**1. Introduction**

Recently, various chemotherapy regimens including inhibitors of DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP-1), which selectively target BRCA-deficient tumors, have been extensively evaluated [1–4]. The underlying concept is that the cell death can be induced by simultaneous inhibition/inactivation of two key DNA repair molecules, PARP-1 and BRCA (breast cancer susceptibility protein), involved in different pathways of removing DNA lesions. PARP-1 binds to DNA breaks and synthesizes a signal polymer poly(ADP-ribose) (PAR) from NAD<sup>+</sup> molecules to activate the excision repair proteins [5–8]. Upon PARP-1 inhibition, the number of double-strand DNA breaks is increased; however, they can still be removed using homologous recombination (i.e., through

an alternative mechanism involving BRCA protein). If BRCA is deficient, genome instability reaches the critical level, resulting in cancer cell death [9–12]. A first-in-class PARP-1 inhibitor, a phthalazine derivative olaparib, was approved by FDA in 2014 and positioned as an innovative drug for the treatment of ovarian cancer in people with hereditary BRCA mutations [1,13,14]. Success of olaparib has inspired further studies of PARP inhibition, but also revealed serious side effects (in particular, hematological toxicity) that accompany the use of synthetic inhibitors [15–19]. The toxicity is likely related to the nonselective interaction with numerous NAD+-binding proteins (including other PARP family members, such as PARP-2) as well as to nonspecific effects on the organism characteristic for the synthetic molecules.

One way to reduce adverse effects of chemotherapy might be the use of natural PARP inhibitors instead of synthetic compounds. Although strong suppression of PARP seems to be inherently toxic due to an important role played by these proteins in the organism, attempts are continuing to find the proper balance between efficacy of natural inhibitors and their toxicity. For example, PARP inhibitors were identified among caffeine metabolites [20,21] and 2,5-diketopiperazines from chicken essence (a food supplement in Asian countries) [22]. Recently we have shown that a natural nitrogenous base, 7-methylguanine (7-MG), inhibits PARP-1 in vitro and accelerates apoptotic death of BRCA-deficient breast cancer cells induced by cisplatin and doxorubicin [23]. 7-MG has an attractive predicted profile of pharmacokinetics and toxicity and exerts no significant adverse effects on the organism in preliminary in vivo tests [24]. It contains a lactam group built in an aromatic scaffold (a common structural feature of effective PARP inhibitors [25,26]) and is expected to form substrate-specific interactions with the Gly863 and Tyr907 residues in the PARP-1 active site.

In this article, we present the results of a study of the 7-MG inhibition mechanism, which includes molecular modeling of the 7-MG binding to PARP-1, kinetics analysis of its ability to suppress the PARP-1-catalysed synthesis of PAR, and microscopy analysis of interaction between 7-MG, PARP-1 and nucleosomal DNA.
