Synthesis and Evaluation of the α-d-/α-l-Rhamnosyl and Amicetosyl Digitoxigenin Oligomers as Antitumor Agents

Abstract

A highly regio- and stereo-selective asymmetric synthesis of rhamnosyl- and amicetosyl-digitoxigenin analogues has been established via palladium-catalyzed glycosylation followed by bis-/tris-dihydroxylation or bis-/tris-diimide reduction. The α-l-rhamnose and α-l-amicetose digitoxin monosaccharide analogues displayed stronger apoptosis inducing activity and cytotoxicity against non-small cell human lung cancer cells (NCI-H460) than its d-diastereomeric isomers in a sugar-chain length dependent manner.

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

“…1A) as previously described (Wang et al , 2010; Wang et al , 2011a). To evaluate whether D6-MA exhibits greater potency than digitoxin to inhibit NCI-H460 cell viability, we performed colorimetric MTT and trypan blue exclusion assays.…”

“…D6-MA, an α-L-rhamnose monosaccharide analog of digitoxin, was synthesized from digitoxin based on a previously described method (Wang et al , 2011a; Zhou and O’Doherty, 2008). Briefly, digitoxin was first subjected to acid hydrolysis to cleave off the trisaccharide moiety and generate free aglycone moiety, digitoxigenin (Fig.…”

“…This screening showed that non-small cell lung carcinoma (NSCLC) cells were more sensitive to digitoxin and its analogs than many other cancer cell lines being tested (Iyer et al , 2010; Wang et al , 2010). Additionally, three monosaccharide analogues, namely β-D-digitoxose, α-L-rhamnose and α-L-amicetose showed at least a 5-fold increase in potency to induce apoptosis and growth inhibition in NSCLC (Wang et al , 2010; Wang et al , 2011a; Wang et al , 2011b). However, these studies failed to identify the mechanisms mediating the anti-neoplastic effects of digitoxin or its synthetic analogs in cancer cells at/or below therapeutically relevant concentrations.…”

A Novel Use of Gentamicin in the ROS-Mediated Sensitization of NCI-H460 Lung Cancer Cells to Various Anticancer Agents

“…16 This unique aminoglycoside/ribosome interaction led to the choice of gentamicin for our study. To demonstrate the generalizability of any sensitization effect, a series of cancer drugs that act at various cellular locations with a range of mechanisms of action was chosen for screening: digitoxin 17 and its α-L-rhamnoside analogue 18,19,20,21,22,23 (extracellular, Na/K-ATPase pump), 24 vinblastine (cytosol, tubulin), 25 5-fluorouracil (nucleus, DNA polymerase), 26 camptothecin (nucleus, Topo I), 27 oxaliplatin (nucleus, DNA), 28 and doxorubicin (nucleus, DNA/TopoII). 29 …”

C5′-Alkyl Substitution Effects on Digitoxigenin α-l-Glycoside Cancer Cytotoxicity

“…More recently, we have had success in performing a series of systematic SAR studies on the carbohydrate portion of digitoxin for apoptotic cytotoxicity in the human lung cancer (NCI-H460) cell line. These studies include a comparison of digitoxin MeNO -neo- and O -glycosides (with O - better than MeNO -neo-glycosides),8 a study of sugar-chain length (with mono-better than di- or tri-saccharides),10 and a stereochemical survey of digitoxin monosaccharides (with β- d - digitoxo -, α- l - amiceto -, and α- l - rhamno -glycosides being the most active) 9. From these studies we concluded that O -glycosides were better than MeNO -neoglycosides,8 and that sugars with β- d - digitoxo -, α- l - amiceto -, and α- l - rhamno -stereochemistry were the most active 9.…”