Immunoproteasome β5i‐Selective Dipeptidomimetic Inhibitors

N,C‐capped dipeptides belong to a class of noncovalent proteasome inhibitors. Herein we report that the insertion of a β‐amino acid into N,C‐capped dipeptides markedly decreases their inhibitory potency against human constitutive proteasome β5c, while maintaining potent inhibitory activity against human immunoproteasome β5i, thereby achieving thousands‐fold selectivity for β5i over β5c. Structure–activity relationship studies revealed that β5c does not tolerate the β‐amino acid based dipeptidomimetics as does β5i. In vitro, one such compound was found to inhibit human T cell proliferation. Compounds of this class may have potential as therapeutics for autoimmune and inflammatory diseases with less mechanism‐based cytotoxicity than agents that also inhibit the constitutive proteasome.     

Kinetics of microwave‐assisted polymerization of ϵ‐caprolactone

The kinetics of polymerization of ?‐caprolactone (CL) in bulk was studied by irradiating with microwave of 350 W and frequency of 2.45 GHz with different cycle‐heating periods (30–50 s). The molecular weight distributions were determined as a function of reaction time by gel permeation chromatography. Because the temperature of the system continuously varied with reaction time, a model based on continuous distribution kinetics with time/temperature‐dependent rate coefficients was proposed. To quantify the effect of microwave on polymerization, experiments were conducted under thermal heating. The polymerization was also investigated with thermal and microwave heating in the presence of zinc catalyst. The activation energies determined from temperature‐dependent rate coefficients for pure thermal heating, thermally aided catalytic polymerization, and microwave‐aided catalytic polymerization were 24.3, 13.4, and 5.7 kcal/mol, respectively. This indicates that microwaves increase the polymerization rate by lowering the activation energy. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 91: 1450–1456, 2004     

Synthesis and characterization of a random terpolymer of L‐lactide, ϵ‐caprolactone and glycolide

A random terpolymer of L ‐lactide (LL), ?‐caprolactone (CL) and glycolide (G) has been synthesized in bulk at 130 °C using stannous octoate as the coordination–insertion initiator. The terpolymer, poly(LL‐ran‐CL‐ran‐G), has been characterized by a combination of analytical techniques: GPC, ¹H NMR, ¹³C NMR, DSC and TG. Molecular weight characterization by GPC shows a unimodal molecular weight distribution with values of M _n = 1.01 × 10⁵ g mol^?1 and M _w / M _n = 2.17. Compositional and microstructural analysis by ¹H NMR and ¹³C NMR, respectively, reveal a terpolymer composition of LL:CL:G = 74:15:11 (mol%) with a chain microstructure consistent with random monomer sequencing. This latter view is supported by the terpolymer temperature transitions (T_g and T_m) from DSC and the thermal decomposition profile from TG. The results and, in particular, the conclusion that it is a random rather than a statistical terpolymer are discussed in the light of current theories regarding the mechanism of this type of polymerization. © 2001 Society of Chemical Industry     

Asymmetric Michael Addition of 5 H‐Oxazol‐4‐ones to Vinyl Sulfones: Stereoselective Synthesis of Monofluorinated Analogs of 2‐Tertiary Hydroxyl‐3‐Methyl‐Substituted Carboxylic Acidl Derivatives

An asymmetric Michael addition of 5H‐oxazol‐4‐ones to vinyl sulfones has been developed. In the presence of 10 mol % of quinine‐based benzyl‐substituted thiourea as catalyst at 0 °C, the products could be obtained with excellent enantio‐ and diastereoselectivity (up to>99 % ee and>20:1 dr). 1.0 mol % of catalyst also produced the corresponding adducts with similar stereoselective results when the temperature was increased to 25 °C. The obtained adducts have been demonstrated as significant synthetic fragments to conveniently access the monofluorinated analogs of biologically important 2‐tertiary hydroxyl‐3‐methyl‐substituted carboxylic acid derivatives.

