Assembling the carbon skeleton of A-74528.

The 2'-phosphodiesterase inhibitor A-74528, which combines an intriguing biosynthesis with unusual biological activity, is one of the most complex type II polyketides. As a synthetic target, it represents a significant challenge due to its size but also due to a unique carbon skeleton that features a hexacarbocyclic core with an appended pyrone. Here we report our efforts toward the synthesis of A-74528, which culminated in the construction of the full carbon skeleton and the correct installation of all but one stereocenter.

Optical Control of Mitosis with a Photoswitchable Eg5 Inhibitor.

Eg5 is a kinesin motor protein that is responsible for bipolar spindle formation and plays a crucial role during mitosis. Loss of Eg5 function leads to the formation of monopolar spindles, followed by mitotic arrest, and subsequent cell death. Several cell-permeable small molecules have been reported to inhibit Eg5 and some have been evaluated as anticancer agents.

Optical Control of Phosphatidic Acid Signaling.

Phosphatidic acids (PAs) are glycerophospholipids that regulate key cell signaling pathways governing cell growth and proliferation, including the mTOR and Hippo pathways. Their acyl chains vary in tail length and degree of saturation, leading to marked differences in the signaling functions of different PA species. For example, in mTOR signaling, saturated forms of PA are inhibitory, whereas unsaturated forms are activating.

Optimized Photoactivatable Lipid Nanoparticles Enable Red Light Triggered Drug Release.

Encapsulation of small molecule drugs in long-circulating lipid nanoparticles (LNPs) can reduce toxic side effects and enhance accumulation at tumor sites. A fundamental problem, however, is the slow release of encapsulated drugs from these liposomal systems at the disease site resulting in limited therapeutic benefit. Methods to trigger release at specific sites are highly warranted.

Optical Control of Lysophosphatidic Acid Signaling.

Lysophosphatidic acid (LPA) is a phospholipid that acts as an extracellular signaling molecule and activates the family of lysophosphatidic acid receptors (LPA). These G protein-coupled receptors (GPCRs) are broadly expressed and are particularly important in development as well as in the nervous, cardiovascular, reproductive, gastrointestinal, and pulmonary systems. Here, we report on a photoswitchable analogue of LPA, termed , which contains an azobenzene photoswitch embedded in the acyl chain.

Structure-function relationships of HDL in diabetes and coronary heart disease.

High-density lipoproteins (HDL) contain hundreds of lipid species and proteins and exert many potentially vasoprotective and antidiabetogenic activities on cells. To resolve structure-function-disease relationships of HDL, we characterized HDL of 51 healthy subjects and 98 patients with diabetes (T2DM), coronary heart disease (CHD), or both for protein and lipid composition, as well as functionality in 5 cell types. The integration of 40 clinical characteristics, 34 nuclear magnetic resonance (NMR) features, 182 proteins, 227 lipid species, and 12 functional read-outs by high-dimensional statistical modeling revealed, first, that CHD and T2DM are associated with different changes of HDL in size distribution, protein and lipid composition, and function.

Pyridyl Radical Cation for C-H Amination of Arenes.

Electron-transfer photocatalysis provides access to the elusive and unprecedented N-pyridyl radical cation from selected N-substituted pyridinium reagents. The resulting C(sp )-H functionalization of (hetero)arenes furnishes versatile intermediates for the development of valuable aminated aryl scaffolds. Mechanistic studies that include the first spectroscopic evidence of a spin-trapped N-pyridyl radical adduct implicate SET-triggered, pseudo-mesolytic cleavage of the N-X pyridinium reagents mediated by visible light.

Synthesis and Structure-Activity Relationship Studies of Anti-Inflammatory Epoxyisoprostane Analogues.

The lactone derivative of the epoxyisoprostane EC is a highly effective inhibitor of the secretion of the proinflammatory cytokine IL-6. Herein, a modular synthesis of analogues is described, allowing flexible variations of the cyclic side chain of the parent lactone. A structure-activity relationship study identified a lactam analogue that retains the high activity.

Total Synthesis of (-)-Rhazinilam and Formal Synthesis of (+)-Eburenine and (+)-Aspidospermidine: Asymmetric Cu-Catalyzed Propargylic Substitution.

A total synthesis of (-)-rhazinilam and formal syntheses of (+)-eburenine and (+)-aspidospermidine that rely on a copper(I)-catalyzed asymmetric propargylic substitution as the key step are reported. A salient feature of the reaction is the asymmetric construction of a quaternary stereocenter in high yield and enantiomeric excess.

Stereochemical studies of the opening of chloro vinyl epoxides: cyclic chloronium ions as intermediates.

A systematic study of the opening of a collection of chlorinated vinyl epoxides is reported, which includes experiments that implicate both five- and four-membered chloronium ions as plausible intermediates in this type of epoxide opening reaction.

Bi(OTf)3-catalyzed three-component synthesis of α-amino acid derivatives.

A highly efficient Bi(OTf)3-catalyzed multicomponent synthesis of arylglycines from readily available starting materials is described. The reaction proceeds under mild conditions and provides a general route to various N-protected arylglycines.