Department of Biotechnology, G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far Eastern Branch of The Russian Academy of Sciences, Vladivostok 69022, Russia.
School of Natural Sciences, Far Eastern Federal University, Vladivostok 690920, Russia.
Int J Mol Med. 2020 Oct;46(4):1335-1346. doi: 10.3892/ijmm.2020.4693. Epub 2020 Aug 6.
Mostotrin (MT), a novel compound, at least five orders of magnitude more soluble in water than its mother substance, was designed and synthesised from tryptanthrin (TR). Its structure was established by nuclear magnetic resonance and mass spectrometry data and confirmed by X‑ray analysis, revealing that MT is a pentacyclic product with an additional pseudo‑cycle formed with the participation of one intramolecular hydrogen bond. Antimicrobial activity and cytotoxic action against tumour cells in vitro, as well as anti‑tumour effects, acute toxicity and anti‑inflammatory activities in vivo, were evaluated. Antimicrobial properties of MT against Mycobacterium spp and Bacillus cereus ATCC 10702 appeared to be the same as that of TR, but against the other strains used it was weaker. Furthermore, MT exhibited 5‑10 times higher cytotoxic activities against tumour cell lines HCT‑116, МСF‑7 and K‑562 than TR, but was less toxic than TR (LD50 of MT was 375 mg/kg, while LD50 for TR was 75 mg/kg). Additionally, compounds MT and TR were studied in DNA binding tests. The quenching of its fluorescence on addition to DNA solution established MT to be capable of binding to DNA. Its anti‑tumour action in vivo on mice with the ascitic form of Ehrlich carcinoma was promising, particularly with joint application of MT and the antitumour drug doxorubicin. In this model, the survival and life span for the doxorubicin and 1 co‑treatment group were significantly higher compared to doxorubicin treatment alone. The compound MT showed a lower immunosuppressive effect than TR at the early stages of inflammation induced in mice by LPS from E. сoli (MT hardly inhibited the release of IL‑1, IL‑2, or INF‑γ). These results demonstrated that MT is a perspective hit compound for drug development. In our opinion, further evaluation on the biological effects of MT and its synthetic analogues could lead to safer and more effective anti‑tumour and anti‑tuberculosis agents than TR itself. MT has also the prospect of application in combination with known anti‑tumour drugs for the treatment of oncological diseases.
莫司他丁（MT）是一种新型化合物，其在水中的溶解度比母体物质至少高出五个数量级，是从色胺酮（TR）设计和合成的。其结构通过核磁共振和质谱数据确定，并通过 X 射线分析证实，表明 MT 是一种具有额外拟环的五环产物，该拟环是通过分子内氢键的参与形成的。评估了其在体外对微生物和肿瘤细胞的抗菌活性和细胞毒性作用，以及体内的抗肿瘤作用、急性毒性和抗炎活性。MT 对分枝杆菌和蜡样芽孢杆菌 ATCC 10702 的抗菌特性似乎与 TR 相同，但对其他使用的菌株则较弱。此外，MT 对 HCT-116、MCF-7 和 K-562 肿瘤细胞系的细胞毒性活性比 TR 高 5-10 倍，但毒性比 TR 低（MT 的 LD50 为 375mg/kg，而 TR 的 LD50 为 75mg/kg）。此外，研究了化合物 MT 和 TR 与 DNA 的结合试验。向 DNA 溶液中加入 MT 会使其荧光猝灭，表明 MT 能够与 DNA 结合。在艾氏腹水癌荷瘤小鼠体内的抗肿瘤作用有前景，特别是与 MT 和抗肿瘤药物阿霉素联合应用时。在该模型中，与单独使用阿霉素相比，阿霉素和 1 联合治疗组的存活和寿命明显更高。与 TR 相比，MT 在 LPS 诱导的小鼠炎症早期的免疫抑制作用较低（MT 几乎不抑制 IL-1、IL-2 或 INF-γ 的释放）。这些结果表明，MT 是一种有前途的药物开发先导化合物。我们认为，进一步评估 MT 及其合成类似物的生物学效应可能会产生比 TR 本身更安全、更有效的抗肿瘤和抗结核药物。MT 也有望与已知的抗肿瘤药物联合应用于治疗肿瘤疾病。
