PO.ET09.06 · 实验与分子治疗
一种新型强效四氢异喹啉类似物：一种细胞抑制性紫杉醇样药物
A novel potent tetrahydroisoquinoline analog: A cytostatic taxol-like agent
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
根据美国化学学会数据，2024年美国女性中将诊断出约310,720例浸润性乳腺癌新病例，42,250名女性将死于乳腺癌。三阴性乳腺癌（TNBC）占所有乳腺癌的10%至15%。TNBC的治疗选择较其他类型的浸润性乳腺癌更少，这限制了靶向激素或HER2导向治疗的有效性，并高度依赖紫杉烷类和长春花生物碱等细胞抑制药物。这些药物疗效有限且副作用日益增加，凸显出对通过新颖但毒性更低机制阻断增殖的替代小分子的迫切需求。我们此前合成并表征了四氢异喹啉（THIQ）衍生物，鉴定出MG-KKR-4-53是一种高溶解性、无毒的细胞抑制药物，可在不作为纺锤体毒物的情况下阻止TNBC细胞增殖。相反，它将细胞周期阻滞于G2/M期。在持续研究中，我们进一步开发了一种更强效的类似物MG-KRR-5-268，并进行了全面的计算机模拟ADMET和化学信息学分析，将其与紫杉醇（Taxol）、长春碱（vinblastine）和MG-KKR-4-53进行比较，这些分析直接映射到由ADMETlab、SwissADME及CYP/清除率数据驱动的知名预测毒理学和代谢数据库/模型。目标化合物在我们实验室中使用O-均三甲苯磺酰羟胺作为氨化剂合成。异喹啉鎓氨基盐与取代的酰氯在无水四氢呋喃中反应得到稳定的叶立德。使用硼氢化钠还原叶立德得到目标THIQ化合物，并通过NMR和元素分析进行表征。化合物3-氟-N-(7-羟基-3,4-二氢异喹啉-2(1H)-基)-4-甲基苯甲酰胺（MG-KKR-5-268）表现出显著的细胞抑制活性，IC50为169 nM，较MG-KKR-4-53（IC50 = 1.2 µM）提高7.1倍。紫杉醇（250 nM）在亚微摩尔浓度下使肿瘤球体固化，而长春碱（123nM）导致其解体。MG-KRR-5-268（257nM）在亚微摩尔剂量范围内强力阻止球体紧缩，通过非微管蛋白机制表型模拟了长春碱表型的解体，与其他THIQ类似物相比更为突出。这些发现凸显出MG-KRR-5-268是最强效的化合物，具有通过转录组重编程而非微管结合来阻止三维肿瘤固化的新颖能力。
查看英文原文 English abstract
In 2024, according to the American Chemical Society, approximately 310,720 new cases of invasive breast cancer will be diagnosed among US women, and 42,250 women will die from breast cancer. Triple-negative breast cancer (TNBC) represents 10 to 15% of all breast cancers. TNBC has fewer treatment options than other types of invasive breast cancer, which limits the effectiveness of targeted hormonal or HER2-directed therapies and is heavily reliant on cytostatic agents such as taxanes and vinca alkaloids. The limited efficacy and increasing side effects of these agents highlight the urgent need for alternative small molecules that block proliferation through novel but less toxic mechanisms. We previously synthesized and characterized tetrahydroisoquinoline (THIQ) derivatives, identifying MG-KKR-4-53 as a highly soluble, non-toxic, and cytostatic agent that halts TNBC cell proliferation without functioning as a spindle poison. Instead, it arrests the cell cycle at G2/M phase. Continuing our research, we further developed a more potent analogue, MG-KRR-5-268, and performed comprehensive in-silico ADMET and cheminformatics analyses, comparing it with Taxol, vinblastine, and MG-KKR-4-53, which map directly to well-known predictive toxicology and metabolism databases/models powered by ADMETlab, SwissADME, and CYP/clearance data. The compounds of interest were synthesized in our lab using O-mesitylene sulfonylhydroxylamine as an aminating agent. Reaction of the Isoquinoliniumamino salt with substituted acid chlorides in anhydrous tetrahydrofuran gave stable ylides. Reduction of the ylides using sodium borohydride gave the target THIQ compounds, which were characterized by NMR and elemental analysis. Compound 3-fluoro-N-(7-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)-4-methylbenzamide (MG-KKR-5-268) showed significant cytostatic activity with IC 50 of 169 nM representing a 7.1-fold increase over MG-KKR-4-53 (IC 50 = 1.2 µM). Paclitaxel (250 nM) solidified tumor spheroids at submicromolar concentrations, whereas vinblastine (123nM) caused their disassembly. MG-KRR-5-268 (257nM) exhibited strong prevention of spheroid compaction across submicromolar doses, phenocopying the disassembly of the vinblastine phenotype through a non-tubulin mechanism, compared to the other THIQ analogs. These findings highlighted MG-KRR-5-268 acted as the most potent compound with a novel capacity to prevent 3D tumor solidification through transcriptome reprogramming rather than microtubule binding.
利益披露 Disclosure
K. K. Redda, None..
M. Gangapuram, None..
S. Eyunni, None..
E. Mazzio, None..
K. F. A. Soliman, None.