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

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.

Figure 1

Examples of classical amidine MGBs with antibacterial, antiparasitic, or anticancer activities.

Figure 2

General structure of some guanidine and 2-aminoimidazole dicationic prototypes previously reported by Rozas’ group.

Figure 3

Compounds proposed in this study as potential MGBs.

Figure 4

Best pose obtained in the docking of compound 1 to the DNA minor groove model (dodecanucleotide d(CGCGAATTCGCG)₂, PDB: 1D64), with a G-score of −8.9 kcal/mol, using a flexible-rigid approach and the Autodock Vina program. Green lines and numbers indicate HBs, and HB distances are in Å.

Scheme 1. Preparation of Bis-guanidinium Derivatives 1–4

Reagents and conditions: (a) 1,3-bis(tert-butoxycarbonyl)guanidine, K₂CO₃, DMF, 50 °C, 2 h, 60% (52 and 53), 61% (54), 70% (55); (b) HCl 4 M in 1,4-dioxane, dioxane, 55 °C, 5 h, 80% (1), 83% (2), 85% (3), 94% (4).

Scheme 2. Preparation of Monoguanidinium Derivatives 5–14

Reagents and conditions: (a) 1,3-bis(tert-butoxycarbonyl)guanidine, K₂CO₃, DMF, 50 °C, 2 h, 57% (76), 55% (77), 59% (78), 60% (79), 94% (80), 84% (81), 90% (82), 83% (83),62% (84); (b) HCl 4 M in 1,4-dioxane, dioxane, 55 °C, 5 h, 77% (5), 92% (6), 86% (7), 33% (8) and 46% (9), 92% (10), 89% (11), 92% (12), 90% (13), 99% (14).