Synthesis of chemical tools to improve water solubility and promote the delivery of salinomycin to cancer cells.

Chemotherapy and radiation are unable to eliminate all cancer cells, particularly apoptosis-resistant cancer cells, despite their ability to kill cancer cluster cells. Thus, it is important to identify methods that eliminate all cancer cells in order to prevent relapse. Salinomycin has the ability to control and eradicate different types of cancer, including breast cancer; however, its molecular mechanism remains unclear. The main difficulty in testing salinomycin activity and understanding the governing mechanisms is its low solubility in water (17 mg/l), which can hinder convenient delivery of salinomycin to the protein receptor at the cell surface of stem cells. In the present study, salinomycin was conjugated to the trans-activator of transcription-protein in order to facilitate its delivery to the cancer cells. Conjugated salinomycin demonstrated improved solubility in both in vitro. Salinomycin was tested in breast cancer cells (MCF7 and JIMT-1) by the cleavage of the linker through photolysis at l≥365 nm during in vitro analysis, in the present study.

A New Caged-Glutamine Derivative as a Tool To Control the Assembly of Glutamine-Containing Amyloidogenic Peptides.

We present the design, synthesis, and characterization of a novel photocaged glutamine derivative (modified on the side chain of glutamine), and describe its use in enhancing peptide stability and solubility. Our results demonstrate that this approach can be used to develop molecular switches to control the folding and ß-sheet formation of amyloidogenic peptides.

Chemical strategies for controlling protein folding and elucidating the molecular mechanisms of amyloid formation and toxicity.

It has been more than a century since the first evidence linking the process of amyloid formation to the pathogenesis of Alzheimer's disease. During the last three decades in particular, increasing evidence from various sources (pathology, genetics, cell culture studies, biochemistry, and biophysics) continues to point to a central role for the pathogenesis of several incurable neurodegenerative and systemic diseases. This is in part driven by our improved understanding of the molecular mechanisms of protein misfolding and aggregation and the structural properties of the different aggregates in the amyloid pathway and the emergence of new tools and experimental approaches that permit better characterization of amyloid formation in vivo. Despite these advances, detailed mechanistic understanding of protein aggregation and amyloid formation in vitro and in vivo presents several challenges that remain to be addressed and several fundamental questions about the molecular and structural determinants of amyloid formation and toxicity and the mechanisms of amyloid-induced toxicity remain unanswered. To address this knowledge gap and technical challenges, there is a critical need for developing novel tools and experimental approaches that will not only permit the detection and monitoring of molecular events that underlie this process but also allow for the manipulation of these events in a spatial and temporal fashion both in and out of the cell. This review is primarily dedicated in highlighting recent results that illustrate how advances in chemistry and chemical biology have been and can be used to address some of the questions and technical challenges mentioned above. We believe that combining recent advances in the development of new fluorescent probes, imaging tools that enabled the visualization and tracking of molecular events with advances in organic synthesis, and novel approaches for protein synthesis and engineering provide unique opportunities to gain a molecular-level understanding of the process of amyloid formation. We hope that this review will stimulate further research in this area and catalyze increased collaboration at the interface of chemistry and biology to decipher the mechanisms and roles of protein folding, misfolding, and aggregation in health and disease.

Rational design of indoleamine 2,3-dioxygenase inhibitors.

Indoleamine 2,3-dioxygenase (IDO) is an important therapeutic target for the treatment of diseases such as cancer that involve pathological immune escape. We have used the evolutionary docking algorithm EADock to design new inhibitors of this enzyme. First, we investigated the modes of binding of all known IDO inhibitors. On the basis of the observed docked conformations, we developed a pharmacophore model, which was then used to devise new compounds to be tested for IDO inhibition. We also used a fragment-based approach to design and to optimize small organic molecule inhibitors. Both approaches yielded several new low-molecular weight inhibitor scaffolds, the most active being of nanomolar potency in an enzymatic assay. Cellular assays confirmed the potential biological relevance of four different scaffolds.

The use of levoglucosenone and isolevoglucosenone as templates for the construction of C-linked disaccharides.

Because of their functionalities (enone, ketone, and acetal) and their bicyclic structure (steric factors), levoglucosenone (1,6-anhydro-3,4-dideoxy-beta-D-glycero-hex-3-enopyran-2-ulose) and isolevoglucosenone (1,6-anhydro-2,3-dideoxy-beta-D-glycero-hex-3-enopyran-4-ulose) are useful templates for the convergent and combinatorial synthesis of (1-->2), (1-->3), and (1-->4)-linked C-disaccharides in reactions combining them with sugar-derived carbaldehydes. Synthetic methods relying on conjugate nucleophilic additions of these enones, their combination with aluminum reagents and aldehydes (Baylis-Hillman reaction) and modified Takai-Hiyama-Nozaki-Kishi couplings of enol triflates derived from them with sugar-derived aldehydes are reviewed. Highly stereoselective methods have thus been developed. These allow the generation of disaccharide mimetics with a high molecular diversity.

C-linked disaccharide analogue of the Thomsen-Friedenreich (T)-epitope alpha-O-conjugated to L-serine.

Condensation of a silylated beta-D-galactopyranosylaldehyde (3) with isolevoglucosenone (4) in the presence of Et(2)AlI provided bicyclic enone 5. Subsequent addition of BnNHOMe gave adduct 6, which was converted into 4-O-acetyl-1,6-anhydro-3-C-[(1 R)-1,3,4,5,7-penta-O-acetyl-2,6-anhydro-D-glycero-L-manno-heptitol-1-C-yl]-2-azido-2,3-dideoxy-beta-D-galacto-hexopyranose after liberation of the 2-amino group, its transformation into a 2-azido moiety, desilylation, and peracetylation. Ring-opening of the 1,6-anhydro galactopyranosyl unit and O-glycosidation with Fmoc-Ser-O-tBu afforded a 5:1 mixture of alpha- and beta-galactosides. Treatment with CH(3)COSH gave pure N-[(9H-fluoren-9-ylmethoxy)carbonyl]-{4,6-di-O-acetyl-3-C-[(1 R)-2,6-anhydro 1,3,4,5,7-penta-O-acetyl-D-glycero-L-manno-heptitol-1-C-yl]-2-[(N-acetyl)amino]-2,3-dideoxy-alpha-D-galactopyranosyl}-l-serine tert-butyl ester (2), a protected form of a C-disaccharide analogue of the Thomsen-Friedenreich (or T) epitope (beta-D-Galp-(1-->3)-alpha-D-GalNAcp) alpha-O-conjugated to L-serine.

Silyl methallylsulfinates: efficient and powerful agents for the chemoselective silylation of alcohols, polyols, phenols and carboxylic acids.

Alcohols, phenols and carboxylic acids are silylated with very good yields in the presence of silyl methallylsulfinates under non-basic conditions and with the formation of volatile co-products.