Jéssica Celerino dos Santos

Background: Heterocycle compounds with acridine, quinoline, indole, and pyridine nuclei are potentially active for anticancer activity since they can promote inhibition of vital enzymes, decreasing cell survival after binding to biomolecules. However, unspecific biological interactions can result in unwanted effects, which should be defined during the synthesis and proposition of new molecules. Thus, the objective of this study was to investigate the biological and teratogenic effects of four nitrogen heterocycles proposed for anticancer therapy. Methods: Four 2-cyano-N-phenylacrylamine type derivatives containing acridine (3a), quinoline (3b), indole (3c), and pyridine (3d) nuclei were synthesized and characterized. They were evaluated for their ability to interact with DNA, physicochemical and pharmacokinetic predictions, in vitro and in silico methodologies, besides in vitro inhibition of the Topoisomerase IIα enzyme, antiproliferative activity in tumor and non-tumor cells, hemolytic activity with human erythrocytes, and in vivo toxicological studies with zebrafish embryos. Results: UV–vis absorption studies with ssDNA revealed different spectroscopic effects, with binding constants (Kb) ranging from 1.41 × 10⁵ to 6.46 × 10⁴ M⁻¹. The fluorescence quenching constant (Ksv) with ethidium bromide (EB) varied between 0.53 and 0.67 × 10³ M⁻¹. The compounds intercalated into DNA base pairs, a mechanism confirmed by molecular docking, with 3b (quinoline) showing the most substantial interaction. All derivatives exhibited antitopoisomerase IIα activity at 100 μM and were cytotoxic against MCF-7 and T47-D breast tumor cells, particularly against the more aggressive T47-D lineage. No hemolytic activity was observed in human erythrocytes. In vivo assays in zebrafish embryos showed no toxicological or cardiotoxic effects. However, all compounds altered superoxide dismutase (SOD) and catalase (CAT) enzymatic activity, requiring further studies on reactive oxygen species (ROS) generation to assess potential adverse effects. Furthermore, significant results were observed in the physicochemical and pharmacokinetic parameters of the synthesized compounds. Conclusions: The findings highlight the quinoline derivative (3b) as the most promising nitrogen heterocycle due to its antiproliferative activity and biomolecular interactions without adverse effects in zebrafish embryos, distinguishing it from clinically available agents.

This study reports the synthesis of four derivatives containing acridine (3a), quinoline (3b), indole (3c), and pyridine (3d) nuclei, as well as their interactions with DNA, physicochemical and pharmacokinetic predictions, antiproliferative activity, in silico and in vivo effects in zebrafish, and enzyme inhibition assays. UV–vis absorption studies with ssDNA revealed different spectroscopic effects, with binding constants (Kb) ranging from 1.41 × 10⁵ to 6.46 × 10⁴ M⁻¹. The fluorescence quenching constant (Ksv) with ethidium bromide (EB) varied between 0.53 and 0.67 × 10³ M⁻¹. The compounds intercalated into DNA base pairs, a mechanism confirmed by molecular docking, with 3b (quinoline) showing the most substantial interaction. All derivatives exhibited antitopoisomerase IIα activity at 100 μM and were cytotoxic against MCF-7 and T47-D breast tumor cells, particularly against the more aggressive T47-D lineage. No hemolytic activity was observed in human erythrocytes. In vivo assays in zebrafish embryos showed no toxicological or cardiotoxic effects. However, all compounds altered superoxide dismutase (SOD) and catalase (CAT) enzymatic activity, requiring further studies on reactive oxygen species (ROS) generation to assess potential adverse effects. Furthermore, good results were observed in the physicochemical and pharmacokinetic parameters of the synthesized compounds. These findings highlight the quinoline derivative (3b) as the most promising nitrogen heterocycle due to its antiproliferative activity and biomolecular interactions without adverse effects in zebrafish embryos, distinguishing it from clinically available agents.

Objective: investigate the medicinal properties of Caatinga plants, focusing on their anti-inflammatory and anticancer capabilities, given the importance of chronic inflammation as a facilitator for cancer cell proliferation. Methods: A comprehensive literature review was conducted, covering articles published from 2004 to March 2023. Experimental studies evaluating the therapeutic potential of various Caatinga plant species were selected. Selection criteria included analysis of time/response of the anti-inflammatory effect, dose concentration, and percentage of inhibition. Additionally, antiproliferative properties were investigated in assays with fractions of plant extracts and/or lectins in various cancer cell lines. Results: Following the evaluation of established criteria, five plant species emerged as particularly promising in terms of anti-inflammatory effects: Myracrodruon urundeuva, Triplaris gardneriana, Annona vepretorum, Pilosocereus gounellei and Croton cordiifolius. Concurrently, seventeen studies were dedicated to investigating the anticancer potential of various plant species, with Cnidoscolus quercifolius, Mimosa caesalpiniifolia and Libidibia ferrea standing out. The most widely investigated cancer cell lines included HCT-116, SF-295, MCF-7, Sarcoma 180, and HL-60. Notably, M. urundeuva demonstrated superior inhibitory capacity against tumor cell viability, proliferation, and survival. Conclusions: This study highlighted the therapeutic potential of certain Caatinga plant species concerning chronic inflammation and cancer. Identifying these species and understanding their mechanisms of action may provide valuable insights for the development of new treatments. However, further research and clinical trials are needed to validate these findings and fully explore their therapeutic potential in human health.