Discovery and Structure Activity Relationship of Small Molecule Inhibitors of Toxic β-Amyloid-42 Fibril Formation

Increasing evidence implicates Aβ peptides self-assembly and fibril formation as crucial events in the pathogenesis of Alzheimer disease. Thus, inhibiting Aβ aggregation, among others, has emerged as a potential therapeutic intervention for this disorder. Herein, we employed 3-aminopyrazole as a key fragment in our design of non-dye compounds capable of interacting with Aβ42 via a donor-acceptor-donor hydrogen bond pattern complementary to that of the β-sheet conformation of Aβ42. The initial design of the compounds was based on connecting two 3-aminopyrazole moieties via a linker to identify suitable scaffold molecules. Additional aryl substitutions on the two 3-aminopyrazole moieties were also explored to enhance π-π stacking/hydrophobic interactions with amino acids of Aβ42. The efficacy of these compounds on inhibiting Aβ fibril formation and toxicity in vitro was assessed using a combination of biophysical techniques and viability assays. Using structure activity relationship data from the in vitro assays, we identified compounds capable of preventing pathological self-assembly of Aβ42 leading to decreased cell toxicity

A new synthetic approach to 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) derivatives via a [2+2+2] cycloaddition reaction

Tetrahydroisoquinoline-3-carboxylic acid derivatives are prepared via a [2+2+2] cycloaddition reaction as a key step using Wilkinson's and CpCo(CO)2 catalysts.© Elsevie

Catalytic metathesis reaction in organic synthesis

763-780Olefin metathesis is one of the most fascinating reactions in the realm of catalysis

First synthesis of optically active benzocyclobutene and biphenylene-based unusual α-amino acid derivatives

Various optically pure benzocyclobutene and biphenylene-based α-amino acid derivatives are prepared in a very high diastereoselective manner via a six step sequence using Schöllkopf chiral auxiliary

Synthesis of benzocycloheptene-based amino acid derivatives via a [4+2] cycloaddition reaction as a key step

The seven-membered diene 5 is prepared from 2-butyne-1,4-diol using double orthoester Claisen rearrangement reaction as a key step. The Diels-Alder reaction of the diene 5 with various dienophiles followed by oxidation delivered the benzocycloheptene-based α-amino acid derivatives in very good yields

Modification of constrained peptides by ring-closing metathesis reaction

Ring-closing metathesis (RCM) with α,α-diallylglycyl peptides is shown to furnish α,α-cyclopentenylglycyl peptides as conformationally restrained analogues in the form of post-translational type peptide modification suitable for both peptidomimetic and combinatorial chemistry applications.© Elsevie

Design and synthesis of polycyclic indoles under green conditions <i>via</i> Fischer indolization

1107-1111A simple and useful synthetic route to aza-polyquinane derivatives involving Fischer indolization under green conditions has been demonstrated. Selenium dioxide is found to be useful for oxidizing some of these indole derivatives

A Short Synthesis of the 2-Bromo-N,9-dimethyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indol-6-amine Building Block

A concise synthesis of pharmaceutically useful (R)-tert-butyl N-(2-bromo-9-methyl-6,7,8,9-tetrahydro-5H-pyrido [2,3-b ] indol-6-yl) -N-methylcarbamate building block 11 is described. The racemic intermediate 17 was prepared in a single step from 2-bromo-6-(1-methylhydrazinyl)pyridine sulfate salt (14) and N,3,3-trimethyl-1,5-dioxaspiro [5.5]undecan-9-amine hydrochloride salt (16). Chiral separation of racemic intermediate 17 by diasteromeric salt recrystallization afforded the diasteromeric salt 18 in 37% yield, which was Boc-protected to afford building block 11. Thus, the process for the synthesis and chiral separation by diasteromeric salt crystallization allowed the synthesis of chiral building block 11 in kilogram quantities in 18% overall yield