新型烷基色氨酸功能化树枝状肽的设计、合成及对神经胶质瘤的活性。

Design, Synthesis and Activity of New -Alkyl Tryptophan Functionalized Dendrimeric Peptides against Glioblastoma.

机构信息

Institute of Organic Chemistry PAS, 01-224 Warsaw, Poland.

Mossakowski Medical Research Institute PAS, 02-106 Warsaw, Poland.

出版信息

Biomolecules. 2022 Aug 13;12(8):1116. doi: 10.3390/biom12081116.

DOI:10.3390/biom12081116

PMID:36009010

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9406037/

Abstract

BACKGROUND

Due to resistance to conventional therapy, a blood-brain barrier that results in poor drug delivery, and a high potential for metastasis, glioblastoma (GBM) presents a great medical challenge. Since the repertoire of the possible therapies is very limited, novel therapeutic strategies require new drugs as well as new approaches. The multiple roles played by -tryptophan (Trp) in tumorigenesis of GBM and the previously found antiproliferative properties of Trp-bearing dendrimers against this malignancy prompted us to design novel polyfunctional peptide-based dendrimers covalently attached to -alkyl tryptophan (Trp) residues. Their antiproliferative properties against GBM and normal human astrocytes (NHA) and their antioxidant potential were tested.

METHODS

Two groups of amphiphilic peptide dendrimers terminated with -butyl and -aminopentane tryptophan were designed. The influence of dendrimers on viability of NHA and human GBM cell lines, displaying different genetic backgrounds and tumorigenic potentials, was determined by the MTT test. The influence of compounds on the clonogenic potential of GBM cells was assessed by colony-formation assay. Dendrimers were tested for radical scavenging potency as well as redox capability (DPPH, ABTS, and FRAP models).

RESULTS

Several peptide dendrimers functionalized with -alkyl-tryptophan at 5 µM concentration exhibited high selectivity towards GBM cells retaining 85-95% viable NHA cells while killing cancer cells. In both the MTT and colony-formation assays, compounds (functionalized with -butyl-Trp and (+)8 charged) and (functionalized with -aminopentane-Trp and (+)12 charged) showed the most promise for their development into anticancer drugs. According to ABTS, DPPH, and FRAP antioxidant tests, dendrimers functionalized with -alkylated Trp expressed higher ROS-scavenging capacity (ABTS and DPPH) than those with unsubstituted Trp.

CONCLUSIONS

Peptide dendrimers functionalized with -alkyl-tryptophan showed varying toxicity to NHA, while all were toxic to GBM cells. Based on their activity towards inhibition of GBM viability and relatively mild effect on NHA cells the most advantageous were derivatives and with the respective di-dodecyl and dodecyl residue located at the C-terminus. As expected, peptide dendrimers functionalized with -alkyl-tryptophan expressed higher scavenging potency against ROS than dendrimers with unsubstituted tryptophan.

摘要

背景

由于对常规治疗的耐药性、导致药物递送不良的血脑屏障以及高转移潜能，胶质母细胞瘤（GBM）带来了巨大的医学挑战。由于可能的治疗方法非常有限，因此需要新的药物和方法来实现新的治疗策略。色氨酸（Trp）在 GBM 肿瘤发生中的多种作用以及含 Trp 的树枝状聚合物对这种恶性肿瘤的先前发现的抗增殖特性促使我们设计了新型的聚功能肽基树枝状聚合物，其通过共价键连接到 -烷基色氨酸（Trp）残基上。我们测试了它们对 GBM 和正常人星形胶质细胞（NHA）的抗增殖特性及其抗氧化潜力。

方法

设计了两组末端带有 -丁基和 -氨基戊基色氨酸的两亲性肽树枝状聚合物。通过 MTT 试验测定树枝状聚合物对具有不同遗传背景和致瘤潜能的 NHA 和人 GBM 细胞系活力的影响。通过集落形成试验评估化合物对 GBM 细胞克隆形成潜力的影响。测试树枝状聚合物的自由基清除能力以及氧化还原能力（DPPH、ABTS 和 FRAP 模型）。

结果

在 5µM 浓度下用 - 烷基 - 色氨酸功能化的几种肽树枝状聚合物对 GBM 细胞具有高选择性，同时保留 85-95%的 NHA 细胞存活，而杀死癌细胞。在 MTT 和集落形成试验中，化合物（用 - 丁基 - Trp 和 (+)8 电荷功能化）和（用 - 氨基戊基 - Trp 和 (+)12 电荷功能化）显示出最有希望开发成抗癌药物。根据 ABTS、DPPH 和 FRAP 抗氧化试验，用 - 烷基化色氨酸功能化的树枝状聚合物比用未取代色氨酸功能化的树枝状聚合物表现出更高的 ROS 清除能力（ABTS 和 DPPH）。

结论

用 - 烷基 - 色氨酸功能化的肽树枝状聚合物对 NHA 的毒性不同，而对 GBM 细胞均有毒性。基于它们对抑制 GBM 活力的活性以及对 NHA 细胞相对温和的影响，最有利的是具有相应的双十二烷基和十二烷基残基位于 C 末端的衍生物和。正如预期的那样，用 - 烷基 - 色氨酸功能化的肽树枝状聚合物表达了比用未取代色氨酸功能化的树枝状聚合物更高的 ROS 清除能力。