Piperazine as a Linker for Incorporating the Nitric Oxide-Releasing Diazeniumdiolate Group into Other Biomedically Relevant Functional Molecules
Abstract
Synthetic procedures have been devised to exploit the bifunctional amine piperazine (pip) as a linker capable of attaching the nitric oxide (NO)-releasing diazeniumdiolate functional group [N(O)NO] - to a diverse selection of biomedically useful molecules. One of the amino groups bears the diazeniumdiolate, which may be substituted on oxygen as necessary to control its dissociation to NO, while the other is used to provide a site suitable for covalent bonding to the molecule requiring NO donor capability. N,N‘-Disubstituted piperazines of the structure R-pip-N(O) NOE were prepared either by using the nucleophilic character of the amino group or by converting it into an electrophilic moiety for reaction with nucleophilic centers in the molecules to be derivatized. Examples are reported in which E = CH 3 and the R groups are bound to the N‘-nitrogen: via amide linkages to the carboxyl groups of the drug ibuprofen and the amino acid derivative N -acetylmethionine; through a urea grouping to the ε-amino group of a protected lysine; via a carbamate linkage to poly(ethylene glycol); and by replacing the NH 2 nitrogens of nicotinamide and adenosine. Synthesis of analogues in which E = vinyl has been facilitated by introduction of BrCH 2 CH 2 OSO 2 Cl as a novel, efficient bromoethylating agent. Spontaneous NO releasers in the diazeniumdiolated piperazine series include both a fluorescent anion of half-life 5.5 min in which E = Na and R = dansyl and “MOM-PIPERAZI/NO” (E = CH 3 OCH 2, R = H), whose half-life for NO release was estimated as 17 days. The latter agent has made possible the conversion of poly(vinyl chloride) and phosphatidylethanolamine to NO-releasing derivatives. This chemistry should allow introduction of diazeniumdiolate groups into a wide variety of natural products, drugs, polymers, and other molecules whose activities could be beneficially combined with the ability to generate NO for biomedical applications.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Meyerhoff and coworkers were among the first to link NO donors to particle fillers or to polymer backbones such as PVC, polyurethane, and silicone rubber.
“Meyerhoff and coworkers were among the first to link these NO donors to particle fillers (such as fumed silica particles236) or to the polymer backbone of polymers such as PVC,34,237 polyurethane (PU),34,110,233 and silicone rubber (SR).238”
From Recent advances in thromboresistant and antimicrobial polymers for biomedical applications: just say yes to nitric oxide (NO) (2016) · cites this paper as [237]
Cites
Maragos, C. M., Morley, D., Wink, D. A., Dunams, T. M., Saavedra, J. E., Hoffman, A., Bove, A. A., Isaac, L., Hrabie, J. A., & Keefer, L. K. (1991) · Journal of Medicinal Chemistry · doi:10.1021/jm00115a013 · Cited by 722 · see citing works
Self-citationNew nitric oxide-releasing zwitterions derived from polyamines
Hrabie, J. A., Klose, J. R., Wink, D. A., & Keefer, L. K. (1993) · The Journal of Organic Chemistry · doi:10.1021/jo00058a030 · Cited by 593 · see citing works
Self-citationSaavedra, J. E., Billiar, T. R., Williams, D. L., Kim, Y., Watkins, S. C., & Keefer, L. K. (1997) · Journal of Medicinal Chemistry · doi:10.1021/jm9701031 · Cited by 273 · see citing works
Self-citationCaged nitric oxide. Stable organic molecules from which nitric oxide can be photoreleased.
