# Antiproliferative Activity of Aminobenzylnaphthols Deriving from the Betti Reaction
## 1 Introduction  
A malignant tumor, also called cancer, is among the most difficult diseases to cure [1]. Surgery, radiation, and chemotherapy are the three main treatments for cancer to date. Among these therapeutic strategies, [(_cis_-Diamine-dichloratin (II), or more commonly \"cisplatin\"] is one of the most used chemotherapeutic agents, since it is employed in the treatment of the testicular, ovarian, lung, head and neck, upper gastrointestinal tract, and other types of solid cancer. Cisplatin moves rapidly into the blood and has a very short retention time in the tumor [2]. Cisplatin's mechanism of action is represented by the formation of DNA adducts blocking fundamental processes such as transcription and replication, leading to cell death [3]. However, the long-term use of the drug leads to the development of resistance, which is related to three main molecular mechanisms: DNA repair, cellular adaptations, and drug inactivation [4]. Next-generation platinum complexes have been developed to increase anticancer efficacy and minimize side effects, thus permitting higher doses to be employed [5]. In the investigations on new chemotherapeutic agents, SH-SYSY human neuroblastoma cells have been used as a model to compare cisplatin toxicity to that of other platinum derivatives. For example, cisplatin induced apoptotic death in undifferentiated cells of SH-SYSY human neuroblastoma [6]. SH-SYSY cells have been employed as a model to compare cisplatin toxicity to that of other platinum derivatives, such as oxaliplatin [oxalate (trans-1,2-diaminocyclohexane) platinum (II), OHP] [7]. As far as new metal complexes tested as antiproliferative agents, cadmium complexes were tested in many cancer cell lines, e.g., MCF-7 (breast), Caco-2 (colorectal), and cisplatin-resistant lung cancer cell lines. The in vitro cytotoxicity of innovative vanadium complexes with orotic and glutamic acids were evaluated against hepatocellular carcinoma and human colorectal adenocarcinoma (Caco-2) [8]. In order to find new synthetic compounds to be employed as chemotherapeutic agents, we tested some aminobenzylnaphthols that had been synthesized with the Betti reaction [9]. This process is a multi-component reaction between 2-naphthol, aryl aldehydes,and amines that yields the cited aminobenzylnaphthols. Since its discovery in the early 20 th century, the Betti reaction was seldom applied until its rediscovery due to our research, starting in 1998 [10] and continuing over the following years [9; 10; 11; 12; 13; 14; 15; 16; 17; 18]. Since 1999, many researchers around the world have applied the Betti reaction [9]. However, aminobenzylnaphthols have seldom been investigated as bioactive compounds during the last two decades (1998-2018) [18; 19; 20]. During the last few years (2019-2022), a new interest in the Betti reaction has emerged. A recent review [21] reported new green routes to accomplish this process, new applications of the products obtained so far, and the evaluation of their bio-activity. To limit the investigations to only antitumor agents, [PERSON] et al. synthesized aminobenzylnaphthols with new amines or \(N\)-heterocycles using the Betti protocol [22]. These new intermediates were tested against some solid tumor cell lines, using cisplatin as a standard. Some of these molecules showed antiproliferative values beyond the GI\({}_{50}<\)10 mM threshold, a value that is promising for future clinical tests. The authors speculated that this interesting activity could be due to the tryptophan mimetic of the Betti bases that is able to inhibit cell proliferation. This hypothesis stimulated new investigations about the employment of Betti base frameworks as antitumor agents. [PERSON] et al. synthesized and tested thiophene containing aminobenzylnaphthols [23] against four tumor cell lines (lung, prostate, breast, and liver). The in vitro results are comparable with those obtained with the standard drug doxorubicin tested against these cell lines. [PERSON] et al.