The availability of precisely modulated chemical modifi cations dramatically affects the physicochemical properties of pristine drugs and should facilitate the amphiphilic self-assembly of prodrugs into supramolecular nanoprodrugs (SNPs). However, rationally designing such prodrugs to achieve favorable clinical outcomes still remains a challenge. Here, a library of prodrugs through site-specifi c attachment of a variety of lipophilic moieties to the antitumor agent SN-38 (7-ethyl-10-hydroxycamptothecin) is constructed. Taking advantage of the role of hydroxyl groups as solvophilic moieties, these prodrugs exhibit self-assembly in aqueous environments, allowing for the identifi cation of fi ve prodrugs capable of self-assembling into SNPs at high drug concentrations. Importantly, in vivo studies demonstrate that the antitumor activity of the SNPs correlates well with their stability and long-term circulation. In addition, the modular feature of this SNP design strategy offers the opportunity to readily incorporate additional valuable functionalities (e.g., tumor-specifi c targeting ligands) to the particle surface, which is further exploited to improve antitumor effi cacy in mouse xenograft models. Thus, this structure-based reconstruction of SN-38 molecules signifi cantly improves the potency of SNPs for clinical use. These results also provide novel mechanistic insights into the rational design of prodrugs.

A small library of water-soluble N-heterocyclic carbene (NHC)-stabilized palladium complexes was prepared and applied for cross-couplings of biomolecules under mild conditions in water. Pd-NHC complexes bearing hydrophilic groups were demonstrated to be efficient catalysts for the Suzuki-Miyaura coupling of various unnatural amino acids and proteins bearing p-iodophenyl functional groups. We further utilized this catalytic system for the rapid bioorthogonal labeling of proteins on the surfaces of mammalian cells. These results demonstrated that NHC-stabilized metal complexes have potential utility in cellular systems.

A direct and practical synthetic route to N-heterocyclic carbene copper complexes of [(NHC)CuX] (X = halide) and [(NHC)2Cu]PF6 types using commercially available copper powder is described. A number of copper-NHC complexes have been obtained in a range of yields from 26 to 99%. The reactions take place in air without removal of moisture and oxygen, and the excess of copper powder can be easily removed via simple filtration after completion. The direct reactions of imidazolium salts and copper powder can also be performed in aqueous media avoiding tedious purification processes. The procedure is also suitable for gram-scale preparation.

An efficientcatalytic approach to the synthesis of N,N-dialkyl-2-alkynylanilinesw as developed by using Pd-catalyzed norbornene-mediated three-component reactions of haloarenes, alkoxyamines (RO-NR 2 ), and alkynes. Thep rocedure forms one C À Nb onda nd one C À Cb onde fficiently in ao ne-pot manner from readily available starting materials.Anumber of 2-alkynylanilinesw ith ab road range of functional groups were afforded in good to excellent yields.