Quinone Methides Tethered to Naphthalene Diimides as Selective G-Quadruplex Alkylating Agents

Abstract

We have developed novel G-quadruplex (G-4) ligand/alkylating hybrid structures, tethering the naphthalene diimide moiety to quaternary ammonium salts of Mannich bases, as quinone-methide precursors, activatable by mild thermal digestion (40 degrees C). The bis-substituted naphthalene diimides were efficiently synthesized, and their reactivity as activatable bis-alkylating agents was investigated in the presence of thiols and amines in aqueous buffered solutions. The electrophilic intermediate, quinone-methide, involved in the alkylation process was trapped, in the presence of ethyl vinyl ether, in a hetero Diels-Alder [4 + 2] cycloaddition reaction, yielding a substituted 2-ethoxychroman. The DNA recognition and alkylation properties of these new derivatives were investigated by gel electrophoresis, circular dichroism, and enzymatic assays. The alkylation process occurred preferentially on the G-4 structure in comparison to other DNA conformations. By dissecting reversible recognition and alkylation events, we found that the reversible process is a prerequisite to DNA alkylation, which in turn reinforces the G-quadruplex structural rearrangement.

Thermodynamics of Binding of Di- and Tetrasubstituted Naphthalene Diimide Ligands to DNA G-Quadruplex

“…[6][7][8] An alternative and novel strategy involving the synthesis of NDIs as hybrid ligand alkylating agents targeting GQ was developed by Freccero and co-authors. 9 A number of di-and tetra-4 substituted naphthalene diimides were synthesized and found to selectively bind to GQ including: thermal activable bis-substituted naphthalene diimides with tethered quinone methides, 10 naphthalene diimides with an oxirane side chain, 11 and naphathalene diimides with engineered phenol moieties conjugated by alkyl-amido spacers. 12 Fluorescent bromo-and aminoor quaternary ammonium substituted naphthalene diimides were also found to act as singlet oxygen photosensitizers.…”

Assessment of gene promoter G-quadruplex binding and modulation by a naphthalene diimide derivative in tumor cells

“…To date, a diverse array of G-4 stabilizing compounds has been identified (17,18). Among them, numerous tri-and tetra-substituted naphthalene diimides (NDIs) have shown high affinity for telomeric G-4s and good antiproliferative activity in different experimental human tumor models (19)(20)(21)(22)(23)(24).…”

Pyridostatin analogues promote telomere dysfunction and long-term growth inhibition in human cancer cells

“…41–50 Previously reported quinoline-based molecules selectively recognize G-quadruplex structures over double-stranded DNA with high potency, making this chemical moiety an attractive feature to exploit for the design of G-quadruplex ligands. 51–54 We previously reported a G-quadruplex stabilizing synthetic small molecule, based on a N , N ′-bis(quinolinyl)pyridine-2,6-dicarboxamide scaffold (Fig.…”