Click-based synthesis of triazolobithiazole ΔF508-CFTR correctors for cystic fibrosis.

Copper catalyzed azide-alkyne cycloaddition (CuAAC) chemistry is reported for the construction of previously unknown 5-(1H-1,2,3-triazol-1-yl)-4,5'-bithiazoles from 2-bromo-1-(thiazol-5-yl)ethanones. These novel triazolobithiazoles are shown to have cystic fibrosis (CF) corrector activity and, compared to the benchmark bithiazole CF corrector corr-4a, improved logP values (4.5 vs 5.

7-Substituted 8-aza-7-deazaadenosines for modification of the siRNA major groove.

Here we describe the synthesis of new 7-substituted 8-aza-7-deazaadenosine ribonucleoside phosphoramidites and their use in generating major groove-modified duplex RNAs. A 7-ethynyl analog leads to further structural diversification of the RNA via post-automated RNA synthesis azide-alkyne cycloaddition reactions. In addition, we report preliminary studies on the effects of eight different purine 7-position modifications on RNA duplex stability and pairing specificity.

Nucleophilic substitution of oxazino-/oxazolino-/benzoxazin [3,2-b]indazoles: an effective route to 1H-indazolones.

A variety of nucleophiles, thiolates, alkoxides, amines, iodide, and cyanide, react with oxazino-, oxazolino-, and benzoxazin[3,2-b]indazoles under microwave conditions to yield a diverse set of 2-substituted 1H-indazolones. The synthetic utility of these indazoles is further demonstrated by ANRORC (addition of the nucleophile, ring-opening, and ring closure) reactions to yield isomeric pyrazoloindazolones by a process wherein iodide acts first as a nucleophile and subsequently as a leaving group.