Chemical methods for degradation of target proteins using designed light-activatable organic molecules

Molecular design, chemical synthesis, and biological evaluation of several designed organic molecules, which target-selectively degrade proteins upon photo-irradiation, are introduced. The designed molecules for protein photo-degradation include 2-phenylquinoline-steroid hormone hybrids and porphyrin derivatives, both of which selectively photo-degrade estrogen receptor-α, and fullerene-sugar and -sulfonic acid hybrids, which selectively photo-degrade HIV-1 protease and amyloid β, respectively. The information will provide a novel and effective way to control specific functions of proteins, and contribute to the molecular design of novel protein photo-degrading agents, which should find wide application in chemistry, biology, and medicine.     

Rh(I)-catalyzed asymmetric synthesis of 3-substituted isoindolinones through CO gas-free aminocarbonylation

A highly efficient and accessible synthesis of chiral 3-substituted isoindolinone frameworks is described. The synthesis involved the Rh(I)-catalyzed asymmetric arylation of boronic acids to 2-halobenzaldimines and the subsequent Rh(I)-catalyzed intramolecular aminocarbonylation of the resulting 2-halobenzylamines using an aldehyde as the carbonyl source. The method tolerates a variety of functional groups, yielding isoindolinone derivatives in moderate to high yields with high ee-values. In addition, two Rh(I)-catalyzed transformations could be efficiently accomplished in a one-pot sequence to give chiral isoindolinones by the simple addition of a ligand and an aldehyde after the Rh(I)-catalyzed asymmetric arylation.     

Programming the supramolecular helical polymerization of dendritic dipeptides via the stereochemical information of the dipeptide

Many natural biomacromolecules are homochiral and are built from constituents possessing identical handedness. The construction of synthetic molecules, macromolecules, and supramolecular structures with tailored stereochemical sequences can detail the relationship between chirality and function and provide insight into the process that leads to the selection of handedness and amplification of chirality. Dendritic dipeptides, previously reported from our laboratory, self-assemble into helical porous columns and serve as fundamental mimics of natural porous helix-forming proteins and supramolecular polymers. Herein, the synthesis of all stereochemical permutations of a self-assembling dendritic dipeptide including homochiral, heterochiral, and differentially racemized variants is reported. A combination of CD/UV-vis spectroscopy in solution and in film, X-ray diffraction, and differential scanning calorimetry studies in solid state established the role of the stereochemistry of the dipeptide on the thermodynamics and mechanism of self-assembly. It was found that the highest degree of stereochemical purity, enantiopure homochiral dendritic dipeptides, exhibits the most thermodynamically favorable self-assembly process in solution corresponding to the greatest degree of helical order and intracolumnar crystallization in solid state. Reducing the stereochemical purity of the dendritic dipeptide through heterochirality or by partially or fully racemizing the dendritic dipeptide destructively interferes with the self-assembly process. All dendritic dipeptides were shown to coassemble into single columns regardless of their stereochemistry. Because these columns exhibit no deracemization, the thermodynamic advantage of enantiopurity and homochirality suggests a mechanism for stereochemical selection and chiral amplification.