ABSTRACT
Myeloperoxidase (MPO) produces hypohalous acids as a key component of the innate immune response; however, release of these acids extracellularly results in inflammatory cell and tissue damage. The two-step, one-pot Davis-Beirut reaction was used to synthesize a library of 2H-indazoles and 1H-indazolones as putative inhibitors of MPO. A structure-activity relationship study was undertaken wherein compounds were evaluated utilizing taurine-chloramine and MPO-mediated H2O2 consumption assays. Docking studies as well as toxicophore and Lipinski analyses were performed. Fourteen compounds were found to be potent inhibitors with IC50 values <1µM, suggesting these compounds could be considered as potential modulators of pro-oxidative tissue injury pertubated by the inflammatory MPO/H2O2/HOCl/HOBr system.
Subject(s)
Indazoles/chemistry , Peroxidase/antagonists & inhibitors , Binding Sites , Catalytic Domain , Chloramines/chemistry , Chloramines/metabolism , Humans , Indazoles/metabolism , Molecular Docking Simulation , Peroxidase/metabolism , Protein Binding , Structure-Activity Relationship , Taurine/chemistry , Taurine/metabolismABSTRACT
A novel, easy method for the syntheses of richly diversified 2H-indazoles and indazolones, called the Davis-Beirut reaction, and other recent 2H-indazole synthetic routes are briefly reviewed. An update on the biological activity of indazoles is also surveyed.
Subject(s)
Indazoles/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Cardiovascular Diseases/drug therapy , Cell Proliferation/drug effects , Fertilization/drug effects , Humans , Indazoles/therapeutic use , Indazoles/toxicity , Isomerism , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase/metabolismABSTRACT
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
A one-pot-three-step method has been developed for the conversion of oxazolino-2H-indazoles into triazolotriazepinoindazolones with three points of diversity. Step one of this process involves a propargyl bromide-initiated ring opening of the oxazolino-2H-indazole (available by the Davis-Beirut reaction) to give an N(1)-(propargyl)-N(2)-(2-bromoethyl)-disubstituted indazolone, which then undergoes -CH(2)Br â -CH(2)N(3) displacement (step two) followed by an uncatalyzed intramolecular azide-alkyne 1,3-dipolar cycloaddition (step three) to form the target heterocycle. Employing 7-bromooxazolino-2H-indazole allows for further diversification through, for example, palladium-catalyzed coupling chemistry, as reported here.
Subject(s)
Alkynes/chemistry , Indazoles/chemical synthesis , Oxazoles/chemistry , Palladium/chemistry , Triazoles/chemical synthesis , Catalysis , Cyclization , Hydrocarbons, Brominated/chemistry , Indazoles/chemistry , Molecular Structure , Triazoles/chemistryABSTRACT
A variety of electrophiles (anhydrides, acid chlorides, carbonochloridates, sulfonyl chlorides, and alkyl bromides) react with 3-methoxy-2H-indazole (1a), benzoxazin[3,2-b]indazole (1d), and oxazolino[3,2-b]indazole (1e) - substrates available by the Davis-Beirut reaction - to yield a diverse set of N(1),N(2)-disubstituted-1H-indazolones. With certain electrophiles, an AERORC (Addition of the Electrophile, Ring Opening, and Ring Closure) process on indazole 1d results in indazoloindazolone formation. An intriguing aspect of these N(1),N(2)-disubstituted-1H-indazolones is that they are poised for diversification through, for example, azide-alkyne cycloaddition chemistry reported here.
Subject(s)
Indazoles/chemical synthesis , Triazoles/chemical synthesis , Combinatorial Chemistry Techniques , Indazoles/chemistry , Molecular Structure , Triazoles/chemistryABSTRACT
A diastereoselective organocatalytic aldol/oxa-Michael reaction has been developed to efficiently deliver medicinally relevant 2,3-ring-substituted chromanones. Development of this synthetic strategy revealed an unexpected kinetic anti-Saytzeff elimination; an origin for the observed selectivity is suggested on the basis of the results of quantum chemical calculations. This unusual kinetic selectivity necessitated an isomerization protocol that in turn led to the discovery of an intriguing Pd-mediated isomerization/intramolecular Friedel-Crafts-type alkylation.
Subject(s)
Chromones/chemical synthesis , Alkylation , Catalysis , Chromones/chemistry , Cyclization , Molecular Structure , Palladium/chemistry , StereoisomerismABSTRACT
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.