ChemInform Abstract: Assignment of the Absolute Configuration of Natural Lentiginosine by Synthesis and Enzymatic Assays of Optically Pure (+) and (‐)‐ Enantiomers.

Brandi, Alberto; Cicchi, Stefano; Cordero, Franca M.; Frignoli, Roberta; Goti, A.; Picasso, Sylviane; Vogel, Pierre

doi:10.1002/chin.199610287

Cited by 3 publications

(5 citation statements)

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“…In order to evaluate the ability of iminosugars to affect the biological activity of Hsp90, we started a chemical-biological study using (+)-lentiginosine (compound 1 in Figure 1 ) as model compound; it was selected because of its simple structure, high water solubility, and significant biological activity [13] , [14] .…”

Section: Resultsmentioning

confidence: 99%

“…(+)-Lentiginosine, a natural occurring dihydroxyindolizidine alkaloid, has been shown to be a selective and the most powerful indolizidine inhibitor of amyloglucosidases [13], [14]. Besides, recently the synthetic enantiomer (−)-lentiginosine was found a proapoptotic inducer with low cytotoxicity [15], [16].…”

Section: Introductionmentioning

confidence: 99%

“…On this basis, we performed a screening oriented to obtain Hsp90 inhibitors on several natural compounds and we focused on the iminosugar (+)-lentiginosine for its chemical and bioactivity characteristics. (+)-Lentiginosine, a natural occurring dihydroxyindolizidine alkaloid, has been shown to be a selective and the most powerful indolizidine inhibitor of amyloglucosidases [13] , [14] . Besides, recently the synthetic enantiomer (−)-lentiginosine was found a proapoptotic inducer with low cytotoxicity [15] , [16] .…”

Section: Introductionmentioning

confidence: 99%

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Natural Iminosugar (+)-Lentiginosine Inhibits ATPase and Chaperone Activity of Hsp90

et al. 2012

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Heat shock protein 90 (Hsp90) is a significant target in the development of rational cancer therapy due to its role at the crossroads of multiple signaling pathways associated with cell proliferation and cell viability. The relevance of Hsp90 as a therapeutic target for numerous diseases states has prompted the identification and optimization of novel Hsp90 inhibitors as an emerging therapeutic strategy. We performed a screening aimed to identify novel Hsp90 inhibitors among several natural compounds and we focused on the iminosugar (+)-lentiginosine, a natural amyloglucosidases inhibitor, for its peculiar bioactivity profile. Characterization of Hsp90 inhibition was performed using a panel of chemical and biological approaches, including limited proteolysis, biochemical and cellular assays. Our result suggested that the middle domain of Hsp90, as opposed to its ATP-binding pocket, is a promising binding site for new classes of Hsp90 inhibitors with multi-target anti-cancer potential.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Natural Iminosugar (+)-Lentiginosine Inhibits ATPase and Chaperone Activity of Hsp90

et al. 2012

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“…Moreover, we must also consider that no glycosidase-inhibitory activity other than that exerted on the fungal amyloglucosidase has been found at the moment for both the enantiomers of lentiginosine. 26 Accordingly, it seems plausible that the alterations of MMP or OMM, which we found after treatment with π(β)lentiginosine, might be routed through a signalling process different from glycosidase inhibition. However, because various glycosidase inhibitors have been proven to exhibit a number of different effects on carbohydrate cell biology, and given the fundamental role for carbohydrate processing in cell proliferation and survival, we can hypothesize that an unknown step in carbohydrate cell metabolism could be the initial target for induction of apoptosis by π(β)lentiginosine through the intrinsic pathway.…”

Section: Discussionmentioning

confidence: 85%

D(−)lentiginosine-induced apoptosis involves the intrinsic pathway and is p53-independent

et al. 2012

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We have recently found that 𝒟(−)lentiginosine, a synthetic iminosugar exerting glucosidase inhibitory activity, but not its natural enantiomer lentiginosine, is endowed with an unexpected, pro-apoptotic activity. Here, we investigated mechanisms involved in apoptosis induced by 𝒟−)lentiginosine in MOLT-3, HT-29 and SH-SY5Y tumour cell lines. The results showed that 𝒟−)lentiginosine increased caspase 9 expression at 18 h in all the cell lines from 1.5–3.1 folds. Cytochrome c in the cytoplasm was found to be increased from 2.3–2.6 folds in treated cells with respect to control cells. These effects were accompanied by a remarkable collapse of the mitochondrial membrane potential and by the downregulation of anti-apoptotic genes, as well as the upregulation of pro-apoptotic genes of the Bcl-2 family. U937Bcl-2 transfectants, highly expressing Bcl-2, were reluctant to undergo apoptosis even following treatment with 500 μM 𝒟−)lentiginosine, whereas apoptosis by 𝒟−)lentiginosine was induced also in U937 cells, naturally deficient in P53. Thus, our study establishes that the enantiomer of a natural iminosugar is endowed with a possible anti-tumorigenic effect that might be ascribed not only to their capacity to inhibit glycosidases but also to other unknown mechanisms. These data encourage further investigation on similar compounds to make them an interesting platform for the generation of new anticancer drugs.

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“…There has been a long dispute around the absolute configuration of natural lentiginosine (Cardona et al 2007), that was cleared up with the synthesis of both enantiomers together with the study of their inhibitory activity (Brandi et al 1995;Goti et al 1996). Natural lentiginosine was assigned as dextrorotatory.…”

Section: Introductionmentioning

confidence: 99%

The novel proapoptotic activity of nonnatural enantiomer of Lentiginosine

et al. 2010

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ChemInform Abstract: Assignment of the Absolute Configuration of Natural Lentiginosine by Synthesis and Enzymatic Assays of Optically Pure (+) and (‐)‐ Enantiomers.

Cited by 3 publications

References 1 publication

Natural Iminosugar (+)-Lentiginosine Inhibits ATPase and Chaperone Activity of Hsp90

Natural Iminosugar (+)-Lentiginosine Inhibits ATPase and Chaperone Activity of Hsp90

D(−)lentiginosine-induced apoptosis involves the intrinsic pathway and is p53-independent

The novel proapoptotic activity of nonnatural enantiomer of Lentiginosine

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