WS9326 A is a tachykinin receptor antagonist and quorum sensing inhibitor discovered from several Streptomyces strains.The structure of WS9326 A features a(Z)-pentenylcinnamoyl moiety attached on a cyclic depsipeptide...WS9326 A is a tachykinin receptor antagonist and quorum sensing inhibitor discovered from several Streptomyces strains.The structure of WS9326 A features a(Z)-pentenylcinnamoyl moiety attached on a cyclic depsipeptide skeleton,which is biosynthesized by nonribosomal peptide synthetases(NRPS).The regioselective cyclization in the last step of NRPS catalysis,which is proposed to be catalyzed by a thioesterase(TE)domain in the last module,has not been experimentally characterized.We here report the synthesis of two substrate mimics(1 and 2)of the TE(WS9326 A-TE)in WS9326 A biosynthesis,by using Fmoc-based solid-phase peptide synthesis(SPPS)method.Compounds 1 and 2 are new compounds whose structures have been elucidated based on NMR and HRESIMS analyses.The N-terminal cinnamoyl moiety and C-terminal methylated L-Ser moiety in 2 were incorporated under the mild SPPS conditions.Given the isolation difficulties of substrate of WS9326 A-TE from the Streptomyces producers of WS9326 A,our synthesis of 1 and 2 set the stage for the reconstitution of WS9326 A-TE’s catalytic reaction in vitro in the future.展开更多
文摘目的制备一种不具有促红细胞生成作用的新型促红细胞生成素(EPO)的衍生肽(DEPO)。方法 9-芴甲氧羰基(Fmoc)固相多肽合成法制备合成新型DEPO,质谱法检测鉴定DEPO相对分子质量,高效液相色谱法鉴定DEPO纯度。健康成年C57BL/6小鼠随机分为EPO(EPO 50μg·kg^(-1))组、DEPO低剂量(DEPO 50μg·kg^(-1))组、DEPO高剂量(DEPO 500μg·kg^(-1))组、生理盐水(生理盐水,0.2 m L)组和溶剂(ACN+Milliq,0.2 m L)组,隔日1次腹腔注射给药,各组于第3、7、14和30天取尾静脉血检测红细胞数变化,探究DEPO对促红细胞生成活性的影响。结果合成了一个新型、由37个氨基酸构成的DEPO,相对分子质量为3 814.8,纯度达95.25%。EPO组给药第3~30天红细胞数呈上升趋势,第14和30天较第3天显著增高(P<0.001)。DEPO低剂量组和DEPO高剂量组红细胞数未见明显增高。结论本研究合成了一种新型DEPO,其在体内不产生促红细胞生成的不良反应,具有一定的临床应用前景。
基金National Natural Science Foundation of China(Grant No.21877002,81673332,81573326 and 81741148)
文摘WS9326 A is a tachykinin receptor antagonist and quorum sensing inhibitor discovered from several Streptomyces strains.The structure of WS9326 A features a(Z)-pentenylcinnamoyl moiety attached on a cyclic depsipeptide skeleton,which is biosynthesized by nonribosomal peptide synthetases(NRPS).The regioselective cyclization in the last step of NRPS catalysis,which is proposed to be catalyzed by a thioesterase(TE)domain in the last module,has not been experimentally characterized.We here report the synthesis of two substrate mimics(1 and 2)of the TE(WS9326 A-TE)in WS9326 A biosynthesis,by using Fmoc-based solid-phase peptide synthesis(SPPS)method.Compounds 1 and 2 are new compounds whose structures have been elucidated based on NMR and HRESIMS analyses.The N-terminal cinnamoyl moiety and C-terminal methylated L-Ser moiety in 2 were incorporated under the mild SPPS conditions.Given the isolation difficulties of substrate of WS9326 A-TE from the Streptomyces producers of WS9326 A,our synthesis of 1 and 2 set the stage for the reconstitution of WS9326 A-TE’s catalytic reaction in vitro in the future.