     

3‐Heterocycle‐Phenyl N‐Alkylcarbamates as FAAH Inhibitors: Design,Synthesis and 3D‐QSAR Studies

Carbamates are a well‐established class of fatty acid amide hydrolase (FAAH) inhibitors. Here we describe the synthesis of meta‐substituted phenolic N‐alkyl/aryl carbamates and their in vitro FAAH inhibitory activities. The most potent compound, 3‐(oxazol‐2yl)phenyl cyclohexylcarbamate ( 2 a ), inhibited FAAH with a sub‐nanomolar IC₅₀ value (IC₅₀=0.74 nM ). Additionally, we developed and validated three‐dimensional quantitative structure–activity relationships (QSAR) models of FAAH inhibition combining the newly disclosed carbamates with our previously published inhibitors to give a total set of 99 compounds. Prior to 3D‐QSAR modeling, the degree of correlation between FAAH inhibition and in silico reactivity was also established. Both 3D‐QSAR methods used, CoMSIA and GRID/GOLPE, produced statistically significant models with coefficient of correlation for external prediction (R²_PRED) values of 0.732 and 0.760, respectively. These models could be of high value in further FAAH inhibitor design.     

Molecular Iodine‐Mediated Domino Reaction for the Synthesis of Benzamides, 2,2‐Diazidobenzofuran‐3(2H)‐ones and Benzoxazolones

A simple and efficient domino protocol has been developed for the preparation of biologically important benzamides, 2,2‐diazidobenzofuran‐3(2H)‐ones and benzoxazolones from various structurally and electronically divergent acetophenones and ortho‐hydroxyacetophenones in the presence of molecular iodine, sodium azide and sodium bicarbonate at 100 °C in good to excellent yields.

     

A Comprehensive Structural Overview of p38α Mitogen‐Activated Protein Kinase in Complex with ATP‐Site and Non‐ATP‐Site Binders

Herein we review all the currently available ATP‐site and non‐ATP‐site ligands bound to p38α mitogen‐activated protein kinase (MAPK) available in the RCSB Protein Data Bank (PDB). The co‐crystallized inhibitors have been classified into different families according to their experimental binding mode and chemical structure, and the ligand–protein interactions are discussed using the most representative compounds. This systematic structural analysis could provide some take‐home lessons for drug discovery programs aimed at the rational identification and optimization of new p38α MAPK inhibitors.     

Inhibition of Human α‐Methylacyl CoA Racemase (AMACR): a Target for Prostate Cancer

The enzyme α‐methylacyl CoA racemase (AMACR) is involved in the metabolism of branched‐chain fatty acids and has been identified as a promising therapeutic target for prostate cancer. By using the recently available human AMACR from HEK293 kidney cell cultures, we tested a series of new rationally designed inhibitors to determine the structural requirements in the acyl component. An N‐methylthiocarbamate (K_i=98 nM ), designed to mimic the proposed enzyme‐bound enolate, was found to be the most potent AMACR inhibitor reported to date.     

Prospects of β‐Secretase Inhibitors for the Treatment of Alzheimer’s Disease

β‐Secretase continues to be an attractive drug discovery target for the therapeutic intervention of Alzheimer’s disease (AD). This enzyme plays a critical role in the production of neurotoxic β‐amyloid (Aβ) peptides in the brain. Over the years, extensive research efforts have led to the development of many promising classes of inhibitors against this protease. Many small‐molecule, peptidomimetic, and nonpeptide β‐secretase inhibitors have now overcome the key challenging development hurdles such as selectivity and brain penetration. A number of inhibitors have also shown further promise in reducing brain Aβ and rescuing cognitive decline in animal models. Recently, several β‐secretase inhibitors have entered into preclinical and phase I studies, and at least one of these inhibitors has advanced to phase II/III human trials. The outlook on β‐secretase inhibitor drugs for the treatment of AD patients is discussed herein.     

Organocatalytic Asymmetric Mannich Reactions of 5H‐Oxazol‐4‐ones: Highly Enantio‐ and Diastereoselective Synthesis of Chiral α‐Alkylisoserine Derivatives

The first organocatalytic Mannich reaction of 5H‐oxazol‐4‐ones with various readily prepared aryl‐ and alkylsulfonimides has been developed. Two commercially available pseudoenantiomeric Cinchona alkaloids‐derived tertiary amine/ureas have been demonstrated as the most efficient catalysts to access the opposite enantiomers of the Mannich products with equally excellent enantio‐ and diastereoselectivities. From the Mannich adducts, important α‐methyl‐α‐hydroxy‐β‐amino acid derivatives, such as the α‐methylated C‐13 side chain of taxol and taxotere, can be conveniently prepared.     

