Biomedical subjects
Publications and source records attributed to Kenneth J Shea.
[Structure: see text] An approach to the core structure of the microtubule-targeting agent welwistatin is described. The approach utilizes the type 2 intramolecular Diels-Alder reaction, with indole serving as the tether between diene and dienophile, to form the natural product's characteristic bicyclo[4.3.1]decane skeleton.
We report the first synthesis of spherical nanoparticles of a bridged polysilsesquioxane. The hard, brittle nanoparticles are prepared by a simple sol-gel polymerization without surfactants or templates. Particle size ranges from 50 to 100 nm. The organic component of these hybrid nanoparticles is composed of a photolabile coumarin dimer. Irradiation with UV light dissociates the photodimer resulting in rupture of the cross-links and subsequent deformation and eventual "melting" of the nanoparticles.
[reaction: see text] The fluorescence emission intensity of the dansyl group is significantly diminished upon appending an ethyldimethylamino group to the N1 nitrogen substituent. Addition of acids and metal ions (i.e., Zn(2+)) to solutions of trimethylethylenediamine naphthalene sulfonamide (trinsyl) 2 produces a >25-fold increase in fluorescence intensity. Trinsyl probe 2 has been used as a diagnostic for the diffusion of protons and metal ions in a network polymer as well as an optical reporter for the glass transition temperature.
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A multifunctional and high-efficiency microfluidic device for droplet generation and fusion is presented. Through unique design of the micro-channels, the device is able to alternately generate droplets, generating droplet ratios ranging from 1 ratio 5 to 5 ratio 1, and fuse droplets, enabling precise chemical reactions in several picoliters on a single chip. The controlled fusion is managed by passive control based on the channel geometry and liquid phase flow. The synthesis of CdS nanoparticles utilizing each fused droplet as a microreactor for rapid and efficient mixing of reagents is demonstrated in this paper. Following alternating droplet generation, the channel geometry allows the exclusive fusion of alternate droplets with concomitant rapid mixing and produces supersaturated solution of Cd2+ and S2- ions to form CdS nanoparticles in each fused droplet. The spectroscopic properties of the CdS nanoparticles produced by this method are compared with CdS prepared by bulk mixing.
[reaction: see text] Two strategies for preparing catalytically active molecularly imprinted nitroxide-containing polymers are outlined. Both strategies rely upon the thermal rearrangement chemistry of tertiary amine N-oxides. To this end, several polymers were prepared and the polymeric nitroxides were revealed by oxidation with m-CPBA. All of the resulting polymeric catalysts proved to be competent mediators of the oxidation of alcohols.
A type II intramolecular Diels-Alder reaction provides access to bicyclo[5.3.1] ring systems with an imbedded bridgehead allylsilane. The Lewis acid catalyzed reactions of these compounds with aldehydes proceed efficiently and with control of stereochemistry. [reaction: see text]
The chiral ruthenium salen complex, 13b, functions as an efficient catalyst for the sequential oxidation and asymmetric Diels-Alder cycloaddition of hydroxamic acids and N-hydroxy formate esters. This result provides evidence for the formation of a ruthenium-nitroso formate (acyl nitroso) intermediate. The Diels-Alder precursors are prepared from simple building blocks, and the cycloadducts, bridged oxazinolactams, can serve as useful intermediates in organic synthesis.
Heteroatom variants of the type 2 intramolecular Diels-Alder reaction provide an efficient method for the preparation of bridged bicyclic heterocycles. The type 2 variant of the intramolecular N-acylnitroso Diels-Alder reaction is an effective method for the synthesis of bridged bicyclic oxazinolactams. Structural studies of the cycloadducts have allowed for quantification of the deformations of the bridgehead functionalities and provided a strategy for the stereoselective synthesis of substituted seven- and eight-membered ring lactams. Diastereoselective cycloadditions followed by cleavage of the oxazine ring afford azepin-2-ones or azocin-2-ones.
Dimethylsulfoxonium methylide reacts with dicyclohexyl alpha-thiophenylmethyl)methylborane via 1,2-alkyl migration and alkyldithiaborolane via 1,2-sulfur migration.
[reaction: see text] A new method for synthesizing the 2-spiro-boraadamantane pyridine complex (2) from 1-ethynylcyclohexylmethyl ether has been developed. The chemistry has been applied to the synthesis of bis-2-spiro-1-boraadamantane.pyridine (1) from trans-1,4-diethynyl-1,4-dimethoxycyclohexane (8). This bis-Lewis acid serves as a self-assembling molecular building block with difunctional Lewis bases.
[reaction: see text] Herein, we describe the synthesis of fluorescent 2-(arylsulfonyl)methacrylates and its polymers. These novel trifunctional monomers, possessing a fluorescent arylsulfonyl (ArSO(2)) group, an alkyl group (R), and a polymerizable olefin, serve as useful building blocks for functionalized fluorescent polymers.
