Novel Steroidal (Thio)barbiturate Hybrids: From Design to Preclinical Assessment in Tumor Therapy

Cancer remains a public health concern with high rates of incidence and mortality, despite the significant advances achieved in recent decades. Therefore, this study aimed to develop novel hybrid molecules with potential anticancer properties. To this end, a steroid nucleus, specifically pregnenolone or dehydroepiandrosterone (DHEA), was covalently linked to a (thio)barbiturate scaffold. The hybrid molecules showed relevant antiproliferative activity against breast (MCF-7) and prostate (PC-3) cancer cells (IC₅₀ = 8.73-38.53 and 4.08-36.01 µM, respectively), with selectivity indices of up to 2.79. The most promising compounds 4b (pregnenolone-barbiturate hybrid) and 7f (DHEA-thiobarbiturate hybrid) induced cell cycle arrest in the G0/G1 phase of breast cancer cells, with the DHEA-thiobarbiturate hybrid demonstrating a 6.6- and a 2.0-fold increase in apoptotic cells compared with untreated cells and cells treated with the anticancer drug 5-fluourouracil, respectively. Interestingly, a docking study suggested that these new hybrids may exhibit significant affinity for CYP17 and 5α-reductase enzymes. Preliminary pharmacokinetic investigation of the most promising hybrids suggested low intestinal absorption, which may be improved through appropriate formulation strategies. Overall, these findings indicate that these novel hybrid compounds, incorporating both (thio)barbiturates and steroid nuclei, represent a promising strategy for the development of anticancer drug candidates.