Dados do Trabalho

Título

EVALUATION OF ANTITUMOR ACTIVITY AND TOXICITY OF HYBRID DRUGS (XANTHENES & PYRANS) IN BREAST TUMOR CELL LINES

Introdução

Hybrid molecule refers to a molecular entity that is formed by the combination of different structural or functional components that act independently on distinct pharmacological targets. Thus, hybrid molecules have gained prominence for their pharmacological potential in cancer treatment. Xanthenes and pyrans in isolation are heterocyclic molecules that have the ability to bind to different receptors, exerting pronounced pharmacological activity against various diseases, including cytotoxic effects against neoplastic cells.

Objetivo

Evaluate the antitumor, pharmacological, and toxicological potential of novel hybrid molecules derived from Xanthenes and Pyrans in breast tumor cells.

Métodos

In silico similarity tests were conducted using predictive models on the Cortellis Drug Discovery Intelligence (CDDI) platform by Clarivate. The pharmacological parameters ADME (Absorption, Distribution, Metabolism, and Excretion) of the molecules were assessed using the SwissADME and ADMETLab platforms. Breast cell lines MDA-MB-231 (triple-negative), T-47D (luminal A), BT-474 (luminal B), and HFF-1 (control group) were employed for the screening of 22 hybrid Xanthene and Pyran molecules through Cell One-Dose Screen and Cell Five-Dose Screen cytotoxicity assays, following the guidelines proposed by the National Cancer Institute (NCI). The IC50 of the most promising molecules was determined using MTS, and parameters related to cell death and cell cycle were evaluated through flow cytometry.

Resultados

The in silico analysis on the SwissADME and ADMETLab platforms revealed that molecule M3 exhibits reliable ADME parameters by demonstrating high human intestinal absorption, low or negligible ability to penetrate the blood-brain barrier, high affinity for cytochromes, and a low half-life. Furthermore, it showed safe values for cardiac and hepatic toxicity, as well as minimal mutagenic effects. Predictive tests for potential molecular targets highlighted G Protein as the primary dominant target of the majority of hybrid molecules tested. In the Cell One-Dose Screen stage, 8 molecules were selected that achieved a 50% reduction in viability and inhibition of cell growth only in the tumor cell lines. Molecule M3 was chosen for the Cell Five-Dose stage, presenting an average IC50 dose of 4.75 μM for the T47D and MDA-MB-231 (triple-negative) cell lines and 6.4 μM for the BT474 cell line. The hybrid molecule M3 exhibited selectivity for the tumor cell lines (I.S >1).

Conclusões

The screening stages of the hybrid molecules derived from Xanthenes and Pyrans indicated in silico results that were favorable for predictors of absorption, distribution, metabolism, excretion, and toxicity. Furthermore, molecule M3 exhibited IC50 values lower than conventional 5-FU treatment, selectivity for breast tumor cell lines, and will proceed to subsequent stages of molecular target identification.

Palavras-chave

Hybrid Molecules, Breast Cancer, Pre-clinical oncology.

Financiador do resumo

CNPq e FAPERGS

Área

Estudo Clínico - Tumores de Mama