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

Abstract

A highly regio- and stereo-selective asymmetric synthesis of various C5'-alkyl side chains of rhamnosyl- and amicetosyl-digitoxigenin analogs has been established via palladium-catalyzed glycosylation with post-glycosylated dihydroxylation or diimide reduction. The C5'-methyl group in both α-l-rhamnose and α-l-amicetose digitoxin analogs displayed a steric directed apoptosis induction and tumor growth inhibition against non-small cell human lung cancer cells (NCI-H460). The anti-tumor activity is significantly reduced when the steric hindrance is increased at C5'-stereocenter.

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

“…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.…”

Cryptocaryols A and B: Total Syntheses, Stereochemical Revision, Structure Elucidation, and Structure–Activity Relationship

“…23 With access to cryptocaryol A and B, two known PDCD4 stabilizers (4.9 and 3.0 mM, see Gustafson’s assay), this comparison can be made. We chose to study MCF-7 breast cancer cells (Table 1 and Figure 2), 24 because of their high expression level of PDCD4. 25 We found that both cryptocaryol A and B possessed growth inhibitory activity against MCF-7 in the mircomolar range and their relative activity was consistent with their PDCD4 stabilizing activity (i.e., 10 slightly more active than 9 ).…”

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 …”