Recent developments of small molecule γ-secretase modulators for Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of progressive neurodegenerative disorder, marked by memory loss and a decline in cognitive function. The major hallmarks of AD are the presence of intracellular neurofibrillary tau tangles (NFTs) composed of hyperphosphorylated tau proteins and extracellular plaques composed of amyloid beta peptides (Aß). The amyloid (Aß) cascade hypothesis proposes that the AD pathogenesis is initiated by the accumulation of Aß peptides in the parenchyma of the brain. An aspartyl intramembranal protease called γ-secretase is responsible for the production of Aß by the cleavage of the amyloid precursor protein (APP). Clinical studies of γ-secretase inhibitors (GSIs) for AD failed due to the lack of substrate specificity. Therefore, γ-secretase modulators (GSMs) have been developed as potential disease modifying agents to modulate the γ-secretase cleavage activity towards the production of toxic Aß42 peptides. Following the first-generation 'nonsteroidal anti-inflammatory drug' (NSAID) based GSMs, second-generation GSMs (carboxylic acid based NSAID derivatives and non-NSAID derived heterocyclic analogues), as well as natural product-based GSMs, have been developed. In this review, we focus on the recent developments of small molecule-based GSMs that show potential improvements in terms of drug-like properties as well as their current status in human clinical trials and the future perspectives of GSM research.

Effect of Poly(sophorolipid) Functionalization on Human Mesenchymal Stem Cell Osteogenesis and Immunomodulation.

Sophorolipids are a class of glycolipids that can be polymerized via ring-opening metathesis polymerization giving rise to bioresorbable biomaterials. The surface chemistry of the resulting poly(sophorolipids) (pLSLs) can be modified using a combination of enzymatic and "click" chemistries to insert bioactive groups that influence cellular behavior. Mesenchymal stem cells (MSCs) are being actively investigated for engineered bone grafts for fracture repair due to their osteogenic potential, and more recently, due to their immunomodulatory capacity. The long-term goal of this work is to utilize functionalized pLSL foams loaded with MSCs as bioresorbable scaffolds for bone fracture healing. Toward this goal, the present study evaluated the effect of various pLSL chemistries on the osteogenic and immunomodulatory behavior of MSCs. pLSLs functionalized with PO4, NH2, or COOH small functional groups were fabricated into open porous foams and then cultured with MSCs in the presence of osteogenic medium for 72 h. Protein level assessments demonstrated that the PO4-functionalized pLSL foams supported the highest degree of MSC osteogenesis as well as the highest levels of immunomodulatory factors pertinent to improve bone fracture healing. Cumulatively, these results suggest that further investigation of the long-term osteogenic commitment of MSCs in PO4-functionalized pLSL foams is warranted.

Cooperative Self-Assembly of Helical Exciton-Coupled Biosurfactant-Functionalized Porphyrin Chromophores.

Biobased, self-organizing molecules are of considerable interest as functional materials due to their structural versatility, sophisticated nanoarchitectures, and sustainable biosynthesis. Here, we study the self-assembly of a systematic series of bioconjugate sophorolipid-functionalized zinc porphyrin complexes with potential applications in optoelectronic devices. Our results provide insight into the molecular features that control the polymerization pathway, in particular the influence of carbohydrate chirality and noncovalent hydrogen-bonding on biosurfactant-driven self-organization of sophisticated light-absorbing supramolecular polymers. The self-assembly process is driven by a combination of hydrogen-bond, steric, and π-π interactions. Compounds under investigation were synthesized to examine the influence of peripheral chiral carbohydrate hydrogen bonding on chromophore aggregation and physicochemical properties through selective acetylation of the sophorose moiety. In dilute methanol/water solution, we found that excitonically coupled helical structures form by strong carbohydrate hydrogen-bonding interactions, in contrast to weakly coupled J-type aggregate formation with acetyl-group substitution of sugar hydroxyl moieties. Temperature-dependent UV/vis absorption and circular dichroism revealed that supramolecular polymerization proceeds through a cooperative mechanism of self-assembly for compounds bearing free OH groups capable of forming hydrogen-bond interactions. In contrast, per-acetylation of the sophorolipid's sugar group leads to micellar aggregation that is governed by a sterically driven isodesmic (noncooperative) assembly mechanism.

