PDF(Pubmed)
Abstract：
Cisplatin remains the unchallenged standard therapy for NSCLC. However, it is not completely curative due to drug resistance and oxidative stress-induced toxicity. Drug resistance is linked to overexpression of matrix metalloproteinases (MMPs) and aberrant calcium signalling. We report synthesis of novel thiazole-triazole hybrids as MMP-9 inhibitors with T-type calcium channel blocking and antioxidant effects to sensitise NSCLC to cisplatin and ameliorate its toxicity. MTT and whole cell patch clamp assays revealed that 6d has a balanced profile of cytotoxicity (IC50 = 21 ± 1 nM, SI = 12.14) and T-type calcium channel blocking activity (⁓60% at 10 μM). It exhibited moderate ROS scavenging activity and nanomolar MMP-9 inhibition (IC50 = 90 ± 7 nM) surpassing NNGH with MMP-9 over -2 and MMP-10 over -13 selectivity. Docking and MDs simulated its receptor binding mode. Combination studies confirmed that 6d synergized with cisplatin (CI = 0.69 ± 0.05) lowering its IC50 by 6.89 folds. Overall, the study introduces potential lead adjuvants for NSCLC platinum-based therapy.
摘要：
顺铂仍然是NSCLC的标准疗法。然而,由于耐药性和氧化应激诱导的毒性，它不能完全治愈。耐药性与基质金属蛋白酶（MMPs）的过表达和异常的钙信号有关。我们报道了新型噻唑-三唑杂化物的合成，作为具有T型钙通道阻断和抗氧化作用的MMP-9抑制剂，可使NSCLC对顺铂敏感并改善其毒性。MTT和全细胞膜片钳分析显示，6d具有平衡的细胞毒性特征（IC50=21±1nM，SI=12.14）和T型钙通道阻断活性（在10μM时60％）。它表现出中等的ROS清除活性和纳摩尔MMP-9抑制（IC50=90±7nM），超过NNGH，其中MMP-9超过-2，MMP-10超过-13选择性。对接和MD模拟其受体结合模式。联合研究证实，6d与顺铂（CI=0.69±0.05）协同作用，使其IC50降低6.89倍。总的来说,该研究引入了NSCLC铂类治疗的潜在先导佐剂.