Non‐isothermal crystallization kinetics of poly(ε‐caprolactone) in hydrogen‐bond‐coupled polymeric‐inorganic hybrid materials

Some hydrogen‐bonding‐interactions‐mediated poly(ε‐caprolactone) (PCL)/silica (SiO₂) polymeric‐inorganic hybrids were prepared by the sol–gel process. The non‐isothermal crystallization kinetics of PCL in the hybrids was investigated by means of differential scanning calorimetry. The results show that the Jeziorny method, together with the combination of the Avrami and Ozawa equations, is applicable to describe the non‐isothermal crystallization kinetics of the PCL in the hybrid system, while the Ozawa theoretical method can be used just for the pure PCL and the 70/30 TEOS/PCL hybrids. Depending on the composition of the PCL/silica, the hybrids displayed microphase separation at various scales, which in turn affect the crystallization behavior and mechanism of PCL in the hybrids. On the one hand, the inorganic component (viz SiO₂) could act as the nucleating agent to facilitate the crystallization of PCL in the hybrids. On the other hand, the SiO₂ networks also confine the crystallization of PCL. Copyright © 2004 Society of Chemical Industry     

Part 7. Effects of poly(L‐lactide‐co‐ϵ‐caprolactone) on morphology,structure, crystallization,and physical properties of blends of poly(L‐lactide) and poly(ϵ‐caprolactone)

Blended films of poly(L ‐lactide) [ie poly(L ‐lactic acid)] (PLLA) and poly(?‐caprolactone) (PCL) without or mixed with 10 wt% poly(L ‐lactide‐co‐?‐caprolactone) (PLLA‐CL) were prepared by solution‐casting. The effects of PLLA‐CL on the morphology, phase structure, crystallization, and mechanical properties of films have been investigated using polarization optical microscopy, scanning electron microscopy, differential scanning calorimetry and tensile testing. Addition of PLLA‐CL decreased number densities of spherulites in PLLA and PCL films, and improved the observability of spherulites and the smoothness of cross‐section of the PLLA/PCL blend film. The melting temperatures (T_m) of PLLA and PCL in the films remained unchanged upon addition of PLLA‐CL, while the crystallinities of PLLA and PCL increased at PLLA contents [X_PLLA = weight of PLLA/(weight of PLLA and PCL)] of 0.4–0.7 and at most of the X_PLLA values, respectively. The addition of PLLA‐CL improved the tensile strength and the Young modulus of the films at X_PLLA of 0.5–0.8 and of 0–0.1 and 0.5–0.8, respectively, and the elongation at break of the films at all the X_PLLA values. These findings strongly suggest that PLLA‐CL was miscible with PLLA and PCL, and that the dissolved PLLA‐CL in PLLA‐rich and PCL‐rich phases increased the compatibility between these two phases. © 2003 Society of Chemical Industry     

Highly Ligand Efficient and Selective N‐2‐(Thioethyl)picolinamide Histone Deacetylase Inhibitors Inspired by the Natural Product Psammaplin A

Novel picolinamide‐based histone deacetylase (HDAC) inhibitors were developed, drawing inspiration from the natural product psammaplin A. We found that the HDAC potency and isoform selectivity provided by the oxime unit of psammaplin A could be reproduced by using carefully chosen heterocyclic frameworks. The resulting (hetero)aromatic amide based compounds displayed very high potency and isoform selectivity among the HDAC family, in addition to excellent ligand efficiency relative to previously reported HDAC inhibitors. In particular, the high HDAC1 isoform selectivity provided by the chloropyridine motif represents a valuable design criterion for the development of new lead compounds and chemical probes that target HDAC1.     

Preparation,characterization, and drug release behaviors of drug‐loaded ε‐caprolactone/L‐lactide copolymer nanoparticles

Copolymers of ε‐caprolactone and L ‐lactide (PCLLA) with different monomer ratio were synthesized by ring opening polymerization, and drug‐loaded nanoparticles of poly‐ε‐caprolactone (PCL), poly‐L ‐lactide (PLLA), and their copolymers were prepared by precipitation method, respectively. The results of differential scanning calorimetry and X‐ray diffraction indicated that the copolymerization of PCLLA decreased the crystallinity of the polymers, and the results of transmission electron micrograph and laser light scattering (LLS) revealed that the prepared nanoparticles had a spherical shape, and the size of PCLLA nanoparticles (∼ 85 nm) was smaller than that of the PCL and PLLA nanoparticles. The experiment of in vitro drug release showed that the drug release rate from PCLLA nanoparticles was slower than that from PCL and PLLA nanoparticles, and the release profile of PCL6/LA4 nanoparticles appeared to follow zero order kinetics. These results suggested that the polymer composition made a great influence on the nanoparticle size and drug release behavior. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 75: 874–882, 2000     

