萘醌基腙杂合体的合成及其对癌细胞系的强大活性。

Naphthoquinone-based Hydrazone Hybrids: Synthesis and Potent Activity Against Cancer Cell Lines.

机构信息

Graduate Collegiate in Natural Resources of the Semiarid, Federal University of San Francisco Valley, Petrolina, PE, Brazil.

Graduate Collegiate in Materials Science, Federal University of San Francisco Valley, Petrolina, PE, Brazil.

出版信息

Med Chem. 2021;17(9):945-955. doi: 10.2174/1573406416666200817164308.

DOI:10.2174/1573406416666200817164308

PMID:32807066

Abstract

BACKGROUND

Natural naphthoquinones have shown diversified biological activities including antibacterial, antifungal, antimalarial, and cytotoxic activities. However, they are also compounds with acute cytotoxicity, immunotoxicity, carcinogenesis, and cardio- and hepatotoxicity, and the modification at their redox center is an interesting strategy to overcome such harmful activity.

OBJECTIVE

In this study, four novel semisynthetic hydrazones, derived from the isomers α- and β- lapachones (α and β, respectively) and coupled with the drugs hydralazine (HDZ) and isoniazid (ACIL), were prepared, evaluated by electrochemical methods and assayed for anticancer activity.

METHODS

The semisynthetic hydrazones were obtained and had their molecular structures established by NMR, IR, and MS. Anticancer activity was evaluated by cell viability determined by reduction of 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (MTT). The electrochemical studies, mainly cyclic voltammetry, were performed, in aprotic and protic media.

RESULTS

The study showed that the compounds 2, 3, and 4 were active against at least one of the cancer cell lines evaluated, compounds 3 and 4 being the most cytotoxic. Toward HL-60 cells, compound 3 was 20x more active than β-lapachone, and 3x more cytotoxic than doxorubicin. Furthermore, 3 showed an SI value of 39.62 for HL-60 cells. Compound 4 was active against all cancer cells tested, with IC values in the range 2.90-12.40 μM. Electrochemical studies revealed a profile typical of self-protonation and reductive cleavage, dependent on the supporting electrolyte.

CONCLUSION

These results therefore indicate that compounds 3 and 4 are strong candidates as prototypes of new antineoplastic drugs.

摘要

背景

天然萘醌类化合物具有多样化的生物活性，包括抗菌、抗真菌、抗疟疾和细胞毒性活性。然而，它们也是具有急性细胞毒性、免疫毒性、致癌性以及心脏和肝脏毒性的化合物，并且其氧化还原中心的修饰是克服这种有害活性的一种有趣策略。

目的

在这项研究中，制备了四种新型半合成腙，它们分别来自异构体 α-和 β-拉帕醌（分别为 α 和 β），并与药物肼屈嗪（HDZ）和异烟肼（ACIL）偶联，通过电化学方法进行评估，并检测其抗癌活性。

方法

通过 NMR、IR 和 MS 确定了半合成腙的结构。通过 3-（4,5-二甲基-2-噻唑）-2,5-二苯基-2H-四唑溴盐（MTT）还原测定细胞活力来评估抗癌活性。进行了电化学研究，主要是循环伏安法，在非质子和质子介质中进行。

结果

研究表明，化合物 2、3 和 4 对至少一种评估的癌细胞系具有活性，化合物 3 和 4 具有最强的细胞毒性。对于 HL-60 细胞，化合物 3 的活性比 β-拉帕醌高 20 倍，比阿霉素高 3 倍。此外，3 对 HL-60 细胞的 SI 值为 39.62。化合物 4 对所有测试的癌细胞均具有活性，IC 值在 2.90-12.40 μM 范围内。电化学研究表明，其谱图典型，取决于支持电解质，表现出自质子化和还原断裂的特性。