Hydrosoluble Perylene Monoimide-Based Telomerase Inhibitors with Diminished Cytotoxicity

Pak Thaichana; Ratasark Summart; Pornngarm Dejkriengkraikul; Puttinan Meepowpan; T Randall Lee; Wirote Tuntiwechapikul

doi:10.1021/acsomega.2c01343

Hydrosoluble Perylene Monoimide-Based Telomerase Inhibitors with Diminished Cytotoxicity

ACS Omega. 2022 May 5;7(19):16746-16756. doi: 10.1021/acsomega.2c01343. eCollection 2022 May 17.

Authors

Pak Thaichana¹, Ratasark Summart¹, Pornngarm Dejkriengkraikul^{1

2}, Puttinan Meepowpan³, T Randall Lee⁴, Wirote Tuntiwechapikul^{1

2}

Affiliations

¹ Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
² Center for Research and Development of Natural Products for Health, Chiang Mai University, Chiang Mai 50200, Thailand.
³ Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand.
⁴ Department of Chemistry and the Texas Center for Superconductivity, University of Houston, Houston, Texas 77204-5003, United States.

Abstract

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 N,N-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, in vitro telomerase inhibition, and suppression of human telomerase reverse transcriptase (hTERT) 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 N,N-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.