Silva-García Mariluz, Herrera-Ramírez Angie, Cardona-Galeano Wilson, Yepes Andrés F
Química de Plantas Colombianas, Faculty of Exact and Natural Sciences, Institute of Chemistry, University of Antioquia-UdeA Medellín Colombia
RSC Med Chem. 2025 Jul 2. doi: 10.1039/d5md00410a.
A series of melatonin biphenyl-linked conjugates was designed and synthesized using a simple, cost-effective, and environmentally friendly method. All the new compounds were evaluated for their cytotoxic or cytostatic activity against SW480 human colorectal adenocarcinoma cells. Screening at 100 μM revealed that most compounds exhibited high activity (≥60% inhibition), with compounds 3b, 3h, 4f, 4g, and 4i-l also demonstrating subtle lethality. Based on these initial results, a subset of the most active hybrids was selected for further in-depth evaluation to calculate three key parameters of cell viability: GI, TGI, and LC values. The results showed that most compounds, except 3c and 4d, significantly outperformed the parental compound (2 and melatonin) in inhibiting cancer cell proliferation, highlighting the efficacy of hybridization in improving cytotoxic potential. Besides, it is noticeable that hybrids 4f-l exhibited superior activity compared to 5-FU, as evidenced by lower GI values. Although hybrids 4f and 4g seemed to exert the greatest activity as demonstrated in the LC values (70.89 ± 11.72 μM and 68.03 ± 0.46 μM, respectively), we observed that only hybrids 4j and 4l showed significant selectivity, as revealed by higher GI concentrations over non-malignant cells (NCM460). The observed total growth inhibition and lack of LC values in 4j and 4l suggest their potential for a cytostatic effect. Lastly, theoretical evaluations of drug-likeness, pharmacokinetic behaviour, and toxicological parameters suggest that the most promising hybrids, compounds 4j and 4l, exhibit strong potential for advancement into preclinical studies. Our findings highlight the effectiveness of a novel melatonin biphenyl-linked scaffold, with 4j and 4l structures in particular serving as prototypes for future innovative adjuvant drugs.
采用一种简单、经济高效且环保的方法设计并合成了一系列褪黑素联苯连接的共轭物。对所有新化合物针对SW480人结肠腺癌细胞的细胞毒性或细胞生长抑制活性进行了评估。在100 μM浓度下筛选发现，大多数化合物表现出高活性（抑制率≥60%），化合物3b、3h、4f、4g和4i - l也显示出轻微的致死性。基于这些初步结果，选择了一组活性最高的杂化物进行进一步深入评估，以计算细胞活力的三个关键参数：GI、TGI和LC值。结果表明，除3c和4d外，大多数化合物在抑制癌细胞增殖方面显著优于母体化合物（2和褪黑素），突出了杂交在提高细胞毒性潜力方面的功效。此外，值得注意的是，杂化物4f - l与5 - FU相比表现出更高的活性，较低的GI值证明了这一点。尽管杂化物4f和4g在LC值方面似乎表现出最大活性（分别为70.89±11.72 μM和68.03±0.46 μM），但我们观察到只有杂化物4j和4l表现出显著的选择性，这通过其对非恶性细胞（NCM460）的GI浓度更高得以体现。在4j和4l中观察到的总生长抑制以及缺乏LC值表明它们具有细胞生长抑制作用的潜力。最后，对药物相似性、药代动力学行为和毒理学参数的理论评估表明，最有前景的杂化物，即化合物4j和4l，具有推进到临床前研究的强大潜力。我们的研究结果突出了新型褪黑素联苯连接支架的有效性，特别是4j和4l结构可作为未来创新辅助药物的原型。
