Mishra Tripti, Sahu Asima, Modi Unnati, Bhatia Dhiraj, Basu Sudipta
Department of Chemistry, Indian Institute of Technology (IIT) Gandhinagar Palaj Gandhinagar Gujarat 382355 India
Department of Physics, Indian Institute of Technology (IIT) Gandhinagar Palaj Gandhinagar Gujarat 382355 India.
RSC Med Chem. 2025 Jul 16. doi: 10.1039/d5md00215j.
The Golgi apparatus (GA), a critical sub-cellular organelle, plays a pivotal role in numerous biological signaling pathways, including the post-translational modification of proteins and their secretion to various cellular destinations. Dysregulation of GA function is implicated in the development of several diseases, including cancer. As a result, detouring clinically approved drugs into the GA for an enhanced anti-cancer effect remained a major challenge. To address this, herein, we designed and synthesized NSAID-based conjugates incorporating a fluorophore (1,8-naphthalimide) and a Golgi-homing moiety (phenylsulfonamide). Screening these conjugates in cervical (HeLa) and colon (HCT-116) cancer cells identified a particularly promising candidate: the ibuprofen-1,8-naphthalimide-phenylsulfonamide conjugate (7a) which exhibited significant cytotoxicity against HCT-116 cells as well as in lung cancer (A549), colon carcinoma (Caco-2) and breast cancer (MCF7) cells. Interestingly, compound 7a self-assembled into nanoscale petal-like structures in water and efficiently homed into the GA as well as in the endoplasmic reticulum (ER) within 30 min to induce morphological damage to the GA. Compound 7a mediated GA damage increased the expression of Beclin and LC3-I/II proteins to induce autophagy which was further inhibited by chloroquine (CQ) and bafilomycin A1 (BFA) leading to remarkable HCT-116 cell death in combination with 7a. Moreover, compound 7a triggered apoptosis by downregulating anti-apoptotic Bcl-2 and Cas-3 as well as cleaving PARP proteins in HCT-116 cells, while demonstrating no toxicity towards non-cancerous human retinal pigment epithelial cells (RPE-1). Interestingly, compound 7a also reduced the size and growth of the HeLa 3D spheroids significantly after 72 h. This ibuprofen derivative (7a) holds promise as a valuable tool for illuminating the chemical biology of the GA in cancer cells and as a potential candidate for anti-cancer therapy.
高尔基体（GA）是一种关键的亚细胞器，在众多生物信号通路中发挥着核心作用，包括蛋白质的翻译后修饰及其向细胞内不同目的地的分泌。GA功能失调与包括癌症在内的多种疾病的发生发展有关。因此，将临床批准的药物引入GA以增强抗癌效果仍然是一项重大挑战。为了解决这个问题，我们在此设计并合成了基于非甾体抗炎药（NSAID）的共轭物，该共轭物包含一个荧光团（1,8-萘二甲酰亚胺）和一个高尔基体靶向部分（苯磺酰胺）。在宫颈癌细胞（HeLa）和结肠癌细胞（HCT-116）中对这些共轭物进行筛选，确定了一个特别有前景的候选物：布洛芬-1,8-萘二甲酰亚胺-苯磺酰胺共轭物（7a），它对HCT-116细胞以及肺癌细胞（A549）、结肠癌细胞（Caco-2）和乳腺癌细胞（MCF7）均表现出显著的细胞毒性。有趣的是，化合物7a在水中自组装成纳米级花瓣状结构，并在30分钟内有效地靶向进入GA以及内质网（ER），从而对GA造成形态损伤。化合物7a介导的GA损伤增加了Beclin和LC3-I/II蛋白的表达，从而诱导自噬，氯喹（CQ）和巴弗洛霉素A1（BFA）可进一步抑制这种自噬，导致与7a联合使用时HCT-116细胞显著死亡。此外，化合物7a通过下调抗凋亡蛋白Bcl-2和Cas-3以及切割HCT-116细胞中的PARP蛋白来触发凋亡，同时对非癌性人视网膜色素上皮细胞（RPE-1）没有毒性。有趣的是，72小时后，化合物7a还显著减小了HeLa 3D球体的大小并抑制了其生长。这种布洛芬衍生物（7a）有望成为阐明癌细胞中GA化学生物学的有价值工具，并成为抗癌治疗的潜在候选药物。
