Hormetic potential of methylglyoxal, a side-product of glycolysis, in switching tumours from growth to death.

Metabolic reprogramming toward aerobic glycolysis unavoidably favours methylglyoxal (MG) and advanced glycation end products (AGEs) formation in cancer cells. MG was initially considered a highly cytotoxic molecule with potential anti-cancer value. However, we have recently demonstrated that MG enhanced tumour growth and metastasis. In an attempt to understand this dual role, we explored MG-mediated dicarbonyl stress status in four breast and glioblastoma cancer cell lines in relation with their glycolytic phenotype and MG detoxifying capacity. In glycolytic cancer cells cultured in high glucose, we observed a significant increase of the conversion of MG to D-lactate through the glyoxalase system. Moreover, upon exogenous MG challenge, glycolytic cells showed elevated amounts of intracellular MG and induced de novo GLO1 detoxifying enzyme and Nrf2 expression. Thus, supporting the adaptive nature of glycolytic cancer cells to MG dicarbonyl stress when compared to non-glycolytic ones. Finally and consistent with the pro-tumoural role of MG, we showed that low doses of MG induced AGEs formation and tumour growth in vivo, both of which can be reversed using a MG scavenger. Our study represents the first demonstration of a hormetic effect of MG defined by a low-dose stimulation and a high-dose inhibition of tumour growth.

Methylglyoxal, a glycolysis side-product, induces Hsp90 glycation and YAP-mediated tumor growth and metastasis.

Metabolic reprogramming toward aerobic glycolysis unavoidably induces methylglyoxal (MG) formation in cancer cells. MG mediates the glycation of proteins to form advanced glycation end products (AGEs). We have recently demonstrated that MG-induced AGEs are a common feature of breast cancer. Little is known regarding the impact of MG-mediated carbonyl stress on tumor progression. Breast tumors with MG stress presented with high nuclear YAP, a key transcriptional co-activator regulating tumor growth and invasion. Elevated MG levels resulted in sustained YAP nuclear localization/activity that could be reverted using Carnosine, a scavenger for MG. MG treatment affected Hsp90 chaperone activity and decreased its binding to LATS1, a key kinase of the Hippo pathway. Cancer cells with high MG stress showed enhanced growth and metastatic potential in vivo. These findings reinforce the cumulative evidence pointing to hyperglycemia as a risk factor for cancer incidence and bring renewed interest in MG scavengers for cancer treatment.

Synthesis of Cryptophanes with Two Different Reaction Sites: Chemical Platforms for Xenon Biosensing.

We report the synthesis of new water-soluble cryptophane host molecules that can be used for the preparation of (129)Xe NMR-based biosensors. We show that the cryptophane-223 skeleton can be modified to introduce a unique secondary alcohol to the propylenedioxy linker. This chemical functionality can then be exploited to introduce a functional group that is different from the six chemical groups attached to the aromatic rings. In this approach, the generation of a statistical mixture when trying to selectively functionalize a symmetrical host molecule is eliminated, which enables the efficient large-scale production of new cryptophanes that can be used as chemical platforms ready to use for the preparation of xenon biosensors. To illustrate this approach, two molecular platforms have been prepared, and the ability of these new derivatives to bind xenon has been investigated.

Total Synthesis and Reassignment of the Structures of the Antimicrobial Lipodepsipeptides Circulocin γ and δ.

The structures of the naturally occurring antimicrobial lipodepsipeptides circulocin γ and circulocin δ have been reported to comprise a common cyclic depsipeptide core attached to 3-hydroxy,ω-guanidino fatty acid chains differing in length by two methylene units, but analysis of the reported data suggested that the originally reported structures had incorrect side chain lengths. The total synthesis of both side chain epimers of the originally reported structure of circulocin γ bearing a 19-guanidino-3-hydroxynonadecanoyl (GHND) side chain has been accomplished using a modular approach involving synthesis of the cyclic depsipeptide and side chain fragments followed by a late stage coupling reaction. This revealed that the originally reported structure for circulocin γ bearing the GHND side chain is incorrect and that this structure is actually that of circulocin δ. It has also enabled the absolute configuration of the side chain hydroxy group of the natural product to be assigned as (R). Subsequent synthesis of the analogue bearing a 17-guanidino-3-(R)-hydroxyheptadecanoyl (GHHD) side chain provided confirmation that this revised structure is that of circulocin γ.

A new method for peptide synthesis in the N→C direction: amide assembly through silver-promoted reaction of thioamides.

The Ag(I)-promoted coupling of amino acids and peptides with amino ester thioamides generates peptide imides without epimerisation. The peptide imides undergo regioselective hydrolysis under mild conditions to generate native peptides. This method was employed to prepare the pentapeptide thymopentin in the N→C direction, in high yield and purity.

Synthesis of cyclic peptide hemicryptophanes: enantioselective recognition of a chiral zwitterionic guest.

The synthesis of the first members of a new class of cyclic peptide-containing hemicryptophanes is described. Synthesis was achieved through attachment of veratryl groups to the L-tyrosine side chains of a cyclic hexapeptide, c(YG)3, followed by intramolecular cyclodehydration to generate the CTV unit. The diastereomeric P- and M-hemicryptophanes were generated in a 2 : 1 ratio and were separated by chromatography. The enantioselective binding properties of the hemicryptophanes were investigated by complexation with carnitine. Both isomers were found to have significant selectivity for binding (R)-carnitine.

A macrolactonization approach to the total synthesis of the antimicrobial cyclic depsipeptide LI-F04a and diastereoisomeric analogues.

The cyclic peptide core of the antifungal and antibiotic cyclic depsipeptide LI-F04a was synthesised by using a modified Yamaguchi macrolactonization approach. Alternative methods of macrolactonization (e.g., Corey-Nicolaou) resulted in significant epimerization of the C-terminal amino acid during the cyclization reaction. The D-stereochemistry of the alanine residue in the naturally occurring cyclic peptide may be required for the antifungal activity of this natural product.

Total synthesis of mycocyclosin.

The first total synthesis of mycocyclosin, a diketopiperazine natural product isolated from M. tuberculosis, is described. While direct oxidative coupling of tyrosine phenolic groups was unsuccessful, construction of the highly strained bicyclic framework was successfully accomplished through an intramolecular Miyaura-Suzuki cross-coupling to generate the biaryl linkage.

Total synthesis and assignment of the side chain stereochemistry of LI-F04a: an antimicrobial cyclic depsipeptide.

The total synthesis of the potent antifungal and antibiotic cyclic depsipeptide LI-F04a and its side chain epimer was accomplished using macrolactonization to assemble the cyclic peptide core, followed by attachment of the 15-guanidino-3-hydroxypentadecanoyl (GHPD) side chain. The side chain was assembled by Yamaguchi-Hirao alkylation of both enantiomers of a chiral epoxide to provide a pair of enantiomeric side chains. The attachment of both these chains to the cyclic peptide allowed the absolute configuration of the side chain hydroxyl group in LI-F04a to be assigned as (R).