Balancing Nonsense Mutation Readthrough and Toxicity of Designer Aminoglycosides for Treatment of Genetic Diseases.

New derivatives of aminoglycosides with a side chain 1,2-aminoalcohol at the 5" position of ring III were designed, synthesized, and biologically evaluated. The novel lead structure (compound 6), exhibiting substantially enhanced selectivity toward eukaryotic versus prokaryotic ribosome, high readthrough activity, and considerably lower toxicity than the previous lead compounds, was discovered. Balanced readthrough activity and toxicity of 6 were demonstrated in three different nonsense DNA-constructs underlying the genetic diseases, cystic fibrosis and Usher syndrome, and in two different cell lines, baby hamster kidney and human embryonic kidney cells. Molecular dynamics simulations within the A site of the 80S yeast ribosome demonstrated a remarkable kinetic stability of 6, which potentially determines its high readthrough activity.

Total Synthesis and Stereochemical Assignment of Penicitide A.

Stereoselective total synthesis of marine secondary metabolite penicitide A has been accomplished for the first time following a convergent approach. The salient feature of this study includes Horner-Wadsworth-Emmons (HWE) olefination, Evans methylations, Crimmins acetate aldol reaction, and cross olefin metathesis. Our synthetic study established the stereochemistry of unassigned C-10 and C-12 centers and also disclosed the absolute configurations of C-3 and C-5 stereocenters.

Studies toward the synthesis of macrotermycin C: stereoselective construction of the acyclic skeleton of the aglycon.

The stereoselective construction of the acyclic skeleton of the aglycon of polyene macrolactam macrotermycin C has been achieved for the first time using a convergent strategy. The important features of this synthesis study include Evans methylation, Takai olefination, Sonogashira coupling followed by selective alkyne reduction, intermolecular Heck coupling, and Wittig olefination. Intramolecular Heck coupling has been tested for macrocyclization.

Total Synthesis of Reported Structure of Baulamycin A and Its Congeners.

A convergent and flexible strategy for the stereoselective total synthesis of the reported structure of baulamycin A and its congeners has been developed for the first time. Synthetic highlights include a Crimmins aldol reaction to construct the C-1' and C-14 centers, a Crimmins acetate aldol reaction to generate the hydroxy group at the C-13 position, Horner-Wadsworth-Emmons olefination to form the C9-C10 bond, and Evans methylation to install the C-8 center. This synthetic study disclosed that the reported structure of baulamycin A needs to be revised, as its spectroscopic data are not identical with those of the synthetic baulamycin A.

Stereoselective total synthesis of cytospolide P.

A short and convergent stereoselective total synthesis of biologically potent cytospolide P has been accomplished from acrolein. The salient features of our synthetic strategy include modified Crimmins aldols, Yamaguchi esterification, and Grubbs ring-closing metathesis reaction.