2. Academic Validation
  3. Synthesis of thieno[3,2-e]pyrrolo[1,2-a]pyrimidine derivatives and their precursors containing 2-aminothiophenes fragments as anticancer agents for therapy of pulmonary metastatic melanoma

Synthesis of thieno[3,2-e]pyrrolo[1,2-a]pyrimidine derivatives and their precursors containing 2-aminothiophenes fragments as anticancer agents for therapy of pulmonary metastatic melanoma

  • Eur J Med Chem. 2023 Jun 5;254:115325. doi: 10.1016/j.ejmech.2023.115325.
Anna Rogova 1,  Irina A Gorbunova 2,  Timofey E Karpov 1,  Roman Yu Sidorov 3,  Aleksander E Rubtsov 2,  Daria A Shipilovskikh 4,  Albert R Muslimov 5,  Mikhail V Zyuzin 6,  Alexander S Timin 7,  Sergei A Shipilovskikh 8
Affiliations

Affiliations

  • 1 School of Physics and Engineering, ITMO University, Lomonosova 9, St. Petersburg, 191002, Russian Federation; Laboratory of nano- and microencapsulation of biologically active compounds, Peter The Great St. Petersburg Polytechnic University, Polytechnicheskaya 29, St. Petersburg, 195251, Russian Federation.
  • 2 Perm State University, Perm, Bukireva 15, Perm, 614990, Russian Federation.
  • 3 Perm State University, Perm, Bukireva 15, Perm, 614990, Russian Federation; Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center, Russian Academy of Sciences, Ural Branch, Goleva 13, Perm, 614081, Russian Federation.
  • 4 Perm State University, Perm, Bukireva 15, Perm, 614990, Russian Federation; Perm National Research Polytechnic University, 29 Komsomolsky prospekt, Perm, 614990, Russian Federation.
  • 5 Laboratory of nano- and microencapsulation of biologically active compounds, Peter The Great St. Petersburg Polytechnic University, Polytechnicheskaya 29, St. Petersburg, 195251, Russian Federation.
  • 6 School of Physics and Engineering, ITMO University, Lomonosova 9, St. Petersburg, 191002, Russian Federation.
  • 7 School of Physics and Engineering, ITMO University, Lomonosova 9, St. Petersburg, 191002, Russian Federation; Laboratory of nano- and microencapsulation of biologically active compounds, Peter The Great St. Petersburg Polytechnic University, Polytechnicheskaya 29, St. Petersburg, 195251, Russian Federation. Electronic address: alexander.timin@metalab.ifmo.ru.
  • 8 School of Physics and Engineering, ITMO University, Lomonosova 9, St. Petersburg, 191002, Russian Federation; Perm State University, Perm, Bukireva 15, Perm, 614990, Russian Federation. Electronic address: s.shipilovskikh@metalab.ifmo.ru.
PMID: 37084598 DOI: 10.1016/j.ejmech.2023.115325
Abstract

The design and synthesis of new promising compounds based on thienopyrimidine scaffold containing 2-aminothiophene fragments with good safety and favorable drug-like properties are highly relevant for chemotherapy. In this study, a series of 14 variants of thieno[3,2-e]pyrrolo[1,2-a]pyrimidine derivatives (11aa-oa) and their precursors (31 compounds) containing 2-aminothiophenes fragments (9aa-mb, 10aa-oa) were synthesized and screened for their cytotoxicity against B16-F10 melanoma cells. The selectivity of the developed compounds was assessed by determining the cytotoxicity using normal mouse embryonic fibroblasts (MEF NF2 cells). The lead compounds 9cb, 10ic and 11jc with the most significant antitumor activity and minimum cytotoxicity on normal non-cancerous cells were chosen for further in vivo experiments. Additional in vitro experiments with compounds 9cb, 10ic and 11jc showed that Apoptosis was the predominant mechanism of death in B16-F10 melanoma cells. With support from in vivo studies, compounds 9cb, 10ic and 11jc demonstrated the biosafety to healthy mice and significant inhibition of the metastatic nodules in pulmonary metastatic melanoma mouse model. Histological analysis detected no abnormal changes in the main organs (the liver, spleen, kidneys, and heart) after the therapy. Thus, the developed compounds 9cb, 10ic and 11jc demonstrate high efficiency in the treatment of pulmonary metastatic melanoma and can be recommended for further preclinical investigation of the melanoma treatment.

Keywords

2-aminothiophene; In vitro screening; In vivo therapy; Metastatic melanoma; Pulmonary metastatic melanoma; Thienopyrymidines.

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