Brandon J. Turunen

Bio: Brandon J. Turunen is an academic researcher from University of Kansas. The author has contributed to research in topics: Chirality (chemistry) & Amide. The author has an hindex of 10, co-authored 15 publications receiving 402 citations.

Amino Acid-Derived Enaminones: A Study in Ring Formation Providing Valuable Asymmetric Synthons

Abstract: A new reaction for the preparation of enaminones has been discovered. This method employs β-amino acids as starting materials to allow diversification as well as incorporation of chirality. The β-amino acids, once converted to ynones, are readily cyclized to the desired six-membered enaminone via a two-step, one-pot protocol. Although disguised as a 6-endo-dig cyclization, the reagents employed in the transformation play a direct role in bond making and bond breaking, thus changing the mode of addition.

Stabilization of the cyclin‐dependent kinase 5 activator, p35, by paclitaxel decreases β‐amyloid toxicity in cortical neurons

Abstract: One hallmark of Alzheimer's disease (AD) is the formation of neurofibrillary tangles, aggregated paired helical filaments composed of hyperphosphorylated tau. Amyloid-beta (Abeta) induces tau hyperphosphorylation, decreases microtubule (MT) stability and induces neuronal death. MT stabilizing agents have been proposed as potential therapeutics that may minimize Abeta toxicity and here we report that paclitaxel (taxol) prevents cell death induced by Abeta peptides, inhibits Abeta-induced activation of cyclin-dependent kinase 5 (cdk5) and decreases tau hyperphosphorylation. Taxol did not inhibit cdk5 directly but significantly blocked Abeta-induced calpain activation and decreased formation of the cdk5 activator, p25, from p35. Taxol specifically inhibited the Abeta-induced activation of the cytosolic cdk5-p25 complex, but not the membrane-associated cdk5-p35 complex. MT-stabilization was necessary for neuroprotection and inhibition of cdk5 but was not sufficient to prevent cell death induced by overexpression of p25. As taxol is not permeable to the blood-brain barrier, we assessed the potential of taxanes to attenuate Abeta toxicity in adult animals using a succinylated taxol analog (TX67) permeable to the blood-brain barrier. TX67, but not taxol, attenuated the magnitude of both basal and Abeta-induced cdk5 activation in acutely dissociated cortical cultures prepared from drug treated adult mice. These results suggest that MT-stabilizing agents may provide a therapeutic approach to decrease Abeta toxicity and neurofibrillary pathology in AD and other tauopathies.

[Bis(2-methoxyethyl)amino]sulfur trifluoride, the Deoxo-Fluor reagent: application toward one-flask transformations of carboxylic acids to amides

Abstract: The use of the Deoxo-Fluor reagent is a versatile method for acyl fluoride generation and subsequent one-flask amide coupling. It provides mild conditions and facile purification of the desired products in good to excellent yields. We have explored the utility of this reagent for the one-flask conversion of acids to amides and Weinreb amides and as a peptide-coupling reagent.

Synthesis of 6- and 7-membered cyclic enaminones: scope and mechanism.

Abstract: Six- and seven-membered cyclic enaminones can be prepared using common, environmentally benign reagents. Amino acids are used as synthetic precursors allowing diversification and the incorporation of chirality. The key reaction in this multistep process involves deprotection of Boc-amino ynones and subsequent treatment with methanolic K2CO3 to induce cyclization. A β-amino elimination side reaction was identified in a few labile substrates that led to either loss of stereochemical purity or degradation. This process can be mitigated in specific cases using mild deprotection conditions. NMR and deuterium-labeling experiments provided valuable insight into the workings and limitations of this reaction. Although disguised as a 6-endo-dig cyclization, the reagents employed in the transformation play a direct role in bond-making and bond-breaking, thus changing the mode of addition to a 6-endo-trig cyclization. This method can be used to construct an array of monocyclic and bicyclic scaffolds, many of which ar...

Overcoming the blood-brain barrier to taxane delivery for neurodegenerative diseases and brain tumors.