Makings, L. R., & Tsien, R. Y. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)37368-4 · Cited by 125 · see citing works
Secondary amine/nitric oxide complex ions, R2N[N(O)NO]-. O-Functionalization chemistry
Saavedra, J. E., Dunams, T. M., Flippen-Anderson, J. L., & Keefer, L. K. (1992) · The Journal of Organic Chemistry · doi:10.1021/jo00049a017 · Cited by 84 · see citing works
Self-citationMolecular farming in plants: Oilseeds as vehicles for the production of pharmaceutical proteins
Boothe, J. G., Saponja, J. A., & Parmenter, D. L. (1997) · Drug Development Research · doi:10.1002/(sici)1098-2299(199711/12)42:3/4 · Cited by 63 · see citing works
Welch, G. N., Upchurch, G. R., & Loscalzo, J. (1996) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(96)68031-8 · Cited by 38 · see citing works
Wolfe, J. L., VanderVelde, D. G., & Borchardt, R. T. (1992) · The Journal of Organic Chemistry · doi:10.1021/jo00049a018 · Cited by 29 · see citing works
Iwamura, H., Ito, T., Kumazawa, Z., & Ogawa, Y. (1975) · Phytochemistry · doi:10.1016/0031-9422(75)80336-0 · Cited by 23 · see citing works
ADDUCTS OF PIPERAZINE WITH NITRIC OXIDE
Hrabie, J. A., Saavedra, J. E., Davies, K. M., & Keefer, L. K. (1999) · Organic Preparations and Procedures International · doi:10.1080/00304949909355709 · Cited by 10 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Recent developments in nitric oxide donor drugs
Miller, M. R., & Megson, I. L. (2007) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707224 · Cited by 626 · see citing works
Nitric oxide release: Part I. Macromolecular scaffolds
Riccio, D. A., & Schoenfisch, M. H. (2012) · Chemical Society Reviews · doi:10.1039/c2cs15272j · Cited by 475 · see citing works
Hrabie, J. A., & Keefer, L. K. (2002) · Chemical Reviews · doi:10.1021/cr000028t · Cited by 466 · see citing works
Self-citationFrost, M. C., Reynolds, M. M., & Meyerhoff, M. E. (2005) · Biomaterials · doi:10.1016/j.biomaterials.2004.06.006 · Cited by 343 · see citing works
Wo, Y., Brisbois, E. J., Bartlett, R. H., & Meyerhoff, M. E. (2016) · Biomaterials Science · doi:10.1039/c6bm00271d · Cited by 251 · see citing works
Mowery, K. A., H. Schoenfisch, M., Saavedra, J. E., Keefer, L. K., & Meyerhoff, M. E. (2000) · Biomaterials · doi:10.1016/s0142-9612(99)00127-1 · Cited by 219 · see citing works
Self-citationDavies, K. M., Wink, D. A., Saavedra, J. E., & Keefer, L. K. (2001) · Journal of the American Chemical Society · doi:10.1021/ja002899q · Cited by 208 · see citing works
Self-citationProgress Toward Clinical Application of the Nitric Oxide–Releasing Diazeniumdiolates
Keefer, L. K. (2003) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.43.100901.135831 · Cited by 189 · see citing works
Self-citationRose, M. J., Fry, N. L., Marlow, R., Hinck, L., & Mascharak, P. K. (2008) · Journal of the American Chemical Society · doi:10.1021/ja801823f · Cited by 188 · see citing works
Shami, P. J., Saavedra, J. E., Wang, L. Y., Bonifant, C. L., Diwan, B. A., Singh, S. V., Gu, Y., Fox, S. D., Buzard, G. S., Citro, M. L., et al. (2003) · PubMed · Cited by 159 · see citing works
Self-citationNovel thromboresistant materials
Jordan, S. W., & Chaikof, E. L. (2007) · Journal of Vascular Surgery · doi:10.1016/j.jvs.2007.02.048 · Cited by 153 · see citing works
Dirhodium Tetracarboxylate Scaffolds as Reversible Fluorescence-Based Nitric Oxide Sensors
