Substituent effects of cyclic naphthalene diimide on G-quadruplex binding and the inhibition of cancer cell growth

• Published in: Bioorganic & medicinal chemistry letters Vol. 50; p. 128323
• Main Authors: Fukuda, Hikaru, Sato, Shinobu, Zou, Tingting, Higashi, Sen, Takahashi, Osamu, Habu, Manabu, Sasaguri, Masaaki, Tominaga, Kazuhiro, Takenaka, Shigeori, Takeuchi, Hiroshi
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-10-2021
• Subjects: Anti-cancer drug; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Bone Marrow Cells - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Circular Dichroism; Cisplatin - pharmacology; Cyclic naphthalene diimide; G-quadruplex binder; G-Quadruplexes; G-quartet DNA; Humans; Imides - chemistry; Imides - pharmacology; Keratinocytes - drug effects; Molecular Structure; Naphthalenes - chemistry; Naphthalenes - pharmacology; Structure-Activity Relationship; Telomerase; G-quartet DNA; Anti-cancer drug; Cyclic naphthalene diimide; G-quadruplex binder; Telomerase
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2021.128323

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•Cyclic naphthalene diimides 1–4 having aliphatic or aromatic part were synthesized.•3 bound to c-myc stronger than to TA-core, whereas 4 showed an opposite selectively.•G-quartet binding, telomerase activity, and cancer suppression was correlated in 1–4.•3 showed growth inhibition of the cancer cell, but not of normal cell at <0.03 μM.
Interaction of cyclic naphthalene diimide derivatives (cNDIs), 1–4, with TA-core and c-myc as G-quartet (G4) DNA was studied under dilute or molecular crowding condition. Binding study for TA-core based on an isothermal titration calorimetry showed that 1–4 has 106 M−1 order of binding affinity with the following order: 1 > 4 > 2 > 3 under both conditions. Meting temperature (Tm) of TA-core obtained from the temperature dependence of circular dichroism spectra shows that TA-core was most stabilized by 4, which is in agreement with the result of PCR stop assay and the stabilization effect for 1–3 was correlated with their binding affinity under dilute condition. 3 showed specific growth inhibition of cancer cell line Ca9-22 at <0.03 μM of IC50, with no inhibitory effect against normal bone marrow cells. 3, which has highest value of ΔH/ΔG, shows the highest inhibition ability for Ca9-22, carrying a highest expression level of telomerase mRNA.