Veliz Eduardo A, Kaplina Anastasiia, Hettiarachchi Sajini D, Yoham Athina L, Matta Carolina, Safar Sabrin, Sankaran Meghana, Abadi Esther L, Cilingir Emel Kirbas, Vallejo Frederic A, Walters Winston M, Vanni Steven, Leblanc Roger M, Graham Regina M
Department of Chemistry, University of Miami, 1301 Memorial Drive, Coral Gables, FL 33146, USA.
Department of Natural Sciences, Miami Dade College, 300 NE Second Ave, Miami, FL 33132, USA.
Pharmaceutics. 2022 Jul 14;14(7):1465. doi: 10.3390/pharmaceutics14071465.
The current prognosis for glioblastoma is dismal. Treatment-resistant glioblastoma stem cells (GSCs) and the failure of most drugs to reach therapeutic levels within the tumor remain formidable obstacles to successful treatment. Chalcones are aromatic ketones demonstrated to reduce malignant properties in cancers including glioblastoma. Nanomedicines can increase drug accumulation and tumor cell death. Carbon-dots are promising nanocarriers that can be easily functionalized with tumor-targeting ligands and anti-cancer drugs. Therefore, we synthesized a series of 4'-amino chalcones with the rationale that the amino group would serve as a "handle" to facilitate covalent attachment to carbon-dots and tested their cytotoxicity toward GSCs. We generated 31 chalcones (22 4'-amino and 9 4' derivatives) including 5 novel chalcones, and found that 13 had an IC below 10 µM in all GSC lines. After confirming that the 4-amino group was not part of the active pharmacophore, chalcones were attached to transferrin-conjugated carbon-dots. These conjugates were significantly more cytotoxic than the free chalcones, with the C-dot-transferrin-2,5, dimethoxy chalcone conjugate inducing up to 100-fold more GSC death. Several of the tested chalcones represent promising lead compounds for the development of novel anti-GSC drugs. Furthermore, designing amino chalcones for carbon-dot mediated drug delivery is a rational and effective methodology.
目前胶质母细胞瘤的预后不容乐观。治疗耐药的胶质母细胞瘤干细胞（GSCs）以及大多数药物在肿瘤内无法达到治疗水平，仍然是成功治疗的巨大障碍。查耳酮是一种芳香酮，已被证明能降低包括胶质母细胞瘤在内的多种癌症的恶性特性。纳米药物可以增加药物积累和肿瘤细胞死亡。碳点是很有前景的纳米载体，可以很容易地用肿瘤靶向配体和抗癌药物进行功能化修饰。因此，我们合成了一系列4'-氨基查耳酮，其原理是氨基将作为一个“手柄”，便于与碳点共价连接，并测试了它们对GSCs的细胞毒性。我们制备了31种查耳酮（22种4'-氨基查耳酮和9种4'衍生物），包括5种新型查耳酮，发现其中13种在所有GSC细胞系中的半数抑制浓度（IC）低于10µM。在确认4-氨基不是活性药效基团的一部分后，将查耳酮连接到转铁蛋白偶联的碳点上。这些偶联物的细胞毒性明显高于游离查耳酮，其中碳点-转铁蛋白-2,5-二甲氧基查耳酮偶联物诱导的GSC死亡高达100倍。几种经过测试的查耳酮代表了开发新型抗GSC药物的有前景的先导化合物。此外，设计用于碳点介导药物递送的氨基查耳酮是一种合理有效的方法。
