Vukea Nyeleti, Oderinlo Ogunyemi, Tukulula Matshawandile, Khanye Setshaba David, Edkins Adrienne Lesley, de la Mare Jo-Anne
Department of Biochemistry, Microbiology and Bioinformatics, Rhodes University, Makhanda (Grahamstown), South Africa.
Department of Chemistry, Rhodes University, Makhanda (Grahamstown), South Africa.
PLoS One. 2025 Jul 17;20(7):e0328155. doi: 10.1371/journal.pone.0328155. eCollection 2025.
In this study, ferrocene-containing thiazolidine-2,4-dione derivatives were screened against triple-negative breast cancer (TNBC) cell lines, which represent an aggressive subtype of the disease predominant in women of African descent. The lack of key receptors in TNBC poses a therapeutic challenge as there are limited targeted treatment options available for this subtype. The ferrocene thiazolidine-2,4-dione derivatives displayed toxicity against HCC70 TNBC cells in the low-moderate micromolar range (5-46 μM) and two compounds were selected for further study, with IC50 values of 7.54 ± 1.07 μM (OY25) and 5.59 ± 1.24 μM (OY29). Additionally, compounds OY25 and OY29 were screened against other cancer and non-tumourigenic cell lines and found to be less toxic against non-cancerous breast epithelial cell line MCF-12A (SI = 2.2188 and 4.4359, respectively) compared to the HCC70 TNBC cell line. Compounds OY25 and OY29 show a dual mode of action involving increased reactive oxygen species generation and induction of DNA damage. In silico docking analysis and competitive DNA binding fluorescence-based assays revealed that the compounds disrupt key DNA damage phosphoprotein levels through binding to the minor groove of DNA. In a combination assay, the compounds acted synergistically and antagonistically with DNA damage-inducing drugs, camptothecin and etoposide, respectively. Meanwhile, in combination with PARP-1 inhibitor, OY25 and OY29 acted synergistically and antagonistically, respectively. Furthermore, in silico results, using the SwissADME web tool, showed that the compounds OY25 and OY29 display desirable ADME (absorption, distribution, metabolism, and excretion) profile with parameters within acceptable range.
在本研究中，针对三阴性乳腺癌（TNBC）细胞系筛选了含二茂铁的噻唑烷 - 2,4 - 二酮衍生物，三阴性乳腺癌是该疾病的一种侵袭性亚型，在非洲裔女性中占主导地位。TNBC中关键受体的缺乏带来了治疗挑战，因为针对该亚型的靶向治疗选择有限。二茂铁噻唑烷 - 2,4 - 二酮衍生物在低 - 中等微摩尔范围内（5 - 46 μM）对HCC70 TNBC细胞显示出毒性，选择了两种化合物进行进一步研究，其IC50值分别为7.54±1.07 μM（OY25）和5.59±1.24 μM（OY29）。此外，针对其他癌症和非致瘤细胞系筛选了化合物OY25和OY29，发现与HCC70 TNBC细胞系相比，它们对非癌性乳腺上皮细胞系MCF - 12A的毒性较小（SI分别为2.2188和4.4359）。化合物OY25和OY29表现出双重作用模式，包括增加活性氧生成和诱导DNA损伤。计算机对接分析和基于竞争性DNA结合荧光的测定表明，这些化合物通过与DNA小沟结合破坏关键的DNA损伤磷蛋白水平。在联合试验中，这些化合物分别与DNA损伤诱导药物喜树碱和依托泊苷协同和拮抗作用。同时，与PARP - 1抑制剂联合使用时，OY25和OY29分别表现出协同和拮抗作用。此外，使用瑞士ADME网络工具的计算机模拟结果表明，化合物OY25和OY29显示出理想的ADME（吸收、分布、代谢和排泄）特征，参数在可接受范围内。
