Synthesis and anti-cancer potential of the positional isomers of NOSH-aspirin (NBS-1120) a dual nitric oxide and hydrogen sulfide releasing hybrid

Federica Vannini; Andrew C MacKessack-Leitch; Erin K Eschbach; Mitali Chattopadhyay; Ravinder Kodela; Khosrow Kashfi

doi:10.1016/j.bmcl.2015.08.023

Synthesis and anti-cancer potential of the positional isomers of NOSH-aspirin (NBS-1120) a dual nitric oxide and hydrogen sulfide releasing hybrid

Bioorg Med Chem Lett. 2015 Oct 15;25(20):4677-82. doi: 10.1016/j.bmcl.2015.08.023. Epub 2015 Aug 14.

Authors

Federica Vannini¹, Andrew C MacKessack-Leitch², Erin K Eschbach¹, Mitali Chattopadhyay¹, Ravinder Kodela¹, Khosrow Kashfi³

Affiliations

¹ Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, 138th Street and Convent Avenue, New York, NY 10031, USA.
² Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, 138th Street and Convent Avenue, New York, NY 10031, USA; EaStCHEM School of Chemistry, University of St. Andrews, St. Andrews, Fife KY16 9ST, UK.
³ Department of Physiology, Pharmacology and Neuroscience, Sophie Davis School of Biomedical Education, City University of New York Medical School, 138th Street and Convent Avenue, New York, NY 10031, USA; Avicenna Pharmaceuticals Inc., 555 West 57th Street, New York, NY 10019, USA. Electronic address: kashfi@med.cuny.edu.

Abstract

We recently reported the synthesis of NOSH-aspirin, a novel hybrid compound capable of releasing both nitric oxide (NO) and hydrogen sulfide (H2S). In NOSH-aspirin, the two moieties that release NO and H2S are covalently linked at the 1, 2 positions of acetyl salicylic acid, i.e., ortho-NOSH-aspirin. Here we report on the synthesis of meta- and para-NOSH-aspirins. We also made a head-to-head evaluation of the effects of these three positional isomers of NOSH-aspirin on colon cancer cell kinetics and induction of reactive oxygen species, which in recent years has emerged as a key event in causing cancer cell regression. Electron donating/withdrawing groups incorporated about the benzoate moiety significantly affected the potency of these compounds with respect to colon cancer cell growth inhibition.

Keywords: Cell kinetics; Colon cancer; Hydrogen sulfide; NOSH-aspirin; Nitric oxide; Reactive oxygen species.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Aspirin / analogs & derivatives*
Aspirin / chemical synthesis
Aspirin / chemistry
Aspirin / pharmacology
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Disulfides / chemical synthesis
Disulfides / chemistry
Disulfides / pharmacology*
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
HT29 Cells
Humans
Hydrogen Sulfide / metabolism*
Molecular Structure
Nitrates / chemical synthesis
Nitrates / chemistry
Nitrates / pharmacology*
Nitric Oxide / metabolism*
Reactive Oxygen Species / metabolism
Structure-Activity Relationship

Substances

4-(3-thioxo-3H-1,2-dithiol-5-yl)phenyl 2-((4-(nitrooxy)butanoyl)oxy)benzoate
Antineoplastic Agents
Disulfides
Nitrates
Reactive Oxygen Species
Nitric Oxide
Aspirin
Hydrogen Sulfide

Grants and funding

R24 DA018055/DA/NIDA NIH HHS/United States