Design, synthesis and biomedical evaluation of mostotrin, a new water soluble tryptanthrin derivative

Popov,Alexander; Klimovich,Anna; Styshova,Olga; Moskovkina,Taisiya; Shchekotikhin,Andrey; Grammatikova,Natalia; Dezhenkova,Lyubov; Kaluzhny,Dmitry; Deriabin,Peter; Gerasimenko,Andrey; Udovenko,Anatoly; Stonik,Valentin

doi:10.3892/ijmm.2020.4693

Design, synthesis and biomedical evaluation of mostotrin, a new water soluble tryptanthrin derivative

Authors:
- Alexander Popov
- Anna Klimovich
- Olga Styshova
- Taisiya Moskovkina
- Andrey Shchekotikhin
- Natalia Grammatikova
- Lyubov Dezhenkova
- Dmitry Kaluzhny
- Peter Deriabin
- Andrey Gerasimenko
- Anatoly Udovenko
- Valentin Stonik
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Affiliations: 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, Department of Chemical Transformation of Antibiotics, Gauze Research Institute for The Search for New Antibiotics, Russian Academy of Medical Sciences, Moscow 119435, Russia, Department of DNA‑protein Interactions, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia, Department of of X‑ray Analysis, Institute of Chemistry, Far Eastern Branch of The Russian Academy of Sciences, Vladivostok 69022, Russia
Published online on: August 6, 2020 https://doi.org/10.3892/ijmm.2020.4693
Pages: 1335-1346
Copyright: © Popov et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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.

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