Sequence-Selective Recognition of the d(GGCGCC)2 DNA Palindrome by Oligopeptide Derivatives of Mitoxantrone. Enabling for Simultaneous Targeting of the Two Guanine Bases Upstream from the Central Intercalation Site in Both Grooves and along Both Strands

Nohad Gresh; Alberto Ongaro; Luc Demange; Giuseppe Zagotto; Giovanni Ribaudo

doi:10.1021/acsomega.4c05099

Sequence-Selective Recognition of the d(GGCGCC)₂ DNA Palindrome by Oligopeptide Derivatives of Mitoxantrone. Enabling for Simultaneous Targeting of the Two Guanine Bases Upstream from the Central Intercalation Site in Both Grooves and along Both Strands

ACS Omega. 2024 Oct 3;9(41):42309-42328. doi: 10.1021/acsomega.4c05099. eCollection 2024 Oct 15.

Authors

Nohad Gresh¹, Alberto Ongaro², Luc Demange³, Giuseppe Zagotto², Giovanni Ribaudo⁴

Affiliations

¹ Laboratoire de Chimie Théorique, UMR 7616 CNRS Sorbonne Universités, Paris 75005, France.
² Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova 35131, Italy.
³ UMR 8038 CNRS CiTCoM, Team PNAS, Faculté de Pharmacie, Université Paris-Cité, 4 Avenue de l'Observatoire, Paris 75006, France.
⁴ DMMT, University of Brescia, Viale Europa 11, Brescia 25121, Italy.

Abstract

The d(GGCGCC)₂ palindrome is encountered in several oncogenic and retroviral sequences. In order to target it, we previously designed several oligopeptide derivatives of the mitoxantrone and ametantrone anticancer intercalators. These have two arms with a cationic side-chain in the major groove, each destined to bind along each strand O₆/N₇ of the two successive guanine bases (G1-G2/G1'-G2') upstream from the central anthraquinone intercalation site. We retained from a previous study (El Hage et al., 2022) a tris-intercalating molecule with two outer 9-aminoacridine (9-AA) intercalators, denoted as III. We sought enhancements in both affinity and selectivity by simultaneously targeting the minor groove of the extracyclic -NH₂ groups of these bases and G4-G4' of the intercalation site. We considered derivatives of distamycin, having each pyrrole ring replaced by an imidazole to act as an in-register electron acceptor from the -NH₂ group of a target guanine. We substituted the C₆ and C₇ carbons of anthraquinone, or the C₈ and C₉ ones of anthracycline, by an (imidazole-amide)3 chain. Four different derivatives of III were designed with different connectors to the anthraquinone/anthracycline and 9-AA. Polarizable molecular dynamics simulations of their complexes with a double-stranded DNA 18-mer with a central d(C GGGC GCCC G)₂ palindrome sequence showed in-register minor groove binding to -NH₂ of G1-G₂/G1'-G2' to coexist with major groove recognition of O₆/N₇. Up to 12 H-bonds could be stabilized in the minor groove coexisting with four bidentate interactions of the alkyl diammonium moieties in the major groove. Since there is no mutual interference, the binding enthalpies, ΔH, contributed by each groove could add up and enable significant enhancements of the affinity constants. As was the case for their Lys precursor, these derivatives are amenable to chemical syntheses and in vitro and in vivo tests, for which the present results provide an incentive. The construction of derivatives III-A-III-D is modular. For in vitro experiments, this should enable unraveling the most important structural elements to further optimize both ΔH and TΔS and sequence selectivity and how this could translate to in vivo tests.