Rational Design,Synthesis, and Potency of N‐Substituted Indoles,Pyrroles, and Triarylpyrazoles as Potential Fructose 1,6‐Bisphosphatase Inhibitors

By using computer modeling and lead structures from our earlier SAR results, a broad variety of pyrrole‐, indole‐, and pyrazole‐based compounds were evaluated as potential fructose 1,6‐bisphosphatase (FBPase) inhibitors. The docking studies yielded promising structures, and several were selected for synthesis and FBPase inhibition assays: 1‐[4‐(trifluoromethyl)benzoyl]‐1H‐indole‐5‐carboxamide, 1‐(α‐naphthalen‐1‐ylsulfonyl)‐7‐nitro‐1H‐indole, 5‐(4‐carboxyphenyl)‐3‐phenyl‐1‐[3‐(trifluoromethyl)phenyl]‐1H‐pyrazole, 1‐(4‐carboxyphenylsulfonyl)‐1H‐pyrrole, and 1‐(4‐carbomethoxyphenylsulfonyl)‐1H‐pyrrole were synthesized and tested for inhibition of FBPase. The IC₅₀ values were determined to be 0.991 and 1.34 μM , and 575, 135, and 32 nM , respectively. The tested compounds were significantly more potent than the natural inhibitor AMP (4.0 μM ) by an order of magnitude; indeed, the best inhibitor showed an IC₅₀ value toward FBPase more than two orders of magnitude better than that of AMP. This level of activity is virtually the same as that of the best currently known FBPase inhibitors. This work shows that such indole derivatives are promising candidates for drug development in the treatment of type II diabetes.     

Transthyretin Mimetics as Anti‐β‐Amyloid Agents: A Comparison of Peptide and Protein Approaches

β‐Amyloid (Aβ) aggregation is causally linked to neuronal pathology in Alzheimer's disease; therefore, several small molecules, antibodies, and peptides have been tested as anti‐Aβ agents. We developed two compounds based on the Aβ‐binding domain of transthyretin (TTR): a cyclic peptide cG8 and an engineered protein mTTR, and compared them for therapeutically relevant properties. Both mTTR and cG8 inhibit fibrillogenesis of Aβ, with mTTR inhibiting at a lower concentration than cG8. Both inhibit aggregation of amylin but not of α‐synuclein. They both bind more Aβ aggregates than monomer, and neither disaggregates preformed fibrils. cG8 retained more of its activity in the presence of biological materials and was more resistant to proteolysis than mTTR. We examined the effect of mTTR or cG8 on Aβ binding to human neurons. When mTTR was co‐incubated with Aβ under oligomer‐forming conditions, Aβ morphology was drastically changed and Aβ‐cell deposition significantly decreased. In contrast, cG8 did not affect morphology but decreased the amount of Aβ deposited. These results provide guidance for further evolution of TTR‐mimetic anti‐amyloid agents.     

Polymerization of ϵ‐caprolactone with maleic anhydride: Synthesis and characterization

High‐molecular‐weight polymers of ϵ‐caprolactone (CL) and maleic anhydride (MA) with anhydride group content of about 1% wt have been synthesized and studied. The polymerization reaction was carried out in bulk under nitrogen atmosphere. Stannous octoate (Sn(oct)₂), and 2,2'‐azobisisobutyronitrile (AIBN) were used as a catalyst and an initiator, respectively. A two‐level design of experiments was used to study the effect of various conditions on the characteristics of the copolymer. Reaction time, temperature, and concentration ratio of various reactants (two monomers, monomer to catalyst, and monomer to initiator) were the independent variables used, and the dependent variables included the molecular weight and the anhydride content in the polymer. Nuclear magnetic resonance (NMR) studies indicate that the succinic anhydride units were incorporated individually either to the polymer chain end or backbone. Anhydride content in the polymer and gel permeation chromatograph (GPC) studies indicate that the maleic anhydride acts as the true initiating species rather than as a comonomer in the system. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 77: 3189–3194, 2000