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  3. Design and one-pot synthesis of new substituted pyrrolo[1,2-a]thieno[3,2-e]pyrimidine as potential antitumor agents: in vitro and in vivo studies

Design and one-pot synthesis of new substituted pyrrolo[1,2-a]thieno[3,2-e]pyrimidine as potential antitumor agents: in vitro and in vivo studies

  • Bioorg Chem. 2024 Jul:148:107468. doi: 10.1016/j.bioorg.2024.107468.
Irina A Gorbunova 1,  Anna Rogova 2,  Darya R Akhmetova 1,  Roman Yu Sidorov 3,  Eugene E Priakhin 4,  Ramiz R Makhmudov 5,  Daria A Shipilovskikh 6,  Olga S Epifanovskaya 7,  Alexander S Timin 8,  Sergei A Shipilovskikh 9
Affiliations

Affiliations

  • 1 ITMO University, Kronverksky Prospekt 49, St. Petersburg 191002, Russian Federation; Peter The Great St. Petersburg Polytechnic University, Polytechnicheskaya 29, St. Petersburg 195251, Russian Federation.
  • 2 Peter The Great St. Petersburg Polytechnic University, Polytechnicheskaya 29, St. Petersburg 195251, Russian Federation.
  • 3 Institute of Ecology and Genetics of Microorganisms, Perm Federal Research Center, Russian Academy of Sciences, Ural Branch, Goleva 13, Perm 614081, Russian Federation; Perm State University, Perm, Bukireva 15, Perm 614990, Russian Federation.
  • 4 Peter The Great St. Petersburg Polytechnic University, Polytechnicheskaya 29, St. Petersburg 195251, Russian Federation; St. Petersburg Academic University, St. Petersburg 194021, Russian Federation.
  • 5 Perm State University, Perm, Bukireva 15, Perm 614990, Russian Federation.
  • 6 Peter The Great St. Petersburg Polytechnic University, Polytechnicheskaya 29, St. Petersburg 195251, Russian Federation; Perm National Research Polytechnic University, 29 Komsomolsky Prospekt, Perm 614990, Russian Federation.
  • 7 RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, Lva Tolstogo 6/8, St. Petersburg 191144, Russian Federation.
  • 8 Peter The Great St. Petersburg Polytechnic University, Polytechnicheskaya 29, St. Petersburg 195251, Russian Federation. Electronic address: a_timin@mail.ru.
  • 9 ITMO University, Kronverksky Prospekt 49, St. Petersburg 191002, Russian Federation; Perm State University, Perm, Bukireva 15, Perm 614990, Russian Federation. Electronic address: shipilovskikh@itmo.ru.
PMID: 38781670 DOI: 10.1016/j.bioorg.2024.107468
Abstract

A new efficient and versatile one-pot three-component synthesis of substituted pyrrolo[1,2-a]thieno[3,2-e]pyrimidine derivatives has been developed. It is based on a multistep cascade reaction from 2-aminothiophenes and 2-hydroxy-4-oxobut-2-enoic acids, and derivatives of cyanoacetic acid catalyzed by diisopropylethylamine. As a result, novel pyrrolo[1,2-a]thieno[3,2-e]pyrimidine derivatives (21 compounds) were synthesized in a mild reaction conditions with a high yield. The structures of the developed compounds were confirmed by NMR and elemental analysis. The influence of electron-withdrawing or electron-donor substituents on the antitumor activity of the developed compounds has been identified. In vitro screening analysis of 21 compounds revealed six lead candidates (12aa, 12dc, 12hc, 12ic, 12lb, and 12mb) that demonstrated the most significant antitumor activity against B16-F10, 4T1 and CT26 cells. Necrosis/Apoptosis assay showed that Apoptosis was the predominant mechanism of cell death. Molecular docking analysis revealed several potential targets for tested compounds, i.e. phosphatidylinositol 5-phosphate 4-kinase (PI5P4K2C), proto-oncogene serine/threonine-protein kinase (Pim-1), nicotinamide phosphoribosyltransferase (NAMPT) and dihydrofolate reductase (DHFR). The lead compound (12aa) can effectively induce cell Apoptosis, possesses a high yield (98 %) and requires low-cost starting chemicals for its synthesis. In vivo experiments with melanoma-bearing mice confirmed that 12aa compound resulted in the significant tumor inhibition on 15 d after the therapy. In particular, tumor volume was ∼0.19 cm3 for 50 mg/kg versus ∼2.39 cm3 in case of untreated mice and tumor weight was ∼71.6 mg for 50 mg/kg versus ∼452.4 mg when considered untreated mice. Thus, our results demonstrated the high potential of the 12aa compound in the treatment of melanoma and can be recommended for further preclinical studies.

Keywords

Antitumor activity; Breast tumor; Colorectal carcinoma; Melanoma; Molecular docking; One-pot synthesis; Regional chemotherapy; Thienopyrimidine.

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