Abstract
We report the antitumor effects of nitric oxide (NO) releasing derivatives of the PARP-1 inhibitor olaparib (1). Compound 5b was prepared by coupling the carboxyl group of 3b and the free amino group of arylated diazeniumdiolated piperazine 4. Analogue 5a has the same structure except that the F is replaced by H. Compound 13 is the same as 5b except that a Me2N-N(O)═NO- group was added para and ortho to the nitro groups of the dinitrophenyl ring. The resulting prodrugs are activated by glutathione in a reaction accelerated by glutathione S-transferase P1 (GSTP1), an enzyme frequently overexpressed in cancers. This metabolism generates NO plus a PARP-1 inhibitor simultaneously, consuming reducing equivalents, leading to DNA damage concomitant with inhibition of DNA repair, and in the case of 13 inducing cross-linking glutathionylation of proteins. Compounds 5b and 13 reduced the growth rates of A549 human lung adenocarcinoma xenografts with no evidence of systemic toxicity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Boronic Acids / pharmacology
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Bortezomib
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Comet Assay
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DNA Damage
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Drug Design
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Drug Synergism
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Enzyme Inhibitors / pharmacology
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Glutathione S-Transferase pi / metabolism*
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Humans
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Isoenzymes / drug effects
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Models, Molecular
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Neoplasms / drug therapy
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Neoplasms / enzymology*
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Nitric Oxide / metabolism*
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerase Inhibitors*
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Prodrugs / chemical synthesis
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Prodrugs / pharmacology
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Pyrazines / pharmacology
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Boronic Acids
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Enzyme Inhibitors
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Isoenzymes
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Poly(ADP-ribose) Polymerase Inhibitors
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Prodrugs
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Pyrazines
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Nitric Oxide
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Bortezomib
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PARP1 protein, human
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Poly (ADP-Ribose) Polymerase-1
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Glutathione S-Transferase pi