Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran.
Cellular and Molecular Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan, Iran.
Bioorg Chem. 2021 Jun;111:104900. doi: 10.1016/j.bioorg.2021.104900. Epub 2021 Apr 9.
Due to their unique pharmacological characteristics, methylxanthines are known as therapeutic agents in a fascinating range of medicinal scopes. In this report, we aimed to examine some biological effects of previously synthesized 8-alkylmercaptocaffeine derivatives. Cytotoxic and antioxidative activity of 8-alkylmercaptocaffeine derivatives were measured in malignant A549, MCF7, and C152 cell lines. Assessment of cGMP levels and caspase-3 activity were carried out using a colorimetric competitive ELISA kit. Computational approaches were employed to discover the inhibitory mechanism of synthesized compounds. Among the twelve synthesized derivatives, three compounds (C1, C5, and C7) bearing propyl, heptyl, and 3-methyl-butyl moieties showed higher and more desirable cytotoxic activity against all the studied cell lines (IC < 100 µM). Furthermore, C5 synergistically enhanced cisplatin-induced cytotoxicity in MCF-7 cells (CI < 1). Both C5 and C7 significantly increased caspase-3 activity and intracellular cGMP levels at specific time intervals in all studied cell lines (P < 0.05). However, these derivatives did not elevate LDH leakage (P > 0.05) and exhibited no marked ameliorating effects on oxidative damage (P > 0.05). Computational studies showed that H-bond formation between the nitrogen atom in pyrazolo[4,3-D] pyrimidine moiety with Gln817 and creating a hydrophobic cavity result in the stability of the alkyl group in the PDE5A active site. We found that synthesized 8-alkylmercaptocaffeine derivatives induced cell death in different cancer cells through the cGMP pathway. These findings will help us to get a deeper insight into the role of methylxanthines as useful alternatives to conventional cancer therapeutics.
由于其独特的药理学特性，甲基黄嘌呤被认为是治疗各种医学领域的治疗剂。在本报告中，我们旨在研究先前合成的 8-烷基巯基咖啡衍生物的一些生物学效应。在恶性 A549、MCF7 和 C152 细胞系中测量 8-烷基巯基咖啡衍生物的细胞毒性和抗氧化活性。使用比色竞争 ELISA 试剂盒评估 cGMP 水平和 caspase-3 活性。采用计算方法发现合成化合物的抑制机制。在所合成的 12 种衍生物中，三种具有丙基、庚基和 3-甲基丁基部分的化合物（C1、C5 和 C7）对所有研究的细胞系均表现出更高和更理想的细胞毒性（IC <100µM）。此外，C5 在 MCF-7 细胞中协同增强顺铂诱导的细胞毒性（CI <1）。C5 和 C7 在所有研究的细胞系中在特定时间间隔内均显著增加 caspase-3 活性和细胞内 cGMP 水平（P <0.05）。然而，这些衍生物不会增加 LDH 渗漏（P >0.05），并且对氧化损伤没有明显的改善作用（P >0.05）。计算研究表明，吡唑并[4,3-D]嘧啶部分中的氮原子与 Gln817 之间形成氢键，并在 PDE5A 活性部位形成疏水性腔，导致烷基在 PDE5A 活性部位的稳定性。我们发现，合成的 8-烷基巯基咖啡衍生物通过 cGMP 途径诱导不同癌细胞死亡。这些发现将帮助我们更深入地了解甲基黄嘌呤作为传统癌症治疗的有用替代品的作用。
