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新型2-氨基苯并噻唑衍生物：作为抗癌剂的对接、合成及生物学评价

Novel 2-Aminobenzothiazole Derivatives: Docking, Synthesis, and Biological Evaluation as Anticancer Agents.

作者信息

Salih Omar M, Al-Sha'er Mahmoud A, Basheer Haneen A

机构信息

Pharmaceutical Sciences Department, College of Pharmacy, Zarqa University, Zarqa 13132, Jordan.

Clinical Pharmacy Department, College of Pharmacy, Zarqa University, Zarqa 13132, Jordan.

出版信息

ACS Omega. 2024 Mar 14;9(12):13928-13950. doi: 10.1021/acsomega.3c09212. eCollection 2024 Mar 26.

DOI:10.1021/acsomega.3c09212
PMID:38559989
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10975593/
Abstract

Sixteen novel 2-aminobenzothiazole compounds with different amines or substituted piperazine moieties were designed, synthesized, and tested using various methods. Potential interactions were assessed by docking new compounds in the adenosine triphosphate (ATP) binding domain of the PI3Kγ enzyme (PDB code: 7JWE) by nucleophilic substitution or solvent-free/neat fusion for docked compound synthesis. Final 2-aminobenzothiazole compounds were characterized by direct probe gas chromatography-mass spectrometry (GC-MS), proton (H-NMR), carbon-13 (C-NMR), and attenuated total reflectance-infrared Fourier transform infrared (ATR FT-IR). The synthesized compounds were investigated for anticancer activities on lung cancer (A549) and breast cancer (MCF-7) cell lines. The compounds' PI3Kγ inhibition was evaluated at a 100 μM concentration. 4-Nitroaniline and piperazine-4-nitroaniline combination in OMS5 and OMS14 reduced lung and breast cancer cell line growth. IC values for OMS5 and OMS14, the strongest compounds, ranged from 22.13 to 61.03 μM. OMS1 and OMS2 inhibited PI3Kγ at the highest rates (47 and 48%, respectively) at a 100 μM concentration. Results show that the PI3Kγ enzyme suppression is not the main mechanism behind these OMS5 and OMS14 anticancer effects. CDK2, Akt, mTOR, and p42/44 MAPK are affected. EGF receptor suppression matters. AKT1, AKT3, CDK1/cyclin B, PDK1 direct, PIK3CA E542 K/PIK3R1 (p110 α/p85 α), PIK3CD/PIK3R1 (p110 δ/p85 α), and PKN inhibition were measured to evaluate the possible mechanism of compound OMS14. PIK3CD/PIK3R1 (p110 δ/p85 α) is the most, with 65% inhibition, suggesting a possible mechanism of anticancer properties. Furthermore, the NCI 60-cell line inhibition demonstrates promising broad anticancer inhibition against numerous cancer cell lines of OMS5 and OMS14, which could be good lead compounds for future development.

摘要

设计、合成并使用多种方法测试了16种具有不同胺基或取代哌嗪部分的新型2-氨基苯并噻唑化合物。通过亲核取代或无溶剂/纯融合对接新化合物至PI3Kγ酶的三磷酸腺苷（ATP）结合域（PDB代码：7JWE）来评估潜在相互作用，以合成对接化合物。最终的2-氨基苯并噻唑化合物通过直接探针气相色谱-质谱联用仪（GC-MS）、质子（H-NMR）、碳-13（C-NMR）以及衰减全反射-傅里叶变换红外光谱（ATR FT-IR）进行表征。研究了合成化合物对肺癌（A549）和乳腺癌（MCF-7）细胞系的抗癌活性。在100μM浓度下评估化合物对PI3Kγ的抑制作用。OMS5和OMS14中4-硝基苯胺与哌嗪-4-硝基苯胺的组合降低了肺癌和乳腺癌细胞系的生长。最强的化合物OMS5和OMS14的半数抑制浓度（IC）值范围为22.13至61.03μM。在100μM浓度下，OMS1和OMS2对PI3Kγ的抑制率最高（分别为47%和48%）。结果表明，PI3Kγ酶抑制并非这些OMS5和OMS14抗癌作用的主要机制。细胞周期蛋白依赖性激酶2（CDK2）、蛋白激酶B（Akt）、哺乳动物雷帕霉素靶蛋白（mTOR）和丝裂原活化蛋白激酶（p42/44 MAPK）均受到影响。表皮生长因子（EGF）受体抑制起重要作用。测量AKT1、AKT3、细胞周期蛋白依赖性激酶1/细胞周期蛋白B（CDK1/cyclin B）、丙酮酸脱氢酶激酶1（PDK1）直接、磷脂酰肌醇-3激酶催化亚基α（PIK3CA）E542K/磷脂酰肌醇-3激酶调节亚基1（PIK3R1）（p110α/p85α）、磷脂酰肌醇-3激酶催化亚基δ/磷脂酰肌醇-3激酶调节亚基1（PIK3CD/PIK3R1）（p110δ/p85α）和蛋白激酶N（PKN）的抑制作用，以评估化合物OMS14的可能作用机制。PIK3CD/PIK3R1（p110δ/p85α）的抑制作用最强，为65%，提示了其抗癌特性的一种可能机制。此外，美国国立癌症研究所（NCI）60细胞系抑制实验表明，OMS5和OMS14对众多癌细胞系具有良好的广谱抗癌抑制作用，它们可能是未来开发的良好先导化合物。

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