183953-29-9Relevant articles and documents
Chemical Approach to Positional Isomers of Glucose-Platinum Conjugates Reveals Specific Cancer Targeting through Glucose-Transporter-Mediated Uptake in Vitro and in Vivo
Patra, Malay,Awuah, Samuel G.,Lippard, Stephen J.
, p. 12541 - 12551 (2016/10/07)
Glycoconjugation is a promising strategy for specific targeting of cancer. In this study, we investigated the effect of d-glucose substitution position on the biological activity of glucose-platinum conjugates (Glc-Pts). We synthesized and characterized all possible positional isomers (C1α, C1β, C2, C3, C4, and C6) of a Glc-Pt. The synthetic routes presented here could, in principle, be extended to prepare glucose conjugates with different active ingredients, other than platinum. The biological activities of the compounds were evaluated both in vitro and in vivo. We discovered that varying the position of substitution of d-glucose alters not only the cellular uptake and cytotoxicity profile but also the GLUT1 specificity of resulting glycoconjugates, where GLUT1 is glucose transporter 1. The C1α- and C2-substituted Glc-Pts (1α and 2) accumulate in cancer cells most efficiently compared to the others, whereas the C3-Glc-Pt (3) is taken up least efficiently. Compounds 1α and 2 are more potent compared to 3 in DU145 cells. The α- and β-anomers of the C1-Glc-Pt also differ significantly in their cellular uptake and activity profiles. No significant differences in uptake of the Glc-Pts were observed in non-cancerous RWPE2 cells. The GLUT1 specificity of the Glc-Pts was evaluated by determining the cellular uptake in the absence and in the presence of the GLUT1 inhibitor cytochalasin B, and by comparing their anticancer activity in DU145 cells and a GLUT1 knockdown cell line. The results reveal that C2-substituted Glc-Pt 2 has the highest GLUT1-specific internalization, which also reflects the best cancer-targeting ability. In a syngeneic breast cancer mouse model overexpressing GLUT1, compound 2 showed antitumor efficacy and selective uptake in tumors with no observable toxicity. This study thus reveals the synthesis of all positional isomers of d-glucose substitution for platinum warheads with detailed glycotargeting characterization in cancer.
The First Total Syntheses of Enantiomerically Pure Naturally Occuring Ellagitannins Gemin D and its Regioisomer Hippomanin A
Khanbabaee, Karamali,Loetzerich, Kerstin,Borges, Markus,Grosser, Mathias
, p. 159 - 166 (2007/10/03)
The total syntheses of naturally occuring ellagitannins gemin D (1) and its regioisomer hippomanin A (2) are reported. In addition, the phase-transfer catalyzed benzylation reaction of the 2,3-glucopyranoside diols 3-7 is described. Our studies have illustrated the influence of the structure of 2,3-glucopyranoside diols on the regioselectivity of the phase-transfer catalyzed benzylation at their free 2,3-OH groups. We could show, that both phase-transfer catalyzed benzylations of 2,3-glucopyranoside diols using tetrabutylammonium hydrogensulfate (Bu4NHSO4) or using tetrabutylammonium iodide (Bu4NI) disfavour the formation of the corresponding 3-O-monobenzylated products and preferentially give the 2-O-monobenzylated products. However, the ratio of the generated 2- versus 3-O-mono- and 2,3-dibenzylated products from these reactions also strongly depends upon the nature of the starting materials. The glucopyranosides 3 and 4 are the first examples, which allow the completely regioselective monobenzylation at the 2-OH positions by a phase-transfer catalyzed reaction.
