Abbas Eman M H, Sabour Rehab, Alsaiari Norah A, Medrasi Hanadi Y, Kassem Asmaa F, Farghaly Thoraya A
Department of Chemistry of Natural and Microbial Products, National Research Centre, Cairo, 12622, Egypt.
Department of Pharmaceutical Medicinal Chemistry and Drug Design, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt.
Curr Med Chem. 2025;32(24):5070-5084. doi: 10.2174/0109298673313163240829094557.
Breast cancer is the most common form of cancer in women and is the leading cause of cancer-related deaths among women globally. In this study, we aimed to synthesize a series of tropane derivatives to investigate their Hsp90 inhibitory activity as well as their cytotoxic impact on breast cancer cells (MCF- 7 and MDA-MB-231).
Novel fused-tropane derivatives were created and produced as inhibitors of Hsp90, taking inspiration from XL888, a tropane medication used for treating cancer. The target compounds were screened to determine their ability to inhibit the activity of Hsp90.
All tropane derivatives displayed a good submicromolar inhibition of Hsp90 with IC values ranging from 52.64 to 76.05 nM, relative to XL888 reference medication (IC = 27.78 nM). Among all the compounds examined, tropane derivative 5 exhibited the highest level of Hsp90 inhibitory action, with an IC value of 52.64 nM. Furthermore, the cytotoxic activity of all compounds was evaluated against two breast cancer cell lines, namely MCF-7 and MDA-MB-231. Tropane derivative 5 exhibited greater potency than doxorubicin against both cell lines. In addition, it demonstrated a safety profile significantly superior to that of doxorubicin when tested on normal human cells (WI-38 cells), thereby confirming its exceptional level of safety. The western blotting analysis demonstrated a 2.4-fold reduction in Hsp90 expression in MCF-7 cells. Furthermore, the molecular docking analysis has provided additional evidence for the capacity of compound 5 to effectively bind with the target Hsp90 enzyme.
We have succeeded in synthesizing novel tropane hybrids exhibiting significant anti-Hsp90 action, similar to XL888 analogues.
乳腺癌是女性中最常见的癌症形式，也是全球女性癌症相关死亡的主要原因。在本研究中，我们旨在合成一系列托烷衍生物，以研究它们对热休克蛋白90（Hsp90）的抑制活性以及对乳腺癌细胞（MCF - 7和MDA - MB - 231）的细胞毒性影响。
以用于治疗癌症的托烷类药物XL888为灵感，设计并合成了新型稠合托烷衍生物作为Hsp90抑制剂。对目标化合物进行筛选，以确定它们抑制Hsp90活性的能力。
所有托烷衍生物对Hsp90均表现出良好的亚微摩尔抑制作用，IC值范围为52.64至76.05 nM，相对于XL888参考药物（IC = 27.78 nM）。在所有检测的化合物中，托烷衍生物5表现出最高水平的Hsp90抑制作用，IC值为52.64 nM。此外，评估了所有化合物对两种乳腺癌细胞系MCF - 7和MDA - MB - 231的细胞毒性活性。托烷衍生物5对两种细胞系的效力均高于阿霉素。此外，在正常人细胞（WI - 38细胞）上进行测试时，它显示出明显优于阿霉素的安全性，从而证实了其卓越的安全水平。蛋白质印迹分析表明MCF - 7细胞中Hsp90表达降低了2.4倍。此外，分子对接分析为化合物5与靶标Hsp90酶有效结合的能力提供了额外证据。
我们成功合成了具有显著抗Hsp90作用的新型托烷杂化物，类似于XL888类似物。
