萘并[1',2':4,5]咪唑并[1,2 - a]吡啶 - 5,6 - 二酮：合成、酶促还原及细胞毒性活性

Naphtho[1',2':4,5]imidazo[1,2-a]pyridine-5,6-diones: Synthesis, enzymatic reduction and cytotoxic activity.

作者信息

Šarlauskas Jonas, Pečiukaitytė-Alksnė Milda, Misevičienė Lina, Marozienė Audronė, Polmickaitė Evelina, Staniulytė Zita, Čėnas Narimantas, Anusevičius Žilvinas

机构信息

Institute of Biochemistry of Vilnius University, Mokslininku 12, LT-08662 Vilnius, Lithuania.

出版信息

Bioorg Med Chem Lett. 2016 Jan 15;26(2):512-517. doi: 10.1016/j.bmcl.2015.11.084. Epub 2015 Nov 24.

DOI:10.1016/j.bmcl.2015.11.084

PMID:26681508

Abstract

Naphtho[1',2':4,5]imidazo[1,2-a]pyridine-5,6-diones (NPDOs), a new type of N-heterocycle-fused o-quinones, have been synthesized. They have been found to be efficient electron-accepting substrates of NADPH-dependent single-electron-transferring P-450R and two-electron transferring NQO1, generating reactive oxygen species (ROS) with a concomitant decrease in NADPH, which is consistent with redox-cycling. The reactivity of NPDOs toward P-450R (in terms of kcat/Km) varied in the range of 10(6)-10(7)M(-1)s(-1), while their reduction by NQO1 proceeded much faster, approaching the diffusion control limit (kcat/Km∼10(8)-10(9)M(-1)s(-1)). NPDOs exhibited relatively high cytotoxic activity against human lung carcinoma (A-549) and breast tumor (MCF-7) cell lines (LC50=0.1-8.3μM), while promyelocytic leukemia cells (HL-60) were less sensitive to NPDOs (LC50⩾10μM). 3-Nitro-substituted NPDO (11) revealed the highest potency against both A-549 and MCF-7 cell lines, with LC50 of 0.12±0.03μM and 0.28±0.08μM, respectively. Dicoumarol partly suppressed the activity of the compounds against A-594 and MCF-7 cell lines, suggesting that their cytotoxic action might be partially influenced by NQO1-mediated bioreductive activation.

摘要

萘并[1',2':4,5]咪唑并[1,2 - a]吡啶 - 5,6 - 二酮（NPDOs），一种新型的N - 杂环稠合邻醌，已被合成。已发现它们是NADPH依赖性单电子转移P - 450R和双电子转移NQO1的有效电子接受底物，伴随NADPH减少产生活性氧（ROS），这与氧化还原循环一致。NPDOs对P - 450R的反应活性（以kcat/Km计）在10(6)-10(7)M(-1)s(-1)范围内变化，而它们被NQO1还原的速度要快得多，接近扩散控制极限（kcat/Km∼10(8)-10(9)M(-1)s(-1)）。NPDOs对人肺癌（A - 549）和乳腺肿瘤（MCF - 7）细胞系表现出相对较高的细胞毒性活性（LC50 = 0.1 - 8.3μM），而早幼粒细胞白血病细胞（HL - 60）对NPDOs不太敏感（LC50⩾10μM）。3 - 硝基取代的NPDO（11）对A - 549和MCF - 7细胞系均显示出最高效力，LC50分别为0.12±0.03μM和0.28±0.08μM。双香豆素部分抑制了这些化合物对A - 594和MCF - 7细胞系的活性，表明它们的细胞毒性作用可能部分受NQO1介导的生物还原激活影响。