Formation of bifunctional cross-linked products due to reaction of NAMI-A with DNA bases – a DFT study

Pramod Kumar Shah,Pradeep Kumar Shukla

doi:10.1007/s11224-022-01897-0

Abstract

It is reported that NAMI-A and other Ru-anticancer complexes preferably bind with the N7 site of guanine and can also form DNA inter-strand cross-links. Therefore, in order to understand the DNA cross-link formation capability of NAMI-A, we have investigated here the structure and energetics of the reactions of the GN7-NAMI-A (a monofunctional adduct of NAMI-A with the N7 site of guanine) with the N3, N7, and O6 sites of guanine; the N1, N3, and N7 sites of adenine; the O2 and N3 sites of cytosine; and the O2 and O4 sites of thymine, using the M06-2X functional of density functional theory. It is found that the GN7-NAMI-A can form stable cross-linked products at all the sites studied here except at the N3 site of cytosine and O2 site of thymine. The calculated reaction free energies and reaction enthalpies indicate that the N3 site of adenine (AN3) and N7 site of guanine (GN7) are most exothermic among all the studied reactions. This study shows that NAMI-A would favorably form the cross-linked products involving the N7 site of guanine at one side and the N7 site of guanine or the N3 site of adenine at the other side.

Highlights

The initiation and development of cancer which is known to be a leading cause of death worldwide is linked with DNA damage caused by a myriad of endogenous and exogenous agents including free radicals, reactive oxygen species (ROS), reactive nitrogen oxide species (RNOS), alkylating agents and ionizing radiation [1,2,3,4,5]
It is reported that NAMI-A and other Ru-anticancer complexes preferably bind with the N7 site of guanine and can form DNA inter-strand cross-links
It is found that the GN7-NAMI-A can form stable cross-linked products at all the sites studied here except at the N3 site of cytosine and O2 site of thymine

Summary

Introduction

The initiation and development of cancer which is known to be a leading cause of death worldwide is linked with DNA damage caused by a myriad of endogenous and exogenous agents including free radicals, reactive oxygen species (ROS), reactive nitrogen oxide species (RNOS), alkylating agents and ionizing radiation [1,2,3,4,5]. These DNA lesions, if not repaired, can cause several other lethal consequences including mutation, aging and neurodegenerative diseases [5, 2,3,4, 6] Anticancer drugs such as cisplatin, temozolamide, mechlorethamine etc. P.M. van Vliet et al [34] showed that the mer-[Ru(III)(terpy)Cl3] complex formed DNA inter-strand cross-linking in vitro via binding with two guanine bases in trans-configuration. Malina et al [35] demonstrated that Rubased drugs such as NAMI, KP1019 and ICR yielded bifunctional inter-strand crosslinks on double helical DNA with guanine as the prevalent binding site. In view of the fact that Ru-based drugs bind predominantly with the N7 site of guanine and are hydrolyzed before reacting with any target, the GN7-NAMI-A (Fig. 1a) has been chosen as a reactant for the present study. The mechanisms of the formation of mono-functional adduct of NAMI-A at the N7 site of guanine can be found in our previous work [36]

Computational Details

Results And Discussion

Conclusions

Compliance with ethical standards