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1.
J Am Chem Soc ; 139(15): 5297-5300, 2017 04 19.
Article in English | MEDLINE | ID: mdl-28375610

ABSTRACT

We report a general method for the synthesis of chiral thiosquaramides, a class of bifunctional catalysts not previously described in the literature. Thiosquaramides are found to be more acidic and significantly more soluble in nonpolar solvents than their oxosquaramide counterparts, and they are excellent catalysts for the unreported, enantioselective conjugate addition reaction of the barbituric acid pharmacaphore to nitroalkenes, delivering the chiral barbiturate derivatives in high yields and high enantioselectivities, even with catalyst loadings as low as 0.05 mol%.


Subject(s)
Alkenes/chemistry , Barbiturates/chemistry , Nitro Compounds/chemistry , Quinine/analogs & derivatives , Sulfhydryl Compounds/chemical synthesis , Molecular Structure , Quinine/chemical synthesis , Quinine/chemistry , Stereoisomerism , Sulfhydryl Compounds/chemistry
2.
Org Lett ; 16(12): 3236-9, 2014 Jun 20.
Article in English | MEDLINE | ID: mdl-24911346

ABSTRACT

Copper(I) and nickel(0) complexes catalyze the formal [4 + 2] cycloaddition reactions of 1,2-diazines and siloxyalkynes, a reaction hitherto best catalyzed by silver salts. These catalysts based on earth abundant metals are not only competent, but the copper catalyst, in particular, promotes cycloadditions of pyrido[2,3-d]pyridazine and pyrido[3,4-d]pyridazine, enabling a new synthesis of quinoline and isoquinoline derivatives, as well as the formal [2 + 2] cycloaddition reaction of cyclohexenone with a siloxyalkyne.


Subject(s)
Alkynes/chemistry , Copper/chemistry , Cyclohexanones/chemistry , Nickel/chemistry , Pyridazines/chemistry , Pyridines/chemistry , Silicon Compounds/chemistry , Catalysis , Cycloaddition Reaction , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Molecular Structure , Quinolines/chemical synthesis , Quinolines/chemistry , Silicon Compounds/chemical synthesis , Silver/chemistry , Stereoisomerism
3.
Angew Chem Int Ed Engl ; 52(51): 13576-9, 2013 Dec 16.
Article in English | MEDLINE | ID: mdl-24346942

ABSTRACT

Cycloaddition uncovered: The title reaction produces novel polycyclic compounds with high efficiency and excellent diastereoselectivity under mild reaction conditions. A small-molecule library, synthesized using this reaction, yielded a novel chemotype which inhibited glycolytic ATP production by blocking glucose uptake in CHO-K1 cells. DMF=N,N-dimethylformamide, Tf=trifluoromethanesulfonyl, TIPS=triisopropylsilyl.


Subject(s)
Alkynes/chemistry , Cycloaddition Reaction/methods , Catalysis , Cyclization , Glycolysis , Molecular Structure , Stereoisomerism
4.
ChemMedChem ; 5(3): 328-49, 2010 Mar 01.
Article in English | MEDLINE | ID: mdl-20043313

ABSTRACT

RNA interference (RNAi) is a post-transcriptional gene silencing mechanism induced by small interfering RNAs (siRNAs) and micro-RNAs (miRNAs), and has proved to be one of the most important scientific discoveries made in the last century. The robustness of RNAi has opened up new avenues in the development of siRNAs as therapeutic agents against various diseases including cancer and HIV. However, there had remained a lack of a clear mechanistic understanding of messenger RNA (mRNA) cleavage mediated by Argonaute2 of the RNA-induced silencing complex (RISC), due to inadequate structural data. The X-ray crystal structures of the Argonaute (Ago)-DNA-RNA complexes reported recently have proven to be a breakthrough in this field, and the structural details can provide guidelines for the design of the next generation of siRNA therapeutics. To harness siRNAs as therapeutic agents, the prudent use of various chemical modifications is warranted to enhance nuclease resistance, prevent immune activation, decrease off-target effects, and to improve pharmacokinetic and pharmacodynamic properties. The focus of this review is to interpret the tolerance of various chemical modifications employed in siRNAs toward RNAi by taking into account the crystal structures and biochemical studies of Ago-RNA complexes. Moreover, the challenges and recent progress in imparting druglike properties to siRNAs along with their delivery strategies are discussed.


Subject(s)
RNA, Small Interfering/chemistry , RNA, Small Interfering/therapeutic use , Animals , Crystallography, X-Ray , Eukaryotic Initiation Factors/chemistry , Eukaryotic Initiation Factors/metabolism , Humans , Models, Molecular , RNA Interference , RNA, Small Interfering/metabolism , RNA-Induced Silencing Complex/chemistry , RNA-Induced Silencing Complex/metabolism
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