Hilderbrand, S. A., Lim, M. H., & Lippard, S. J. (2004) · Journal of the American Chemical Society · doi:10.1021/ja038471j · Cited by 144 · see citing works
Fitzhugh, A. L., & Keefer, L. K. (2000) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(00)00251-3 · Cited by 132 · see citing works
Self-citationReynolds, M. M., Frost, M. C., & Meyerhoff, M. E. (2004) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2004.06.019 · Cited by 116 · see citing works
Shami, P. J., Saavedra, J. E., Bonifant, C. L., Chu, J., Udupi, V., Malaviya, S., Carr, B. I., Kar, S., Wang, M., Jia, L., et al. (2006) · Journal of Medicinal Chemistry · doi:10.1021/jm060022h · Cited by 107 · see citing works
Self-citationRay, W. C., & Grinstaff, M. W. (2003) · Macromolecules · doi:10.1021/ma025872v · Cited by 97 · see citing works
Saavedra, J. E., Srinivasan, A., Bonifant, C. L., Chu, J., Shanklin, A. P., Flippen-Anderson, J. L., Rice, W. G., Turpin, J. A., Davies, K. M., & Keefer, L. K. (2001) · The Journal of Organic Chemistry · doi:10.1021/jo0016529 · Cited by 97 · see citing works
Self-citationOrganic Radical Reactions Associated with Nitrogen Monoxide
Hartung, J. (2009) · Chemical Reviews · doi:10.1021/cr900085j · Cited by 94 · see citing works
Paul, S., Pan, S., Mukherjee, A., & De, P. (2021) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.1c00486 · Cited by 78 · see citing works
New biomaterials for the sustained release of nitric oxide: past, present and future
Friedman, A., & Friedman, J. M. (2009) · Expert Opinion on Drug Delivery · doi:10.1517/17425240903196743 · Cited by 67 · see citing works
Nitric Oxide Generating/Releasing Materials
Liang, H., Nacharaju, P., Friedman, A., & Friedman, J. M. (2015) · Future Science OA · doi:10.4155/fso.15.54 · Cited by 67 · see citing works
Glycosylated diazeniumdiolates: a novel class of enzyme-activated nitric oxide donors
Wu, X., Tang, X., Xian, M., & Wang, P. G. (2001) · Tetrahedron Letters · doi:10.1016/s0040-4039(01)00614-1 · Cited by 61 · see citing works
Design, Synthesis, and Evaluation of Fimbrolide–Nitric Oxide Donor Hybrids as Antimicrobial Agents
Kutty, S. K., Barraud, N., Pham, A., Iskander, G. M., Rice, S. A., Black, D. S., & Kumar, N. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm400951f · Cited by 55 · see citing works
Yepuri, N. R., Barraud, N., Mohammadi, N. S., Kardak, B. G., Kjelleberg, S. J., Rice, S. A., & Kelso, M. J. (2013) · Chemical Communications · doi:10.1039/c3cc40869h · Cited by 53 · see citing works
Hilderbrand, S. A., & Lippard, S. J. (2004) · Inorganic Chemistry · doi:10.1021/ic049649l · Cited by 46 · see citing works
Rose, M. J., & Mascharak, P. K. (2008) · Chemical Communications · doi:10.1039/b805332d · Cited by 42 · see citing works
Valdez, C. A., Saavedra, J. E., Showalter, B. M., Davies, K. M., Wilde, T. C., Citro, M. L., Barchi, J. J., Deschamps, J. R., Parrish, D. A., El-Gayar, S., et al. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm8000482 · Cited by 41 · see citing works
Self-citationMaciag, A. E., Holland, R. J., Kim, Y., Kumari, V., Luthers, C. E., Sehareen, W. S., Biswas, D., Morris, N. L., Ji, X., Anderson, L. M., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm401550d · Cited by 38 · see citing works
Self-citationHibbard, H. A. J., & Reynolds, M. M. (2019) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2019.103318 · Cited by 37 · see citing works
Carpenter, A. W., Reighard, K. P., Saavedra, J. E., & Schoenfisch, M. H. (2013) · Biomaterials Science · doi:10.1039/c3bm00153a · Cited by 36 · see citing works
