Thaichana Pak, Summart Ratasark, Dejkriengkraikul Pornngarm, Meepowpan Puttinan, Lee T Randall, Tuntiwechapikul Wirote
Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
Center for Research and Development of Natural Products for Health, Chiang Mai University, Chiang Mai 50200, Thailand.
ACS Omega. 2022 May 5;7(19):16746-16756. doi: 10.1021/acsomega.2c01343. eCollection 2022 May 17.
Telomerase is essential for the immortality characteristics of most cancers. Telomerase-specific inhibitors should render cancer cells to replicative senescence without acute cytotoxicity. Perylene-based G-quadruplex (G4) ligands are widely studied as telomerase inhibitors. Most reported perylene-based G4 ligands are perylene diimides (PDIs), which often suffer from self-aggregation in aqueous solutions. Previously, we found that PM2, a perylene monoimide (PMI), exhibited better solubility, G4 binding affinity, and telomerase inhibition than PIPER, the prototypic PDI. However, the acute cytotoxicity of PM2 was about 20-30 times more than PIPER in cancer cells. In this report, we replaced the piperazine side chain of PM2 with ethylenediamine to yield PM3 and replaced the ,-diethylethylenediamine side chain of PM2 with the 1-(2-aminoethyl) piperidine to yield PM5. We found that asymmetric PMIs with two basic side chains (PM2, PM3, and PM5) performed better than PIPER (the prototypic PDI), in terms of hydrosolubility, G4 binding, telomerase inhibition, and suppression of human telomerase reverse transcriptase () expression and telomerase activity in A549 cells. However, PM5 was 7-10 times less toxic than PM2 and PM3 in three cancer cell lines. We conclude that replacing the ,-diethylethylenediamine side chain with the 2-aminoethylpiperidine on PMIs reduces the cytotoxicity in cancer cells without impacting G4 binding and telomerase inhibition. This study paves the way for synthesizing new PMIs with drug-like properties for selective telomerase inhibition.
端粒酶对于大多数癌症的永生特性至关重要。端粒酶特异性抑制剂应使癌细胞进入复制性衰老而无急性细胞毒性。基于苝的G-四链体（G4）配体作为端粒酶抑制剂被广泛研究。大多数报道的基于苝的G4配体是苝二亚胺（PDIs），其在水溶液中常发生自聚集。此前，我们发现苝单亚胺（PMI）PM2比原型PDI PIPER表现出更好的溶解性、G4结合亲和力和端粒酶抑制作用。然而，在癌细胞中，PM2的急性细胞毒性比PIPER高约20 - 30倍。在本报告中，我们将PM2的哌嗪侧链替换为乙二胺得到PM3，并将PM2的β,β-二乙基亚乙二胺侧链替换为1-(2-氨基乙基)哌啶得到PM5。我们发现具有两个碱性侧链的不对称PMIs（PM2、PM3和PM5）在水溶性、G4结合、端粒酶抑制以及抑制人端粒酶逆转录酶（hTERT）表达和A549细胞中端粒酶活性方面比PIPER（原型PDI）表现更好。然而，在三种癌细胞系中，PM5的毒性比PM2和PM3低7 - 10倍。我们得出结论，在PMIs上用2-氨基乙基哌啶替换β,β-二乙基亚乙二胺侧链可降低癌细胞中的细胞毒性，而不影响G4结合和端粒酶抑制。本研究为合成具有类药物性质的新型PMIs以选择性抑制端粒酶铺平了道路。