Trialkyl and triaryl organoboranes undergo multiple, repetitive homologations upon reaction with dimethylsulfoxonium methylide (1). This multiple homologation reaction, or polyhomologation, produces polymethylene in a living reaction. Applying the polyhomologation reaction to cyclic and polycyclic organoboranes permits the construction of unique oligomeric and polymeric architectures that are not readily accessible by standard olefin polymerization. The polyhomologation of 1-boraadamantane.THF (2) by ylide 1 generates novel macrotricyclic trialkylboranes (3). The oxidation of these macrocyclic organoboranes generates a three-armed star polymethylene polymer (4) incorporating a cis,cis-1,3,5-trisubstituted cyclohexane core. Interestingly, only one-third of the initiators lead to product formation, resulting in an observed degree of polymerization 3 times higher than expected. Close examination of the initial stages of polymerization show that 1-boraadamantane.THF reacts with 1 equiv of 1 to afford a monohomologated product. Subsequent homologations were found to contain branch points leading to isomeric tricyclic products after the third, fourth, and fifth methylene insertions. At these stages of homologation, all of the propagating species result in tricyclic trialkylborane cages with collapsed, inverted pyramidal boron centers that are substantially less reactive toward ylide. Approximately two-thirds of the species discontinue polymerization at these stages. However, one-third of these species continue to propagate and eventually result in the formation of giant macrotricyclic polymers of narrow polydispersity. Molecular modeling and kinetic simulation have aided in the analysis of the probable pathways through which the reaction proceeds.
A variety of amine complexes with 1-boraadamatane were synthesized and subsequently evaluated for an antiproliferative effect on CD81-enriched cell lines to provide evidence for binding and activation of CD81. CD81 is a member of the tetraspanin family of membrane proteins found in all cell lineages in the liver. CD81 signals for antiproliferation when bound by antibodies. It is known that the HCV-E2 envelope glycoprotein binds to the CD81 protein. While it is unclear whether virus entry into host cells is directly linked to virus attachment via CD81 for HCV, this step in the viral life cycle has recently proven to be an effective point of attack for other viruses including HIV and rhinoviruses. The aim of the current study concerns the synthesis of amantidine analogues by appending primary amines to 1-boraadamantane to evaluate such compounds for CD81-dependent antiproliferation of CD81-enriched cell lines (astrocyte) vs CD81-deficient cell lines (C6 glioma). If the antiproliferative effect of these amantidine analogues proves to be an effect of binding and activating CD81, then these compounds may have the potential to prevent or treat HCV infections. Each compound's potential for preventive and therapeutic activity stems from the compound's potential to block viral attachment, virus-cell fusion, or virus entry into host cells or to counter potential mechanisms of HCV immune evasion. Out of a library of over 500 compounds, including randomly selected small molecules and rationally designed small molecules, only the 1-boraadamantaneamine compounds and structurally similar analogues display a significant antiproliferative effect on the CD81-enriched astrocytes relative to the CD81-deficient cell lines. In fact, 1-boraadamantane.l-phenylalanine methyl ester complex (5), 1-boraadamantane.ethanolamine complex (8), and (S)-2-[(adamantane-1-carbonyl)amino]-3-phenylpropionic acid (15) show a dose-dependent, astrocyte-selective antiproliferative activity in the concentration range 0.1-10 microM. This is consistent with the binding and activation of CD81 and represents a 2-fold improvement compared to the clinically prescribed anti-HCV agent, amantidine, in the same concentration range. Consequently, the 1-boraadamantaneamine derivatives present a promising lead in the development of small molecules with potential to bind to CD81 and treat HCV infections.
The intramolecular Diels-Alder reaction of N-3,5-hexadienoyl ethyl acrylimidates provides an efficient method for the synthesis of cis-fused hexahydroisoquinolones. As a demonstration of the stereochemical control offered by this cycloaddition, two approaches to the construction of the DE rings of reserpine are reported. In the second entry, N-((4-(trimethylsilyl)ethoxymethoxy)methyl-6-benzyloxy-3Z,5E-hexadienoyl)-1-aza-2-ethoxy-1,3-butadiene (40) undergoes cycloaddition to produce as the major product (4aS,7R,8aS)-7-benzyloxy-5-((2-trimethylsilyl)ethoxymethoxy)methyl-3,4,4a,7,8,8a-hexahydroisoquinol-3-one (41). Cycloadduct 41 is then stereospecifically elaborated to (4aS,5S,6R,7R,8aR)-6-methoxy-5-methoxycarbonyl-7-(3,4,5-trimethoxy)benzoyldecahydroisoquinoline-2-carboxylic acid methyl ester (3), a key intermediate previously transformed to reserpine.
[reaction: see text] Synthesis of the A-D rings of the cortical hormone (+)-aldosterone is described. The key step incorporates a chiral tether in a type 2 intramolecular Diels-Alder reaction that establishes the absolute configuration of four contiguous asymmetric centers. This approach provides an efficient route for either enantiomer of the steroid skeleton.
Molecular imprinting is a general method for synthesizing robust, network polymers with highly specific binding sites for small molecules. Recently, combinatorial and computational approaches have been employed to select an optimal molecularly imprinted polymer (MIP) formulation for a targeted analyte. The use of MIPs in the combinatorial field, specifically their use for screening libraries of small molecules, has also been developed.
[reaction: see text] The type 2 intramolecular N-acylnitroso Diels-Alder reaction has been employed for the synthesis of substituted bridged bicyclic oxazinolactams. Upon oxidation of hydroxamic acid 6, a 3-benzylated oxazinolactam (7) was synthesized with complete diastereoselectivity. Elaboration of cycloadduct 7 liberated a cis-3,7-disubstituted azocin-2-one (9).