ABSTRACT
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. Finally, the effect on RNAi activity of this type of modification at eight different positions in an siRNA guide strand has been explored. Analogs were identified with large 7-position substituents that maintain adenosine pairing specificity and are well-tolerated at specific positions in an siRNA guide strand.
Subject(s)
Adenosine/chemistry , Aza Compounds/chemistry , Organophosphorus Compounds/chemistry , RNA, Small Interfering/chemistry , Ribonucleosides/chemistry , Adenosine/pharmacology , Aza Compounds/pharmacology , Drug Stability , HeLa Cells , Humans , Models, Molecular , Molecular Structure , Organophosphorus Compounds/pharmacology , Protein Denaturation , RNA, Small Interfering/drug effects , Ribonucleosides/pharmacology , TemperatureABSTRACT
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 5.96).
Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Cystic Fibrosis/drug therapy , Thiazoles/pharmacology , Triazoles/pharmacology , Dose-Response Relationship, Drug , Molecular Structure , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistry , Triazoles/chemical synthesis , Triazoles/chemistryABSTRACT
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.