Gresh Nohad, Ongaro Alberto, Demange Luc, Zagotto Giuseppe, Ribaudo Giovanni
Laboratoire de Chimie Théorique, UMR 7616 CNRS Sorbonne Universités, Paris 75005, France.
Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova 35131, Italy.
ACS Omega. 2024 Oct 3;9(41):42309-42328. doi: 10.1021/acsomega.4c05099. eCollection 2024 Oct 15.
The d(GGCGCC) 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 O/N 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 . We sought enhancements in both affinity and selectivity by simultaneously targeting the minor groove of the extracyclic -NH 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 -NH group of a target guanine. We substituted the C and C carbons of anthraquinone, or the C and C ones of anthracycline, by an (imidazole-amide)3 chain. Four different derivatives of 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) palindrome sequence showed in-register minor groove binding to -NH of G1-G/G1'-G2' to coexist with major groove recognition of O/N. 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, Δ, 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 - is modular. For in vitro experiments, this should enable unraveling the most important structural elements to further optimize both Δ and Δ and sequence selectivity and how this could translate to in vivo tests.
d(GGCGCC)回文序列存在于多个致癌和逆转录病毒序列中。为了靶向该序列，我们之前设计了米托蒽醌和氨甲蒽醌抗癌嵌入剂的几种寡肽衍生物。这些衍生物有两个臂，在大沟中有一个阳离子侧链，每个臂旨在沿着中央蒽醌嵌入位点上游两个连续鸟嘌呤碱基（G1-G2/G1'-G2'）的每条链的O/N结合。我们从之前的一项研究（El Hage等人，2022年）中保留了一种三嵌入分子，其具有两个外部9-氨基吖啶（9-AA）嵌入剂，记为 。我们通过同时靶向这些碱基的环外-NH基团的小沟和嵌入位点的G4-G4'来寻求亲和力和选择性的增强。我们考虑了偏端霉素的衍生物，其每个吡咯环被咪唑取代，以作为来自靶鸟嘌呤-NH基团的共线电子受体。我们用（咪唑-酰胺）3链取代蒽醌的C和C碳，或蒽环类药物的C和C碳。设计了四种不同的 衍生物，它们与蒽醌/蒽环类药物和9-AA有不同的连接基团。对它们与具有中央d(C GGGC GCCC G)回文序列的双链DNA 18聚体形成的复合物进行的可极化分子动力学模拟表明，与G1-G/G1'-G2'的-NH的共线小沟结合与O/N的大沟识别共存。在小沟中最多可稳定12个氢键，同时在大沟中存在烷基二铵部分的四个双齿相互作用。由于不存在相互干扰，每个沟贡献的结合焓Δ可以相加，从而显著提高亲和常数。与它们的赖氨酸前体情况一样，这些衍生物适合进行化学合成以及体外和体内测试，本文的结果为这些测试提供了动力。衍生物 - 的构建是模块化的。对于体外实验，这应该能够揭示最重要的结构元件，以进一步优化Δ和Δ以及序列选择性，以及这如何转化为体内测试。