Grown Ultrathin Bacterial Cellulose Mats for Optical Applications.

A facile and effective method is described for the biosynthesis of ultrathin bacterial cellulose (BC) mats, which are green, inexpensive, lightweight, and flexible. Physical properties studied include thickness, morphology, reflectance, transmittance, and crystallinity index. BC mat thickness was varied by controlling the depth of the culture broth so that films with predictable thickness, between 113 and 1114 nm, were produced. These BC films have similar fiber morphology to corresponding mm thick BC films prepared under static culture conditions. To increase BC film hydrophobicity, surface trihexylsilylated BC (THSBC) mats with DSavg 0.015 were prepared. Both native and THSBC mats were investigated as antireflection coatings for silicon substrates. The 328 ± 42 nm thick BC mat demonstrated broadband, interference type antireflection over a spectral range of 500-1800 nm. Different reflection properties obtained as a function of BC film orientation reveals that engineered density gradients can be used to manipulate BC optical properties. Thus, optical quality and environmental friendly ultrathin BC films are promising biomaterials for next-generation optoelectronic devices.

Biosurfactant-functionalized porphyrin chromophore that forms J-aggregates.

Structurally complex biosynthesized building blocks whose structures can be systematically varied are of great interest for the synthesis of manipulable self-organizing supramolecular systems. Sophorolipids (SLs) are an important class of glycolipid biosurfactants that consists of a sophorose (glucose disaccharide) polar head group that allows structural diversification by full or selective acetylation at the 6'- and 6''-positions. Porphyrins are a group of naturally-occurring heterocyclic macromolecular organic compounds that have efficient charge transfer properties. Herein we describe the synthesis of SL-porphyrin conjugates where the number of sophorolipid arms, availability of hydrogen bonding sophorose hydroxyl groups and rigidity of the lipid chain were systematically varied. SLs differing in 'sophorose acetylation' and 'lipid unsaturation' were conjugated to zinc-porphyrin dyes by copper(i)-catalyzed azide-alkyne cycloaddition (CuAAC) 'click' chemistry. Mono-, di-, and tetra-conjugation of SL-arms to the zinc-porphyrin core provided variation in SL-arm steric effects. UV-vis spectra in methanol/water reveal features indicative of supramolecular J-type aggregates. The synthesized compounds were designed to provide a library of unique bio-based molecules with built-in variation in non-covalent interactions, hydrogen-bonding, π-π stacking, metal-ligand coordination, dipole-dipole, van der Waals, and hydrophobic interactions for future interrogation of supramolecular self-assembly into functional materials for electro-optical applications.

A scalable, nonenzymatic synthesis of highly stereopure difunctional C4 secondary methyl linchpin synthons.

In response to the continuing widespread use of heterodifunctional C4 secondary methyl building blocks in asymmetric synthesis, we have developed a mole-scale, two-step synthesis of a 1:1 mixture of the diastereomers of 3-bromo-2-methyl-1-propyl camphorsulfonate (casylate). One isomer (2S) has been crystallized to >99:1 dr in ∼25% yield. Equilibration of the mother liquor (enriched in 2R) to a 1:1 mixture and recrystallization significantly raises the overall yield of 2S. Applications of 2S include chemoselective Grignard coupling, enabling the very short synthesis of highly stereopure long-chain natural products containing remote, methyl-bearing stereogenic centers [e.g., (R)-tuberculostearic acid], with complete control of configuration. Also, Ag-mediated, completely chemoselective Br displacement from 2S leads to a range of >99:1 er difunctional synthons. Both applications incorporate concurrent recovery of CasO. The enantiomer of 2S can be made from commercial (1R)-10-CasOH.