Synthesis, nitric oxide release, and anti-leukemic activity of glutathione-activated nitric oxide prodrugs: Structural analogues of PABA/NO, an anti-cancer lead compound

Chakrapani, Harinath; Wilde, Thomas; Citro, Michael L.; Goodblatt, Michael M.; Keefer, Larry K.; Saavedra, Joseph E.

doi:10.1016/j.bmc.2007.11.035

Cited by 27 publications

(19 citation statements)

References 24 publications

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“…The diazeniumdiolate compounds release NO· and have been shown in several models to have potential anti cancer properties. For example, the compound PABA/NO designed by Keefer’s group was shown to inhibit human leukemia cell proliferation and release free NO· upon activation by glutathione [88]. Another compound produced by this group is JS-K.…”

Section: No· Releasing Drugsmentioning

confidence: 99%

Nitric Oxide and Cancer Therapy: The Emperor has NO Clothes

Hickok

Thomas

2010

CPD

128

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The role of nitric oxide (NO·) as a mediator of cancer phenotype has led researchers to investigate strategies for manipulating in vivo production and exogenous delivery of this molecule for therapeutic gain. Unfortunately, NO· serves multiple functions in cancer physiology. In some instances, NO· or nitric oxide synthase (NOS) levels correlate with tumor suppression and in other cases they are related to tumor progression and metastasis. Understanding this dichotomy has been a great challenge for researchers working in the field of NO· and cancer therapy. Due to the unique chemical and biochemical properties of NO·, it’s interactions with cellular targets and the subsequent downstream signaling events can be vastly different based upon tumor heterogeneity and microenvironment. Simple explanations for the vast range of NO-correlated behaviors will continue to produce conflicting information about the relevance of NO· and cancer. Paying considerable attention to the chemical properties of NO· and the methodologies being used will remove many of the discrepancies in the field and allow for in depth understanding of when NO-based chemotherapeutics will have beneficial outcomes.

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Section: No· Releasing Drugsmentioning

confidence: 99%

Nitric Oxide and Cancer Therapy: The Emperor has NO Clothes

Hickok

Thomas

2010

CPD

128

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“…This compound, a novel nitrate containing an NSAID and disulfide pharmacophores, exhibits antiproliferative activity and exerts a G 2 /M cell cycle block in cultured colon cancer cells [13]. Finally, the so-called NONO-NSAIDs have been synthesized and studied for their anti-inflammatory and anticancer properties [14][15][16]. It should not be forgotten that the organic nitrates are also NO-donating compounds.…”

Section: No-nsaids: Rationale and Structurementioning

confidence: 99%

NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action

Rigas

Williams

2008

Nitric Oxide

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Nitric oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) consist of a conventional NSAID to which an NO-releasing moiety is attached covalently, often via a spacer molecule. NONSAIDs represent an emerging class of compounds with chemopreventive properties against a variety of cancers, demonstrated in preclinical models including cell culture systems and animal tumor models; their potential efficacy in humans has not been assessed. Their mechanism of action appears complex and involves the generation of reactive oxygen species, suppression of microsatellite instability in mismatch repair-deficient cells, and modulation of several signaling cascades that culminate in inhibited cell renewal and enhanced apoptosis. NO, long appreciated to be able to protect from and also promote cancer, is released form NO-NSAIDs and constitutes their defining property. Existing data are consistent with the notion that NO may mediate their anticancer effect. In addition there is evidence that long term administration of NO-donating compounds is not associated with increased incidence of colon cancer. Whether NO release is required for the anticancer effect of NO-NSAIDs has being questioned by recent data indicating that, at least in the case of NO-aspirin, the NO-releasing moiety may serve as a leaving group while the spacer actually being the moiety responsible for its pharmacological action. Regardless of mechanistic issues, these compounds promise to contribute to the control of cancer.

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“…37, 38 For example, Chakrapani and coworkers synthesized O 2 -(2,4-dinitro-5-(4-(N-methylamino) benzoyloxy)phenyl)-1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (PABA/NO) as an anti-cancer NO prodrug with efficacy against human leukemia and A2780 human ovarian cancer xenografts. 39 Both the NO payload and release kinetics were shown to influence the anticancer activity. The study of how chemical structure impacts the rate of NO release from small molecule NO donors has been an active area of research, particularly with respect to biological activity.…”

Section: Introductionmentioning

confidence: 99%

Structurally Diverse Nitric Oxide-Releasing Poly(propylene imine) Dendrimers

Yuan

Sun

2011

Chem. Mater.

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Structurally diverse secondary amine-functionalized poly(propylene imine) (PPI) dendrimers capable of tunable nitric oxide (NO) release were synthesized in a straightforward, one-step manner using ring-opening or conjugate-addition reactions with propylene oxide (PO), styrene oxide (SO), acrylonitrile (ACN), poly(ethylene glycol) methyl ether acrylate (average Mn = 480) (PEG) or 1,2-epoxy-9-decene (ED). N-Diazeniumdiolate nitric oxide donors were formed on the resulting secondary amine-functionalized G2–G5 PPI dendrimers by reaction with NO gas in basic solution. The NO storage and release kinetics for the resulting dendritic scaffolds were diverse (0.9–3.8 μmol NO/mg totals and 0.3 to 4.9 h half lives), illustrating the importance of the exterior chemical modification (e.g., steric environments, hydrophobicity, etc.) on diazeniumdiolate stability/decomposition. Tunable NO release was demonstrated by combining two donor systems on the exterior of one macromolecular scaffold. Additionally, a mathematical model was developed that allows for the simulation of dual NO release kinetics using the NO release data from the two single NO donor systems. The approaches described herein extend the range and scope of NO-releasing macromolecular scaffolds by unlocking a series of materials for use as dopants in biomedical polymers or stand-alone therapeutics depending on the exterior modification.

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Synthesis, nitric oxide release, and anti-leukemic activity of glutathione-activated nitric oxide prodrugs: Structural analogues of PABA/NO, an anti-cancer lead compound

Cited by 27 publications

References 24 publications

Nitric Oxide and Cancer Therapy: The Emperor has NO Clothes

Nitric Oxide and Cancer Therapy: The Emperor has NO Clothes

NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action

Structurally Diverse Nitric Oxide-Releasing Poly(propylene imine) Dendrimers

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