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.

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%.

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.

A newly uncovered Brønsted acid-promoted [2+2+2] cycloaddition between siloxy alkynes and 1,2-diazines produces novel polycyclic compounds with high efficiency and excellent diastereoselectivity under exceedingly mild 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.

The synthesis of new nitrogen-containing heterocycles plays a pivotal role in chemical biology and medicinal chemistry, as reflected by their many applications in the development of pharmacological probes and drugs. [1] Despite notable progress, there is a significant need for the identification of new nitrogen heterocycles which target previously unexplored regions of biogenic chemical space. Among the many possible synthetic strategies to such compounds, cycloadditions involving C-N multiple bonds are particularly attractive as they generate complex cyclic products by simultaneous formation of multiple bonds starting from readily available precursors. [2] Herein, we describe the discovery and development of a formal [2+2+2] cycloaddition of siloxy alkynes with phthalazines, a process that had not been previously described for either 1,2-diazines or electron-rich alkynes. [3][4][5][6][7] This effort has not only afforded heterocyclic products with a unique pentacyclic ring system but has also enabled the identification of a novel chemotype that inhibits glycolytic ATP production by direct blockage of glucose uptake in CHO-K1 cells. As a result of the prevalence of the Warburg effect in many human cancers, such compounds may prove useful in the development of new therapeutics which target reprogrammed energy metabolism of rapidly proliferating cells. [8] Our study began by examining the reaction of phthalazine (1) with the siloxy alkyne 2 in the presence of common Brønsted acids. While no reaction between 1 and 2 was observed in the absence of such additives, even at elevated temperatures, we found that addition of simple pyridinium salts promoted the formation of a new pentacyclic product (3; Scheme 1).After examining a range of mono-and bis(pyridinium) salts in various solvents, we determined the optimum protocol to entail the use of a stoichiometric amount of pyridinium trifluoromethanesulfonimide in CH 2 Cl 2 at room temperature, thus producing the lactam 3 as a single diastereomer in 77 % yield. While most of the known [2+2+2] cycloadditions typically require the presence of a transition-metal catalyst, [9] the present method promotes the condensation under remarkably mild reaction conditions, using only a simple, weak Brønsted acid. The excellent diastereoselectivity of this transformation is also highly noteworthy. The atom connectivity within the reaction product was initially determined to be that in 3 and is based on extensive use of NMR spectroscopic methods. Ultimately, the structure was secured and the relative stereochemistry of the three newly created stereogenic centers was defined through X-ray crystallographic analysis (see below).Interestingly, while a range of substituted mono-and bis(pyridinium) trifluoromethanesulfonimides were found to be effective as reaction promoters, the use of only HNTf 2 , in the absence of pyridine, produced 3 with lower efficiency (48 % yield) and diminished diastereoselectivity (83:17). Furthermore, the use of either pyridinium chloride, pyridinium p-toluenesulfo...