Quinone methides tethered to naphthalene diimides as selective G-quadruplex alkylating agents.
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.
Di Antonio
Marco
M
Dipartimento di Scienze Farmaceutiche, Università di Padova,Via Marzolo, 5, 35131 Padova, Italy.
Doria
Filippo
F
Richter
Sara N
SN
Bertipaglia
Carolina
C
Mella
Mariella
M
Sissi
Claudia
C
Palumbo
Manlio
M
Freccero
Mauro
M
D000477:Alkylating Agents / Q000737:chemistry*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000737:chemistry*; D054856:G-Quadruplexes; D006801:Humans; D007094:Imides / Q000737:chemistry* / Q000494:pharmacology; D045563:Indolequinones / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D009281:Naphthalenes / Q000737:chemistry* / Q000494:pharmacology
D000477:Alkylating Agents; D007094:Imides; D045563:Indolequinones; D009281:Naphthalenes; C068040:quinone methide; C542131:naphthalenediimide; D004247:DNA