Fast Cyclization of a Proline-Derived Self-Immolative Spacer Improves the Efficacy of Carbamate Prodrugs

Self-immolative (SI) spacers are sophisticated chemical constructs designed for molecular delivery or material degradation. We describe herein a (S)-2-(aminomethyl)pyrrolidine SI spacer that is able to release different types of anticancer drugs (possessing either a phenolic or secondary and tertiary hydroxyl groups) through a fast cyclization mechanism involving carbamate cleavage. The high efficiency of drug release obtained with this spacer was found to be beneficial for the in vitro cytotoxic activity of protease-sensitive prodrugs, compared with a commonly used spacer of the same class. These findings expand the repertoire of degradation machineries and are instrumental for the future development of highly efficient delivery platforms.     

Protease-Catalyzed Kinetically Controlled Peptide Synthesis

In spite of the enormous progress in the synthesis of peptides and proteins using commercial peptide synthesizers and the immense technological possibilities of recombinant DNA technology, a C? N ligase is an indispensable tool for the racemization-free fragment condensation of peptides. Since activation of the C-terminal α-carboxyl group of a peptide segment could cause partial racemization, chemical condensations of peptide fragments are prone to racemization. For the synthesis of the huge number of peptides and proteins, however, nature has only developed the ribosomal peptidyltransferase, which exhibits its full catalytic function independent of the side-chain functions of the amino acids being coupled. However, its function requires coordination with numerous other ribosomal factors. Besides the limited possibilities of using multienzyme complexes of bacterial peptide synthesis systems, the only alternatives to peptidyltransferase are proteases, which, based on their in vivo function as hydrolases, cannot act as ideal ligases. However, by exploiting the intrinsic reversibility of hydrolytic reactions and by adjusting appropriate physicochemical reaction parameters, the protease acitivity can be used in the direction of ligation. Undoubtedly, the course of kinetically controlled, serine and cysteine protease-catalyzed reactions can be more efficiently influenced than the equilibrium-controlled protease-catalyzed synthesis. This article describes the influence of the enzyme specificity on the efficiency of kinetically controlled synthesis and points the way toward a broad exploitation of serine and cysteine proteases for the catalysis of C? N bond formation.     

An efficient synthesis of LY544344·HCl: a prodrug of mGluR2 agonist LY354740

LY544344·HCl was efficiently prepared in two steps from LY354740. The key step highlighted the in situ masking of the carboxylic acid groups as trimethylsilyl esters to facilitate an effective acylation reaction.     

磷酸化肽段质量数的分布特征

基于双向电泳和液相色谱的蛋白质鉴定是蛋白质组最常用的技术,质谱谱图的好坏对鉴定的成功率起决定性作用。其中,某些不确定的修饰和非蛋白污染物是影响谱图质量的难以忽略的因素。Mann等曾经建立过"肽的可能的质量列表",并指出存在"肽质量禁区MFZ(MassForbiddenZone)",其研究的质量范围为0～2000u。本文在此基础上,编写了基于Web的肽段质量数分析统计软件PMFstat,研究了0～5000u质量范围的胰蛋白酶酶切肽段的质量分布,并特别考察了磷酸化肽段的质量数特征。结果表明:磷酸化效应导致"肽质量禁区"明显变窄和肽质量分布峰值左移。     

Peptide synthesis on fluorous support

New fluorous supports were synthesized and used to prepare a peptide having a C-terminal COOH based on fluorous chemistry. The hexakisfluorous chain-type support was suitable for the synthesis of a pentapeptide or a peptide derivative on a fluorous support whose fluorine content is over 40 w/w%. A bioactive peptide, Leu-enkephalin, was easily synthesized using an Fmoc-strategy based on fluorous chemistry.     

多肽树枝状大分子合成的研究进展

多肽树枝状大分子具有不同于链状多肽和其它树枝状大分子的物理化学性质,在化学、生物、医学等领域中有广泛应用。本文综述了近年来所报道的多肽树枝状大分子的合成进展。