Novel Pyridazin-3(2 H)-one-Based Guanidine Derivatives as Potential DNA Minor Groove Binders with Anticancer Activity

María Carmen Costas-Lago; Noemí Vila; Adeyemi Rahman; Pedro Besada; Isabel Rozas; José Brea; María Isabel Loza; Elisa González-Romero; Carmen Terán

doi:10.1021/acsmedchemlett.1c00633

Novel Pyridazin-3(2 H)-one-Based Guanidine Derivatives as Potential DNA Minor Groove Binders with Anticancer Activity

ACS Med Chem Lett. 2022 Feb 10;13(3):463-469. doi: 10.1021/acsmedchemlett.1c00633. eCollection 2022 Mar 10.

Authors

María Carmen Costas-Lago^{1

2}, Noemí Vila^{1

2}, Adeyemi Rahman³, Pedro Besada^{1

2}, Isabel Rozas³, José Brea⁴, María Isabel Loza⁴, Elisa González-Romero⁵, Carmen Terán^{1

2}

Affiliations

¹ Departamento de Química Orgánica, Universidade de Vigo, 36310 Vigo, España.
² Instituto de Investigación Sanitaria Galicia Sur, Hospital Álvaro Cunqueiro, 36213 Vigo, España.
³ School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, Ireland.
⁴ Drug Screening Platform/Biofarma Research Group, CIMUS Research Center. Departamento de Farmacoloxía, Farmacia e Tecnoloxía Farmacéutica. Universidade de Santiago de Compostela, 15782 Santiago de Compostela, España.
⁵ Departamento de Química Analítica y Alimentaria, Universidade de Vigo, 36310 Vigo, España.

Abstract

Novel aryl guanidinium analogues containing the pyridazin-3(2H)-one core were proposed as minor groove binders (MGBs) with the support of molecular docking studies. The target dicationic or monocationic compounds, which show the guanidium group at different positions of the pyridazinone moiety, were synthesized using the corresponding silyl-protected pyridazinones as key intermediates. Pyridazinone scaffolds were converted into the adequate bromoalkyl derivatives, which by reaction with N,N'-di-Boc-protected guanidine followed by acid hydrolysis provided the hydrochloride salts 1-14 in good yields. The ability of new pyridazin-3(2H)-one-based guanidines as DNA binders was studied by means of DNA UV-thermal denaturation experiments. Their antiproliferative activity was also explored in three cancer cell lines (NCI-H460, A2780, and MCF-7). Compounds 1-4 with a bis-guanidinium structure display a weak DNA binding affinity and exhibit a reasonable cellular viability inhibition percentage in the three cancer cell lines studied.