Pravin D. Gagare

Prevention of posttraumatic axon sprouting by blocking collapsin response mediator protein 2-mediated neurite outgrowth and tubulin polymerization

Epileptogenesis following traumatic brain injury (TBI) is likely due to a combination of increased excitability, disinhibition, and increased excitatory connectivity via aberrant axon sprouting. Targeting these pathways could be beneficial in the prevention and treatment of posttraumatic epilepsy. Here, we tested this possibility using the novel anticonvulsant (R)-N-benzyl 2-acetamido-3-methoxypropionamide ((R)-lacosamide [LCM]), which acts on both voltage-gated sodium channels and collapsin response mediator protein 2 (CRMP2), an axonal growth/guidance protein. LCM inhibited CRMP2-mediated neurite outgrowth, an effect phenocopied by CRMP2 knockdown. Mutation of LCM-binding sites in CRMP2 reduced the neurite inhibitory effect of LCM by ∼8-fold. LCM also reduced CRMP2-mediated tubulin polymerization. Thus, LCM selectively impairs CRMP2-mediated microtubule polymerization, which underlies its neurite outgrowth and branching. To determine whether LCM inhibits axon sprouting in vivo, LCM was injected into rats subjected to partial cortical isolation, an animal model of posttraumatic epileptogenesis that exhibits axon sprouting in cortical pyramidal neurons. Two weeks following injury, excitatory synaptic connectivity of cortical layer V pyramidal neurons was mapped using patch clamp recordings and laser scanning photostimulation of caged glutamate. In comparison with injured control animals, there was a significant decrease in the map size of excitatory synaptic connectivity in LCM-treated rats, suggesting that LCM treatment prevented enhanced excitatory synaptic connectivity due to posttraumatic axon sprouting. These findings suggest, for the first time, that LCMs mode of action involves interactions with CRMP2 to inhibit posttraumatic axon sprouting.

Bis-exo-2-norbornylboron Triflate for Stereospecific Enolization of 3,3,3-Trifluoropropionates

The first boron-mediated enolization-aldolization of 3,3,3-trifluoropropionates has been reported. The preparation and application of bis-exo-bicyclo[2.2.1]heptan-2-ylboron triflate as a superior reagent for diastereospecific enolization has also been described.

One-Pot Synthesis of Ammonia–Borane and Trialkylamine–Boranes from Trimethyl Borate

A one-pot procedure for the preparation of ammonia borane from trimethyl borate in 90% yield and >99% purity has been reported. This methodology has been modified to prepare a series of trialkylamine-boranes in 70-82% yields from trimethyl borate and lithium hydride/aluminum chloride in the presence of the corresponding trialkylamine.

Synthetic α-(aminomethyl)-γ-butyrolactones and their anti-pancreatic cancer activities

Aminated α-methylene-γ-butyrolactones, which are readily synthesized with facile control of the diastereoisomerism, provide an economical and commercially-viable alternative to the use of aminated natural products. These aminoloactones, which exhibit excellent activity against three pancreatic cancer cell lines when measured at 10 μM-Panc-1, MIA PaCa-2, and BxPC-3-and are comparable to or better than parthenolide and dimethylaminoparthenolide (DMAPT, LC-1). It has also been shown that there is an effect on the biological activity depending on the identity of the amine.

One-Pot Asymmetric Synthesis of 2- and 2,3-Disubstituted Tetrahydrofuran Derivatives

A novel and convenient one-pot asymmetric synthesis of 2- and 2,3-disubstituted tetrahydrofurans has been achieved in 56-81% yields and 86-99% ee from aliphatic and aromatic aldehydes via an allyl/crotyl/alkoxyallylboration-hydroboration-iodination-cyclization reaction sequence.