Diversity‐oriented synthesis of diol‐based peptidomimetics as potential HIV protease inhibitors and antitumor agents

Peptidomimetic HIV protease inhibitors are an important class of drugs used in the treatment of AIDS. The synthesis of a new type of diol-based peptidomimetics is described. Our route is flexible, uses d-glucal as an inexpensive starting material, and makes minimal use of protection/deprotection cycles. Binding affinities from molecular docking simulations suggest that these compounds are potential inhibitors of HIV protease. Moreover, the antiproliferative activities of compounds 33 a, 35 a, and 35 b on HT-29, M21, and MCF7 cancer cell lines are in the low micromolar range. The results provide a platform that could facilitate the development of medically relevant asymmetrical diol-based peptidomimetic

Age-associated changes in long-chain fatty acid profile during healthy aging promote pro-inflammatory monocyte polarization via PPARγ

Differences in lipid metabolism associate with age-related disease development and lifespan. Inflammation is a common link between metabolic dysregulation and aging. Saturated fatty acids (FAs) initiate pro-inflammatory signalling from many cells including monocytes; however, no existing studies have quantified age-associated changes in individual FAs in relation to inflammatory phenotype. Therefore, we have determined the plasma concentrations of distinct FAs by gas chromatography in 26 healthy younger individuals (age 50 years). Linear mixed models were used to explore the association between circulating FAs, age and cytokines. We showed that plasma saturated, poly- and mono-unsaturated FAs increase with age. Circulating TNF-α and IL-6 concentrations increased with age, whereas IL-10 and TGF-β1 concentrations decreased. Oxidation of MitoSOX Red was higher in leucocytes from FA adults, and plasma oxidized glutathione concentrations were higher. There was significant colinearity between plasma saturated FAs, indicative of their metabolic relationships. Higher levels of the saturated FAs C18:0 and C24:0 were associated with lower TGF-β1 concentrations, and higher C16:0 were associated with higher TNF-α concentrations. We further examined effects of the aging FA profile on monocyte polarization and metabolism in THP1 monocytes. Monocytes preincubated with C16:0 increased secretion of pro-inflammatory cytokines in response to phorbol myristate acetate-induced differentiation through ceramide-dependent inhibition of PPARγ activity. Conversely, C18:1 primed a pro-resolving macrophage which was PPARγ dependent and ceramide dependent and which required oxidative phosphorylation. These data suggest that a midlife adult FA profile impairs the switch from proinflammatory to lower energy, requiring anti-inflammatory macrophages through metabolic reprogramming

Diastereoselectivity in the directed aldol condensation of 2-trimethylsiloxyfuran with aldehydes. A stereodivergent route to <i>threo</i> and <i>erythro</i> δ-hydroxy-γ-lactones

Threo and erythro-δ-hydroxy-α,β-unsaturated γ-lactones are obtained with useful diastereoselection by condensing 2-trimethylsiloxyfuran and aldehydes by varying the reaction reaction conditions. A stereomechanistic rationale is presented together with a practical two-step synthesis of the threo and erythro 5-hydroxy-4-decanolides (L factors)

Total synthesis of bromobeckerelide

The first synthesis of (±)-bromobeckerelide has been accomplished in five steps from 5-methylfurfural by exploiting the regiospecific aldolization of a dialkylboron 2-furanolate

The regio- and Stereo-controlled Synthesis of <i>cis-p</i>-Menth-3-ene-1,2-diol by means of a 1,2,4-Trioxane Intermediate

A concise synthesis of (±)-cis-p-menth-3-ene-1,2-diol from α-terpinene is described which relies on the regio- and stereo-controlled construction of a 1,2,4-trioxane intermediate; structures proposed for two aroma constituents of Ferula jaeschkeana oil are revised

A New Reaction of 1,2-Dioxetanes. Formation of 1,2,4-Trioxanes from Aldehydes

1,2-Dioxetanes bearing different 3-phenoxy substituents add to aldehydes to give 1,2,4-trioxanes in yields of 17–75% depending on the nature of the para-phenyl substituent. Illustrations of this new reaction are described

A short, stereodivergent synthesis of the racemic erythro and threo diastereomers of 6-acetoxy-5-hexadecanolide, a mosquito oviposition attractant pheromone

A versatile 3-step synthesis of the title lactones has been accomplished by the stereocontrolled addition of n-decylmetallic reagents to acrolein dimer. Stereocontrol of the first step enables selective synthesis of either diastereomeric lactone

Reactions of cyclic peroxides with aldehydes and ketones catalysed by trimethylsilyl trifluoromethanesulphonate. An efficient synthesis of 1,2,4-trioxanes

Trimethylsilyl trifluoromethanesulphonate is found to be an efficient catalyst for the reaction of 1,4-endoperoxides and 1,2-dioxetanes with aldehydes and ketones to give 1,2,4-trioxanes in high yields.</p

Efficient Preparation of 1,2,4,5-Tetroxanes from Bis(trimethylsilyl) Peroxide and Carbonyl Compounds

Symmetrically 3,6-disubstituted and 3,3,6,6-tetrasubstituted 1,2,4,5-tetroxanes are prepared in good yields by the condensation of bis(trimethylsilyl) peroxide with aldehydes and ketones in the presence of trimethylsilyl trifluoromethanesulfonate.</p