Mookda Pattarawarapan

A peptidomimetic of NT-3 acts as a TrkC antagonist

Neurotrophins are a family of growth factors that regulate the peripheral and central nervous system. We designed and tested a mini-library of small molecules peptidomimetics based on beta-turns of the neurotrophin growth factor polypeptides NT-3, which is the natural ligand for TrkC receptors. Biological studies identified a peptidomimetic 2Cl that exhibited selective antagonism of TrkC. 2Cl reduces TrkC activation and signaling promoted by NT-3, and selectively blocks ligand-dependent cell survival. 2Cl also blocks ligand-independent TrkC activation and signals that take place when the receptor is over-expressed. This work adds to our understanding of how the neurotrophins function through Trk receptors, and demonstrates that peptidomimetics can be designed to selectively disturb neurotrophin-receptor interactions, and receptor activation.

Preferred Secondary Structures as a Possible Driving Force for Macrocyclization

Abstract The purpose of the work described in this paper was to explore links that may exist between conformational bias in macrocyclic products and the ease with which they are formed in solid phase S N Ar reactions. Solid phase synthesis of compounds 2 proceeds more efficiently than of compounds 3 under similar conditions. Compounds 2 were designed to mimic β-turn conformations in the dipeptide residues whereas compounds 3 were thought to be unable to show a similar conformational preference. The second assertion was shown to be correct but, surprisingly, CD, NMR, and molecular simulation experiments for 2a indicate another conformation is preferred in solution. This may involve H-bonding of the asparagine side-chain to a backbone amide-carbonyl. Molecular dynamics simulations indicate that cyclization to form compound 2a is statistically more favorable than that to form 3a .

Approach to the Synthesis of 2,3-Disubstituted-3H-quinazolin-4-ones Mediated by Ph3P–I2

Readily available N-substituted amides or their requisite carboxylic acids or acid chlorides have been used to construct 2,3-disubstituted-3H-quinazolin-4-ones in a one-pot procedure. Key transformation in this convergent approach involves Ph3P-I2-mediated formation of amidine upon condensation of an amide or the intermediate amide with methyl anthranilate. Cyclization of the amidine-tethered anthranilate then affords 2,3-disubstituted-3H-quinazolin-4-ones in good to excellent yields under mild conditions.

Ultrasound-Assisted Solvent-Free Parallel Synthesis of 3-Arylcoumarins Using N-Acylbenzotriazoles

An ultrasound-assisted one-pot acylation/cyclization reaction between N-acylbenzotriazoles and 2-hydroxybenzaldehydes has been developed for the synthesis of substituted 3-arylcoumarins. Using ultrasound not only allows rapid and clean conversion but also simplifies experimental setup and parallel workup leading to rapid generation of 3-arylcoumarin libraries under mild, solvent-free, and chromatography-free conditions.

Syntheses of second generation, 14-membered ring β-turn mimics

Efficient solid phase syntheses of the constrained β-turn peptidomimetics 1–3 were devised, and the conformational properties of three representative compounds in DMSO were determined.

Application of N-Acylbenzotriazoles in the Synthesis of 5-Substituted 2-Ethoxy-1,3,4-oxadiazoles as Building Blocks toward 3,5-Disubstituted 1,3,4-Oxadiazol-2(3H)-ones

5-Substituted-2-ethoxy-1,3,4-oxadiazoles were conveniently prepared through a one-pot sequential N-acylation/dehydrative cyclization between ethyl carbazate and N-acylbenzotriazoles in the presence of Ph3P-I2 as a dehydrating agent. Subsequent treatment with a stoichiometric amount of alkyl halides (X = Cl, Br, I) enables a rapid access to a variety of 3,5-disubstituted 1,3,4-oxadiazol-2(3H)-ones in good to excellent yields.