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首页> 外文期刊>Chemistry: A European journal >Synthesis and Biological Evaluation of RGD Peptidomimetic-Paclitaxel Conjugates Bearing Lysosomally Cleavable Linkers
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Synthesis and Biological Evaluation of RGD Peptidomimetic-Paclitaxel Conjugates Bearing Lysosomally Cleavable Linkers

机译：RGS拟肽-紫杉醇偶联物的合成及生物学评价，其具有溶酶体可裂解的接头。

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摘要

Two small-molecule-drug conjugates (SMDCs, 6 and 7) featuring lysosomally cleavable linkers (namely the Val-Ala and Phe-Lys peptide sequences) were synthesized by conjugation of the alpha(v)beta(3)-integrin ligand cyclo[DKP-RGD]-CH2NH2 (2) to the anticancer drug paclitaxel (PTX). A third cyclo[DKP-RGD]-PTX conjugate with a nonpeptide "uncleavable" linker (8) was also synthesized to be tested as a negative control. These three SMDCs were able to inhibit biotinylated vitronectin binding to the purified alpha(v)beta(3)-integrin receptor at nanomolar concentrations and showed good stability at pH 7.4 and pH 5.5. Cleavage of the two peptide linkers was observed in the presence of lysosomal enzymes, whereas conjugate 8, which possesses a nonpeptide "uncleavable" linker, remained intact under these conditions. The antiproliferative activities of the conjugates were evaluated against two isogenic cell lines expressing the integrin receptor at different levels: the acute lymphoblastic leukemia cell line CCRF-CEM (alpha(v)beta(3)-) and its subclone CCRF-CEM alpha(v)beta(3) (alpha(v)beta(3)+). Fairly effective integrin targeting was displayed by the cyclo[DKP-RGD]-Val-Ala-PTX conjugate (6), which was found to differentially inhibit proliferation in antigen-positive CCRF-CEM alpha(v)beta(3) versus antigen-negative isogenic CCRF-CEM cells. The total lack of activity displayed by the "uncleavable" cyclo[DKP-RGD]-PTX conjugate (8) clearly demonstrates the importance of the peptide linker for achieving the selective release of the cytotoxic payload.
机译：通过结合α（v）beta（3）-整联蛋白配体环[，]合成了两个具有溶酶体可裂解的接头（即Val-Ala和Phe-Lys肽序列）的小分子药物偶联物（SMDC，6和7）。 DKP-RGD] -CH2NH2（2）用作抗癌药紫杉醇（PTX）。还合成了具有非肽“不可裂解的”接头（8）的第三种环[DKP-RGD] -PTX缀合物，以作为阴性对照进行测试。这三个SMDC能够抑制生物素化的玻连蛋白在纳摩尔浓度下与纯化的α（v）β（3）-整联蛋白受体的结合，并在pH 7.4和pH 5.5下显示出良好的稳定性。在溶酶体酶的存在下观察到两个肽接头的切割，而具有非肽“不可切割”接头的缀合物8在这些条件下保持完整。针对两种不同水平表达整联蛋白受体的同基因细胞系评估了缀合物的抗增殖活性：急性淋巴细胞白血病细胞系CCRF-CEM（alpha（v）beta（3）-）及其亚克隆CCRF-CEM alpha（v ）beta（3）（alpha（v）beta（3）+）。环[DKP-RGD] -Val-Ala-PTX偶联物（6）显示了相当有效的整联蛋白靶向性，发现该偶联物可差异性抑制抗原阳性CCRF-CEM alpha（v）beta（3）与抗原-负等基因CCRF-CEM细胞。由“不可切割的”环[DKP-RGD] -PTX偶联物（8）表现出的完全缺乏活性清楚地证明了肽接头对于实现细胞毒性有效载荷的选择性释放的重要性。

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