Enhancing the force sensitivity of a squeezed light optomechanical interferometer.

Application of frequency-dependent squeezed vacuum improves the force sensitivity of an optomechanical interferometer beyond the standard quantum limit by a factor of e-r, where r is the squeezing parameter. In this work, we show that the application of squeezed light along with quantum back-action nullifying meter in an optomechanical cavity with mechanical mirror in middle configuration can enhance the sensitivity beyond the standard quantum limit by a factor of e-reff, where reff = r + ln(4Δ/ζ)/2, for 0 < ζ/Δ < 1, with ζ as the optomechanical cavity decay rate and Δ as the detuning between cavity eigenfrequency and driving field. The technique described in this work is restricted to frequencies much smaller than the resonance frequency of the mechanical mirror. We further studied the sensitivity as a function of temperature, mechanical mirror reflectivity, and input laser power.

Mitochondria targeting molecular transporters: synthesis, lipophilic effect, and ionic complex.

As mitochondria are potential therapeutic targeting sites for the treatment of human diseases, delivering cytotoxic drugs, antioxidants, and imaging molecules to mitochondria can provide new therapeutic opportunities. In an attempt to develop a new mitochondria-targeting vector, we synthesized sorbitol-based molecular transporters with multiple guanidines, measured their partition coefficients, compared their targeting efficiency using fluorescent images and Pearson's correlation coefficients, and studied cellular uptake mechanisms. To increase the targeting ability of these molecular transporters to mitochondria, alanine-naphthalene as a lipophilic group was attached to the molecular transporter, which improved translocation across cellular membranes and led to higher accumulation in mitochondria. The molecular transporter was able to form an ionic complex with antibiotics, resulting in low cell viability. These data demonstrate that the molecular transporter with a lipophilic group could be utilized as a potential drug delivery vector for treating mitochondrial dysfunction.

Bridged α-helix mimetic small molecules.

Herein, we report a strategy for generating conformationally restricted α-helix mimetic small molecules by introducing covalent bridges that limit rotation about the central axis of α-helix mimetics. We demonstrate that the bridged α-helix mimetics have enhanced binding affinity and specificity to the target protein due to the restricted conformation as well as extra interaction of the bridge with the protein surface.

A guanidine-appended scyllo-inositol derivative AAD-66 enhances brain delivery and ameliorates Alzheimer's phenotypes.

Alzheimer's disease (AD) is a degenerative brain disease that destroys memory and other important mental functions but lacks efficient therapeutic agents. Blocking toxic amyloid ß (Aß) could be beneficial for AD and represents a promising therapeutic strategy for AD treatment. scyllo-Inositol (SI) is a potential therapeutic for AD by directly interacting with the Aß peptide to inhibit Aß42 fiber formation. Clinical studies of SI showed promising benefits on mild to moderate AD, however, with limitations on dosage regime. A new strategy to enhance the brain delivery of SI is needed to achieve the efficacy with minimum adverse effects. Herein, we report that a novel guanidine-appended SI derivative AAD-66 resulted in more effective reductions of brain Aß and plaque deposits, gliosis, and behavioral memory deficits in the disease-established 5xFAD mice. Overall, our present study reveals the potential of AAD-66 as a promising therapeutic agent for AD.

Intracellular and transdermal protein delivery mediated by non-covalent interactions with a synthetic guanidine-rich molecular carrier.

The impermeability of the cell plasma membrane is one of the major barriers for protein transduction into mammalian cells, and it also limits the use of proteins as therapeutic agents. Protein transduction has usually been achieved based on certain invasive processes or cell penetrating peptides (CPP). Herein we report our study in which a synthetic guanidine-rich molecular carrier is used as a delivery vector for intracellular and transdermal delivery of proteins. First a sorbitol-based molecular carrier having 8 guanidine units (Sor-G8) was synthesized, and then was simply mixed with a cargo protein of varying sizes to form the non-covalent complex of carrier-cargo proteins. These ionic complexes were shown to have efficient cellular uptake properties. The optimum conditions including the molar ratio between cargo protein and carrier, and the treatment time have been defined. Several protein cargoes were successfully examined with differing sizes and molecular weights: green fluorescent protein (MW 27kDa), albumin (66kDa), concanavalin A (102kDa), and immunoglobulin G (150kDa). These non-covalent complexes were also found to have excellent transdermal penetration ability into the mouse skin. The skin penetration depth was studied histologically by light microscopy as well as two-photon microscopy thus generating a depth profile. These complexes were largely found in the epidermis and dermis layers, i.e. down to ca. 100µm depth of the mouse skin. Our synthetic Sor-G8 carrier was found to be substantially more efficient that Arg8 in both the intracellular transduction and the transdermal delivery of proteins. The mechanism of the cellular uptake of the complex was briefly studied, and the results suggested macropinocytosis.

Which one is preferred: Myers-Saito cyclization of ene-yne-allene or Garratt-Braverman cyclization of conjugated bisallenic sulfone? A theoretical and experimental study.

A competitive scenario between Myers-Saito (MS) and Garratt-Braverman (GB) cyclization has been created in a molecule. High-level computations indicate a preference for GB over MS cyclization. The activation energies for the rate-determining steps of the GB and MS cyclizations were found to be the same (24.4 kcal/mol) at the B3LYP/6-31G* level of theory; thus, from the kinetic point of view, both reactions are feasible. However, the main biradical intermediate GB2 of the GB reaction is 6.2 kcal/mol lower in energy than the biradical MS2, which is the main intermediate of MS reaction, so GB cyclization is thermodynamically favored over MS cyclization. To verify the prediction by computational techniques, bisenediynyl sulfones 1-4 and bisenediynyl sulfoxide 17 were synthesized. Under basic conditions, these molecules isomerized to a system possessing both the ene-yne-allene and the bisallenic sulfone. The isolation of only one product, identified as the corresponding naphthalene- or benzene-fused sulfone 8-11, indicated the occurrence of GB cyclization as the sole reaction pathway. No product corresponding to the MS cyclization pathway could be isolated. Though the theoretical prediction showed a preference for the GB pathway over the MS pathway, the exclusive preference for GB over MS cyclization is very striking. Further analysis showed that the intramolecular self-quenching nature of the GB pathway may play an important role in the complete preference for this reaction. Apart from the mechanistic studies, these sulfones showed DNA cleavage activity that had an inverse relation with the reactivity order. Our findings are important for the design of artificial DNA-cleaving agents.

Design and synthesis of bisenediyne bissulfones and their reactivity under basic condition.

A new class of bisenediyne bis sulfones has been synthesized. These molecules underwent cycloaromatization under basic conditions via isomerization to allene and were able to cleave ds-stranded plasmid DNA.

Studies on the porcine liver esterase-catalyzed hydrolysis of pentaacetyl catechin and epicatechin: application to the synthesis of novel dimers and trimers.

Porcine liver esterase-catalyzed hydrolysis of 3,5,7,3',4'-pentaacetylated catechin was studied. The selectivity of the enzyme in hydrolyzing the acetate moiety is time dependent. Careful control of the duration of hydrolysis makes it possible to isolate the differentially protected catechins. Similar result was also obtained in the epicatechin series. These results are important for elaboration of epicatechin or catechin into different derivatives with defined regiochemistry. These include novel dimeric and trimeric architectures.

Chemistry of enediynyl azides: activation through a novel pathway.

The spontaneous activation of a nonaromatic enediynyl azide under ambient conditions has been demonstrated. The aromatic enediyne followed the expected cycloaddition with the alkene in the neighbouring arm to form a stable bridged bicyclic enediyne.