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C3′/C4′‐Stereochemical Effects of Digitoxigenin a‐L‐/a‐D‐Glycoside in Cancer Cytotoxicity
Author(s) -
McKenna Sean,
Hinds John
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1014.8
Subject(s) - digitoxin , digitoxigenin , chemistry , cytotoxicity , cardiac glycoside , biochemistry , proto oncogene tyrosine protein kinase src , monosaccharide , glycoside , stereochemistry , pharmacology , ouabain , signal transduction , biology , medicine , digoxin , in vitro , heart failure , organic chemistry , sodium
Digitoxin, used for the treatment of congestive heart failure, has more recently been recognized for its potential application in oncology. The mechanism of action occurs via an increase of Ca 2+ influx as a result of inhibition of the extracellular Na + /K + ‐ATPase pump. In contrast to the cardiotonic effects, less detail is known for the mechanism of antitumor activity. Several studies suggest that in cancer cells, a cardiac glycoside‐bound Na + /K + ‐ATPase complex signals via Src‐tyrosine kinase and 1,4,5‐ triphosphoinositol (IP3), ultimately leading to apoptosis. This signaling pathway is believed to occur through specific isoforms of the Na + /K + ‐ATPase pump. Using our lead digitoxin analogue (a‐L‐rhamno 1 ), we conducted a systematic SAR study, focusing on the stereochemistry and functionality of the C3′‐ and C4′‐stereocenters. We examined the cytotoxicity of digitoxin analouges against four different cancer cell lines: NCI‐H460, A549, MCF‐7, and MDA‐MB‐231. MTT assays were performed from nM to M concentrations. This study helps define limits of digitoxin monosaccharide carbohydrate substitution on cytotoxicity and points towards further analogue design. In contrast to substitution at the C‐2,4 and 5‐positions of the carbohydrate, this study shows the potential for C‐3 substitution for Na/K‐ATP‐ase isoform selectivity without loss of activity.