Abstract: The blood-brain barrier (BBB) effectively prevents microtubule (MT)-stabilizing drugs from readily entering the central nervous system (CNS). A major limiting factor for microtubule-stabilizing drug permeation across the BBB is the active efflux back into the circulation by the overexpression of the multidrug-resistant gene product 1 (MDR1) or P-glycoprotein (P-gp). This study has focused on strategies to overcome P-gp-mediated efflux of Taxol analogs, MT-stabilizing agents that could be used to treat brain tumors and, potentially, neurodegenerative diseases such as Alzheimer's disease. However, taxol is a strong P-gp substrate that limits its distribution across the BBB and therapeutic potential in the CNS. We have found that addition of a succinate group to the C-10 position of paclitaxel (Taxol) results in an agent, Tx-67, with reduced interactions with P-gp and enhanced permeation across the BBB in both in vitro and in situ models. Our studies demonstrate the feasibility of making small chemical modifications to Taxol to generate analogs with reduced affinity for the P-gp but retention of MT-stabilizing properties, i.e., a taxane that may reach and treat therapeutic targets in the CNS.

Amide bond formation: beyond the myth of coupling reagents

Abstract: Amide bond formation is a fundamentally important reaction in organic synthesis, and is typically mediated by one of a myriad of so-called coupling reagents. This critical review is focussed on the most recently developed coupling reagents with particular attention paid to the pros and cons of the plethora of “acronym” based reagents. It aims to demystify the process allowing the chemist to make a sensible and educated choice when carrying out an amide coupling reaction (179 references).

Electrocatalysis on bimetallic surfaces: modifying catalytic reactivity for oxygen reduction by voltammetric surface dealloying.

Abstract: We report a synthetic electrochemical strategy to deliberately modify the catalytic reactivity of Pt bimetallic surfaces. The strategy consists of voltammetric surface dealloying of the non-noble constituent from Pt-poor bimetallic precursor compounds. We exemplify this method by dealloying carbon-supported Pt25Cu75 alloy nanoparticle precursors and testing the resulting active catalyst phase for the oxygen reduction reaction (ORR). We show that dealloyed Pt−Cu electrocatalysts exhibit an extraordinary increase in intrinsic reactivity of 4−6 times as compared to pure Pt electrocatalysts. Our results indicate that electrochemical treatment of the alloy precursors selectively dissolves Cu near the particle surface. The partially dealloyed particles constitute the active catalyst phase. While Cu is retained in the core of the particles after dealloying, the essentially pure Pt surface suggests a core−shell structure of the active catalyst. Geometric effects, such as exposure of more active crystallographic f...

Molecular Mechanisms of Neurodegeneration in Alzheimer’s Disease

Abstract: Alzheimer's disease (AD) is characterized by cognitive impairment, progressive neurodegeneration and formation of amyloid-β (Aβ)-containing plaques and neurofibrillary tangles composed of hyperphosphorylated tau The neurodegenerative process in AD is initially characterized by synaptic damage accompanied by neuronal loss In addition, recent evidence suggests that alterations in adult neurogenesis in the hippocampus might play a role Synaptic loss is one of the strongest correlates to the cognitive impairment in patients with AD Several lines of investigation support the notion that the synaptic pathology and defective neurogenesis in AD are related to progressive accumulation of Aβ oligomers rather than fibrils Abnormal accumulation of Aβ resulting in the formation of toxic oligomers is the result of an imbalance between the levels of Aβ production, aggregation and clearance Aβ oligomers might lead to synaptic damage by forming pore-like structures with channel activity; alterations in glutamate receptors; circuitry hyper-excitability; mitochondrial dysfunction; lysosomal failure and alterations in signaling pathways related to synaptic plasticity, neuronal cell and neurogenesis A number of signaling proteins, including fyn kinase; glycogen synthase kinase-3β (GSK3β) and cyclin-dependent kinase-5 (CDK5), are involved in the neurodegenerative progression of AD Therapies for AD might require the development of anti-aggregation compounds, pro-clearance pathways and blockers of hyperactive signaling pathways

Pt-Based Core–Shell Catalyst Architectures for Oxygen Fuel Cell Electrodes

Abstract: Pt-based core–shell nanoparticles have emerged as a promising generation of highly active electrocatalysts to accelerate the sluggish kinetics of oxygen reduction reaction (ORR) in fuel cell systems. Their electronic and structural properties can be easily tailored by modifying the Pt shell thickness, core composition, diameter, and shape; this results in significant improvements of activity and durability over state-of-the-art pure Pt catalysts. Prompted by the relevance of efficient and robust ORR catalysts for electrochemical energy conversion, this Perspective reviews several concepts and selected recent developments in the exploration of the structure and composition of core–shell nanoparticles. Addressing current achievements and challenges in the preparation as well as microscopic and spectroscopic characterization of core–shell nanocatalysts, a concise account of our understanding is provided on how the surface and subsurface structure of multimetallic core–shell nanoparticles affect their reactiv...