两个Galaxamide类似物的固相合成及抗肿瘤活性研究

Study on Solid Phase Synthesis and Anti-Tumor of Two Galaxamide Analogues

摘要:

以N-芴甲氧羰基亮氨酸（Fmoc-Leu-OH）和N-芴甲氧羰基脯氨酸（Fmoc-Pro-OH）为原料，采用经典的Fmoc固相合成法，通过对氨基酸N端的保护及脱保护、氨基酸的甲基化、缩合等步骤合成线性五肽，以缩合试剂六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷（PyBOP）关环，以59.5 %和41.1 %的环合收率得到了两个新的环五肽化合物G1和G2，结构通过1HNMR，13CNMR，ESI-MS进行确认。采用MTT法对目标化合物G1和G2进行了体外抗肿瘤活性的研究。结果表明，含有脯氨酸片段的Galaxamide类似物G2具有良好的活性，尤其对人乳腺癌细胞株（MCF - 7）具有较好的细胞毒性，其 IC50 值为5.85 mg /L。

Abstract:

With N-[(9H-Fluoren-9-ylmethoxy)carbonyl]-leucine ( Fmoc-Leu-OH ) and N-[(9H-Fluoren-9-ylmethoxy)carbonyl]-proline ( Fmoc-Pro-OH ) as starting materials, the classic Fmoc solid phase synthesis scheme for cyclopentapetide was employed. The linear peptapeptides were synthesized by protecting and deprotecting the amine using standard Fmoc solid phase peptide synthesis, including N-methylated amino acid. The cyclization step was completed using Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate ( PyBOP ) as coupling reagent. Herein, two Galaxamide analogues G1 and G2 were synthesized and characterized by means of 1HNMR, 13CNMR, ESI-MS. Their anti-tumor activity in vitro were investigated through the MTT assay. The results demonstrated that proline-containing Galaxamide analogue G2 possess potent cytotoxicity on human breast cancer cell line MCF-7, which exhibited IC50 values of 5.85 mg /L.