Synthesis, characterization, and anti-melanoma activity of tetra-O-substituted analogs of nordihydroguaiaretic acid

doi:10.1016/j.bmcl.2009.06.063

Bioorganic & Medicinal Chemistry Letters

Volume 19, Issue 16, 15 August 2009, Pages 4752-4755

https://doi.org/10.1016/j.bmcl.2009.06.063 Get rights and content

Abstract

Synthesis of seven semi-synthetic analogs of NDGA is described. An approach to NDGA derivatization is described in which the ortho-phenolic groups are tethered together by one atom, forming a 5-membered heterocyclic ring. The analogs were evaluated for cytotoxicity in four cancer cell lines and compared to NDGA and tetra-O-methyl-NDGA (M4N) (1a). NDGA bis-cyclic sulfate (2a), NDGA bis-cyclic carbonate (2b), and methylenedioxyphenyl-NDGA (2d) and NDGA tetra acetate (1b) showed anti-cancer activity in vitro. Two compounds, (1b) and (2b), were evaluated for anticancer activity in a mouse xenograft model of human melanoma and showed dose-dependent activity.

Graphical abstract

Novel derivatives of nordihydoguaiaretic acid were synthesized and tested for in vitro and in vivo anticancer activity.

Section snippets

Acknowledgments

The authors would like to acknowledge Bhashyam S. Iyengar and William A. Remers for their assistance in the naming and characterization of the compounds described in this Letter. Sponsorship: The study was funded by grant CA017094 from the National Institutes of Health, Bethesda, Maryland, USA.

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Reaction products of bisulfite and caftaric acid were found in wines containing sulfites as a preservative. Acidic compounds were separated from wine and analyzed by HPLC combined with DAD and QTOF mass spectrometer. HPLC chromatograms of the expected [M−H]⁻ ion and UV absorption revealed the presence of five possible reaction products (a–e). These compounds were isolated then characterized by NMR and confirmed to be the reaction products as follows; 5-sulfo-(E)-caftaric acid (a), 2-sulfo-(Z)-caftaric acid (b), 2-sulfo-(E)-caftaric acid (c), (E)-caftaric acid-4-O-sulfate (d) and (E)-caftaric acid-3-O-sulfate (e). UV spectra and high resolution product ion spectra of the five compounds also supported their identity. The reaction products were confirmed to be commonly present in commercial wines across four vintages and two varieties. Their concentration was found to be as much as that of 2-S-glutathionyl caftaric acid, suggesting that bisulfite consistently competes as a nucleophile with glutathione for the o-quinone of caftaric acid.
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Synthesis, characterization, and anti-melanoma activity of tetra-O-substituted analogs of nordihydroguaiaretic acid

Abstract

Graphical abstract

Section snippets

Acknowledgments

Tetrahedron

Antiviral Res.

Antiviral Res.

Antiviral Res.

Bioorg. Med. Chem. Lett.

Cancer Lett.

Toxicon

The Honest Herbal a Sensible Guide to the Use of Herbs and Related Remedies

Biochemistry

J. Med. Chem.

Exp. Hematol.

J. Clin. Invest.