Determinants for Tight and Selective Binding of a Medicinal Dicarbene Gold(I) Complex to a Telomeric DNA G-Quadruplex: a Joint ESI MS and XRD Investigation

Carla Bazzicalupi (1) , Marta Ferraroni (1) , Francesco Papi (1, 2) , Lara Massai (1) , Benoît Bertrand (3) , Luigi Messori (1) , Paola Gratteri (2) , Angela Casini (4)

1 UniFI - Università degli Studi di Firenze = University of Florence = Université de Florence
2 NEUROFARBA Department [Firenze, Italy]
3 ICMUB - Institut de Chimie Moléculaire de l'Université de Bourgogne [Dijon]
4 Cardiff University

The dicarbene gold(I) complex [Au(9-methylcaffein-8-ylidene)(2)]BF4 is an exceptional organometallic compound of profound interest as a prospective anticancer agent. This gold(I) complex was previously reported to be highly cytotoxic toward various cancer cell lines invitro and behaves as a selective G-quadruplex stabilizer. Interactions of the gold complex with various telomeric DNA models have been analyzed by a combined ESI MS and X-ray diffraction (XRD) approach. ESI MS measurements confirmed formation of stable adducts between the intact gold(I) complex and Tel 23 DNA sequence. The crystal structure of the adduct formed between [Au(9-methylcaffein-8-ylidene)(2)](+) and Tel 23 DNA G-quadruplex was solved. Tel 23 maintains a characteristic propeller conformation while binding three gold(I) dicarbene moieties at two distinct sites. Stacking interactions appear to drive noncovalent binding of the gold(I) complex. The structural basis for tight gold(I) complex/G-quadruplex recognition and its selectivity are described.

Mots clés: cancer; ESI mass spectrometry; gold; G-quadruplexes; X-ray diffraction; potential anticancer agents; pancreatic-cancer cells; metal-complexes; carbene complexes; crystal-structure; loop flexibility; small molecules; stabilization; inhibition; apoptosis

Domaines: Chimie; Cancer

Carla Bazzicalupi, Marta Ferraroni, Francesco Papi, Lara Massai, Benoît Bertrand, et al.. Determinants for Tight and Selective Binding of a Medicinal Dicarbene Gold(I) Complex to a Telomeric DNA G-Quadruplex: a Joint ESI MS and XRD Investigation. Angewandte Chemie International Edition, 2016, 55 (13), pp.4256 - 4259. ⟨10.1002/anie.201511999⟩. ⟨hal-01399300⟩