity and antitumor properties in a variety of cancer models both in vitro and in vivo. The current study of the metabolic actions of JS-K was undertaken to investigate mechanisms of its cytotoxicity. Consistent with model chemical reactions, the activating step in the metabolism of JS-K in the cell is the dearylation of the diazeniumdiolate by glutathione (GSH) via a nucleophilic aromatic substitution reaction. The resulting product (CEP/NO anion) spontaneously hydrolyzes, releasing two equivalents of NO. The GSH/GSSG redox couple is considered to be the major redox buffer of the cell, helping maintain a reducing environment under basal conditions. We have quantified the effects of JS-K on cellular GSH content, and show that JS-K markedly depletes GSH, due to JS-K's rapid uptake and cascading release of NO and reactive nitrogen species. The depletion of GSH results in alterations in the redox potential of the cellular environment, initiating MAPK stress signaling pathways, and inducing apoptosis. Microarray analysis confirmed signaling gene changes at the transcriptional level and revealed alteration in the expression of several genes crucial for maintenance of cellular redox homeostasis, as well as cell proliferation and survival, including MYC. Pre-treating cells with the known GSH precursor and nucleophilic reducing agent N-acetylcysteine prevented the signaling events that lead to apoptosis. These data indicate that multiplicative depletion of the reduced glutathione pool and deregulation of intracellular redox balance are important initial steps in the mechanism of JS-K's cytotoxic action
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o2 functionalized methylamine Diazeniumdiolates evidence for e z equilibration in an acyclic system
Journal of Organic Chemistry, 2012Co-Authors: Debanjan Biswas, Larry K Keefer, Zhao Cao, Ryan J Holland, Jeffrey R Deschamps, Joseph E SaavedraAbstract:Diazeniumdiolates that have the structure RHN-N(O)═NOR' are of interest as prodrug (caged) forms of the bioeffectors nitric oxide (NO) and nitroxyl (HNO). Previous work has focused on examples possessing α-branched R groups, with isopropylamine (IPA)/NO (R = isopropyl) being the smallest examined to date. To probe the effect of minimizing the alkyl-group size on the chemistry of IPA/NO, we prepared the corresponding methylamine derivative as a sodium salt that was highly unstable but could be trapped in very low overall yield as the stable O(2)-benzyl derivative. To prepare enough for efficient characterization, we devised an alternate synthesis involving a novel N-dealkylation route. CH(3)HN-N(O)═NOBn, synthesized in high yield and crystallized as the Z isomer as determined by X-ray crystallography, was observed to exist as a 11:1 mixture of two isomeric forms in dynamic equilibrium in solution. Similar results were seen for the O(2)-ethyl derivative, whose two equilibrium constituents were partially separated by HPLC to reveal essentially identical UV and mass spectra, indicating them to be Z and E isomers of CH(3)HN-N(O)═NOEt. The results could lead the way to a fuller understanding of the chemistry of the acyclic (E)-Diazeniumdiolates.
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js k a glutathione s transferase activated nitric oxide donor with antineoplastic activity in malignant gliomas
Neurosurgery, 2012Co-Authors: Astrid Weyerbrock, Joseph E Saavedra, Larry K Keefer, Nadja Osterberg, Nikolaos Psarras, Brunhilde Baumer, Evangelos Kogias, Anna Werres, Stefanie Bette, Anna PapazoglouAbstract:Background Glutathione S-transferases (GSTs) control multidrug-resistance and are upregulated in many cancers including malignant gliomas. The diazeniumdiolate JS-K generates nitric oxide (NO) on enzymatic activation by glutathione and GST, showing promising NO-based anticancer efficacy.