Synthesis, Binding and Antiviral Properties of Potent Core-Extended Naphthalene Diimides Targeting the HIV‑1 Long Terminal Repeat Promoter G‑Quadruplexes

• Published in: Journal of medicinal chemistry Vol. 58; no. 24; pp. 9639 - 9652
• Main Authors: Perrone, Rosalba, Doria, Filippo, Butovskaya, Elena, Frasson, Ilaria, Botti, Silvia, Scalabrin, Matteo, Lago, Sara, Grande, Vincenzo, Nadai, Matteo, Freccero, Mauro, Richter, Sara N
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.12.2015; Amer Chemical Soc
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Chemistry, Medicinal; G-Quadruplexes; HEK293 Cells; HeLa Cells; HIV Long Terminal Repeat; HIV-1 - drug effects; HIV-1 - genetics; Human immunodeficiency virus 1; Humans; Imides - chemical synthesis; Imides - chemistry; Imides - pharmacology; Life Sciences & Biomedicine; Ligands; Naphthalenes - chemical synthesis; Naphthalenes - chemistry; Naphthalenes - pharmacology; Pharmacology & Pharmacy; Promoter Regions, Genetic; Protein Binding; Science & Technology; Structure-Activity Relationship; CANCER-CELLS; HUMAN GENOME; RNA; RECOGNITION; STRUCTURAL BASIS; ALKYLATING-AGENTS; TRANSCRIPTION; DNA FORMATION; LIGAND; IONIZATION MASS-SPECTROMETRY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.5b01283

We have previously reported that stabilization of the G-quadruplex structures in the HIV-1 long terminal repeat (LTR) promoter suppresses viral transcription. Here we sought to develop new G-quadruplex ligands to be exploited as antiviral compounds by enhancing binding toward the viral G-quadruplex structures. We synthesized naphthalene diimide derivatives with a lateral expansion of the aromatic core. The new compounds were able to bind/stabilize the G-quadruplex to a high extent, and some of them displayed clear-cut selectivity toward the viral G-quadruplexes with respect to the human telomeric G-quadruplexes. This feature translated into low nanomolar anti-HIV-1 activity toward two viral strains and encouraging selectivity indexes. The selectivity depended on specific recognition of LTR loop residues; the mechanism of action was ascribed to inhibition of LTR promoter activity in cells. This is the first example of G-quadruplex ligands that show increased selectivity toward the viral G-quadruplexes and display remarkable antiviral activity.