Self-citationUdupi, V., Yu, M. K., Malaviya, S., Saavedra, J. E., & Shami, P. J. (2006) · Leukemia Research · doi:10.1016/j.leukres.2005.12.007 · Cited by 33 · see citing works
Self-citationReynolds, M. M., Saavedra, J. E., Showalter, B. M., Valdez, C. A., Shanklin, A. P., Oh, B. K., Keefer, L. K., & Meyerhoff, M. E. (2010) · Journal of Materials Chemistry · doi:10.1039/c000152j · Cited by 29 · see citing works
Self-citationNitrosation of Sugar Oximes: Preparation of 2‐Glycosyl‐1‐hydroxydiazene‐2‐oxides
Brand, J., Huhn, T., Groth, U., & Jochims, J. C. (2005) · Chemistry - A European Journal · doi:10.1002/chem.200500325 · Cited by 26 · see citing works
Konter, J., Abuo‐Rahma, G. E. A., El-Emam, A. A.-R., & Lehmann, J. (2006) · European Journal of Organic Chemistry · doi:10.1002/ejoc.200600662 · Cited by 24 · see citing works
Chakrapani, H., Goodblatt, M. M., Udupi, V., Malaviya, S., Shami, P. J., Keefer, L. K., & Saavedra, J. E. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2007.12.044 · Cited by 23 · see citing works
Self-citationAndrei, D., Maciag, A. E., Chakrapani, H., Citro, M. L., Keefer, L. K., & Saavedra, J. E. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm800831y · Cited by 21 · see citing works
Self-citationHibbard, H. A. J., & Reynolds, M. M. (2020) · ACS Applied Bio Materials · doi:10.1021/acsabm.0c00670 · Cited by 21 · see citing works
Nitric Oxide Reacts with Methoxide
DeRosa, F., Keefer, L. K., & Hrabie, J. A. (2008) · The Journal of Organic Chemistry · doi:10.1021/jo7020423 · Cited by 21 · see citing works
Self-citationSaavedra, J. E., Mooradian, D. L., Mowery, K. A., Schoenfisch, M. H., Citro, M. L., Davies, K. M., Meyerhoff, M. E., & Keefer, L. K. (2000) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/s0960-894x(00)00086-x · Cited by 21 · see citing works
Self-citationNovel protection–deprotection strategies in diazeniumdiolate chemistry: synthesis of V-IPA/NO
Nandurdikar, R. S., Keefer, L. K., & Saavedra, J. E. (2011) · Chemical Communications · doi:10.1039/c1cc12130h · Cited by 20 · see citing works
Self-citationKutty, S. K., Barraud, N., Ho, K. K. K., Iskander, G. M., Griffith, R., Rice, S. A., Bhadbhade, M. M., Willcox, M. D. P., Black, D. S., & Kumar, N. (2015) · Organic & Biomolecular Chemistry · doi:10.1039/c5ob01373a · Cited by 18 · see citing works
Hydrophobic N‐Diazeniumdiolates and the Aqueous Interface of Sodium Dodecyl Sulfate (SDS) Micelles
Mohr, A., Vila, T. P., Korth, H., Rehage, H., & Sustmann, R. (2008) · ChemPhysChem · doi:10.1002/cphc.200800399 · Cited by 15 · see citing works
Nandurdikar, R. S., Maciag, A. E., Citro, M. L., Shami, P. J., Keefer, L. K., Saavedra, J. E., & Chakrapani, H. (2009) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2009.03.115 · Cited by 15 · see citing works
Self-citationKaczmarek, M. Z., Holland, R. J., Lavanier, S. A., Troxler, J. A., Fesenkova, V. I., Hanson, C. A., Cmarik, J. L., Saavedra, J. E., Keefer, L. K., & Ruscetti, S. K. (2013) · Leukemia Research · doi:10.1016/j.leukres.2013.12.002 · Cited by 13 · see citing works
Self-citationLocalization of HydrophobicN-Diazeniumdiolates in Aqueous Micellar Solution
Mohr, P. C., Mohr, A., Vila, T. P., & Korth, H. (2010) · Langmuir · doi:10.1021/la101619y · Cited by 9 · see citing works
Huang, Z., Zhang, Y., Fang, L., Zhang, Z., Lai, Y., Ding, Y., Cao, F., Zhang, J., & Peng, S. (2009) · Chemical Communications · doi:10.1039/b820535c · Cited by 9 · see citing works
