A Direct Comparison of the Anticancer Activities of Digitoxin MeON-Neoglycosides and O-Glycosides

Abstract

Digitoxin is a cardiac glycoside currently being investigated for potential use in oncology. While a number of structure-activity relationship studies have been conducted, an investigation of anticancer activity as a function of oligosaccharide chain length has not yet been performed. We generated mono-, di-, and tri-O-digitoxoside derivatives of digitoxin and compared their activity to the corresponding MeON-neoglycosides. Both classes of cardenolide derivatives display comparable oligosaccharide chain length-dependent cytotoxicity toward human cancer cell lines. Further investigation revealed that both classes of compounds induce caspase-9-mediated apoptosis in non-small cell lung cancer cells (NCI-H460). Since O-glycosides and MeON-neoglycosides share a similar mode of action, the convenience of MeON-neoglycosylation could be exploited in future SAR work to rapidly survey large numbers of carbohydrates to prioritize selected O-glycoside candidates for traditional synthesis.

Digitoxin and a synthetic monosaccharide analog inhibit cell viability in lung cancer cells

“…Digitoxin-bound Na + /K + ATPase activates tyrosine kinase Src, PI3K, phospholipase C and Ras/MAPK pathways which leads to anti-proliferative downstream effects related to cell growth and apoptosis (Xie and Cai, 2003; Newman et al , 2008). Given that the integrated sugars give the unique biological function of CGs (Iyer et al , 2010; Langenhan et al , 2008; Zhou and O’Doherty, 2008), digitoxin provides an excellent model to efficiently modify its carbohydrate moiety and assess the biological impact of novel synthetic derivatives using cellular-based experiments. Therefore, synthesis of CG derivatives has become a potential approach for developing safer and more effective anti-neoplastic drugs.…”

Autophagy‐Induced Apoptosis in Lung Cancer Cells by a Novel Digitoxin Analog

“…MonoD is the β-D digitoxose analog of Digitoxin, which was synthesized using a palladium-based de-novo method that has been developed by our group as described previously (Iyer et al, 2010). Both Digitoxin and MonoD consist of identical aglycone regions, but vary in the sugar region.…”

“…To alleviate this problem, we designed a novel set of cardenolide analogs that can mimic the anticancer effects of Digitoxin but at lower doses, thereby recapitulating the therapeutic benefits of Digitoxin signaling while overcoming Digitoxin-associated toxicity. Our preliminary study demonstrated potent anti-tumorigenic effects against several forms of cancer (Iyer et al, 2010). Of the synthesized analogs, the β-D-Digitoxose (henceforth abbreviated as MonoD) form was identified as having the greatest anti-tumor potential in our lung cancer model.…”

“…The β-D-Digitoxose (Mono D) form of Digitoxin was synthesized as described previously by O’Doherty et al (Iyer et al, 2010). …”

Neoglycosylation and neoglycorandomization: enabling tools for the discovery of novel glycosylated bioactive probes and early stage leads

“…84 A subsequent study to assess the impact of the length of the digitoxose saccharide chain for both O - and MeON-glycosides of digitoxin towards cytotoxicity revealed the monodigitoxoside to be the best in both formats. 85 …”