Ingram, M. J., Moynihan, H. A., Powell, M. W., & Rostron, C. (2001) · Journal of Pharmacy and Pharmacology · doi:10.1211/0022357011775578 · Cited by 7 · see citing works
Abuo‐Rahma, G. E. A., Horstmann, A., Radwan, M. F., El-Emam, A. A.-R., Glusa, E., & Lehmann, J. (2005) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2004.11.003 · Cited by 6 · see citing works
Sun, J., Qi, S.-J., Chen, Q., Liu, K., Liu, H., Zheng, H., Sun, B., & Lou, H. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c02733 · Cited by 5 · see citing works
Modulated nitric oxide delivery in three-dimensional biomaterials for vascular functionality
Wang, Z., Wen, F., Zhang, R., & Zhang, Q. (2017) · MRS Communications · doi:10.1557/mrc.2017.40 · Cited by 5 · see citing works
Cinco, M. Á. B., Wu, G. X., & Hayton, T. W. (2023) · Inorganic Chemistry · doi:10.1021/acs.inorgchem.3c02188 · Cited by 4 · see citing works
Biomedical applications of polymeric nitric oxide (NO) donors
Paul, S., Kumar, M., Mukherjee, A., & De, P. (2023) · Elsevier eBooks · doi:10.1016/b978-0-443-13342-8.00017-x · Cited by 3 · see citing works
Diazeniumdiolates (Formerly NONOates) in Cardiovascular Research and Potential Clinical Applications
Saavedra, J. E., Fitzhugh, A. L., & Keefer, L. K. (2000) · Humana Press eBooks · doi:10.1007/978-1-59259-002-5_24 · Cited by 2 · see citing works
Self-citationBasavaiah, D., & Reddy, R. M. (2001) · Journal of Chemical Research · doi:10.3184/030823401103170250 · Cited by 2 · see citing works
Nitric Oxide-Releasing Biomedical Materials
Damodaran, V. B., & Reynolds, M. M. (2016) · Taylor & Francis eBooks · doi:10.1081/e-ebpp-120049951 · Cited by 2 · see citing works
Li, M., Yuan, S., Chen, J., Lv, L., Guo, S., & Zhou, W. (2018) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2018.08.015 · Cited by 1 · see citing works
Development of JS-K, a First-in-Class Arylated Diazeniumdiolate, for the Treatment of Cancer
Shami, P. J. (2023) · Critical Reviews™ in Oncogenesis · doi:10.1615/critrevoncog.2023048725 · Cited by 1 · see citing works
Novel nitric oxide donors for the dispersal and control of Pseudomonas aeruginosa biofilms
Poh, W. H. (2018) · doi:10.32657/10356/74583 · Cited by 1 · see citing works
Synthesis and characterization of dendrimer-based nitric oxide delivery systems
Stasko, N. (2019) · Carolina Digital Repository (University of North Carolina at Chapel Hill) · doi:10.17615/yse0-mv38
Navuluri, C. S. (2016) · Encyclopedia of Reagents for Organic Synthesis · doi:10.1002/047084289x.rn01917
- Authors
- Saavedra, J. E., Booth, M. N., Hrabie, J. A., Davies, K. M., & Keefer, L. K.
- Affiliations
- George Mason University (US)
- Venue
- The Journal of Organic Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 1999-06-15
- Volume
- 64
- Issue
- 14
- Pages
- 5124-5131
- ISSN
- 0022-3263 (ISSN-L)
- 1520-6904
- OpenAlex
- W1967517379
- Cited by
- 60
- References
- 10
- Citations by year
- 2025: 1 · 2023: 3 · 2021: 1 · 2020: 1 · 2019: 2 · 2018: 2 · 2017: 1 · 2016: 3 · 2015: 2 · 2014: 1 · 2013: 4 · 2012: 1
- FWCI
- 1.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Organic Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Keywords
- piperazine, diazeniumdiolates, nitric oxide donors, N-acetylmethionine, polyethylene glycol, nicotinamide, adenosine, polyvinyl chloride, phosphatidylethanolamine, NO release kinetics
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
