2. Academic Validation
  3. ZIM, a Norbornene Derived from 4-Aminoantipyrine, Induces DNA Damage and Cell Death but in Association Reduces the Effect of Commercial Chemotherapeutics

ZIM, a Norbornene Derived from 4-Aminoantipyrine, Induces DNA Damage and Cell Death but in Association Reduces the Effect of Commercial Chemotherapeutics

  • Chem Res Toxicol. 2023 Jan 16;36(1):66-82. doi: 10.1021/acs.chemrestox.2c00275.
Rodrigo Juliano Oliveira 1 2,  Ingridhy Ostaciana Maia Freitas da Silveira 3 4,  Silvia C das Neves 1 2,  Barbara Mitsuyasu 4 5,  Allana C Martins 4,  Claudia Berno 1,  Jiyan Mohammad 4,  Halie Raj 4,  Flavio H S de Araujo 1,  Cristiane Regina Hortelan 6,  Luana Machado 7 8,  Eufrânio N da Silva Júnior 7,  Marcelo L B Vilela 9,  Valter Aragão Nascimento 2,  Adilson Beatriz 3,  Roberto da Silva Gomes 4
Affiliations

Affiliations

  • 1 Stem Cell, Cell Therapy and Toxicological Genetics Research Centre (CeTroGen), Medical School, Federal University of Mato Grosso do Sul, Campo Grande, Mato Grosso do Sul79080-190, Brazil.
  • 2 Graduate Program in Health and Development in the Midwest Region, Medical School, Federal University of Mato Grosso do Sul, Campo Grande, Mato Grosso do Sul79070-900, Brazil.
  • 3 Institute of Chemistry, Federal University of Mato Grosso do Sul, Campo Grande, Mato Grosso do Sul79070-900, Brazil.
  • 4 Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota58102, United States.
  • 5 Department of Chemical and Biological Sciences, Institute of Biosciences, São Paulo State University (UNESP), Botucatu, SP18618-689, Brazil.
  • 6 Instituto Federal de Mato Grosso do Sul, Dourados, MSCEP 79833-520, Brazil.
  • 7 Institute of Exact Sciences, Department of Chemistry, Federal University of Minas Gerais, Belo Horizonte, MGCEP 31270-901, Brazil.
  • 8 Department of Chemistry, Fluminense Federal University, Niteroi, RJ24020-141, Brazil.
  • 9 Medical School, Federal University of Mato Grosso do Sul, Campo Grande, Mato Grosso do Sul79070-900, Brazil.
PMID: 36548215 DOI: 10.1021/acs.chemrestox.2c00275
Abstract

Cancer incidence is increasing, and the drugs are not very selective. These drugs cause adverse effects, and the cells become resistant. Therefore, new drugs are needed. Here, we evaluated the effects of ZIM, a candidate for chemotherapy, and 4-AA alone and in association with commercial chemotherapeutic agents. Subsequently, the results of ZIM and 4-AA were compared. Male Swiss mice were treated with doses of 12, 24, or 48 mg/kg ZIM or 4-AA alone or in association with cisplatin (6 mg/kg), doxorubicin (16 mg/kg), and cyclophosphamide (100 mg/kg). Biometric parameters, DNA damage (comet and micronuclei), cell death, and splenic phagocytosis were evaluated. DNA docking was also performed to confirm the possible interactions of ZIM and 4-AA with DNA. 4-AA has been shown to have low genotoxic potential, increase the frequency of cell death, and activate phagocytosis. ZIM causes genomic and chromosomal damage in addition to causing cell death and activating phagocytosis. In association with chemotherapeutical agents, both 4-AA and ZIM have a chemopreventive effect and, therefore, reduce the frequency of DNA damage, cell death, and splenic phagocytosis. The association of 4-AA and ZIM with commercial chemotherapeutic agents increased the frequency of lymphocytes compared to chemotherapeutic agents alone. Molecular docking demonstrated that ZIM has more affinity for DNA than 4-AA and its precursors (1 and 2). This was confirmed by the lower interaction energy of the complex (-119.83 kcal/mol). ZIM can break the DNA molecule and, therefore, its chemotherapeutic effect can be related to DNA damage. It is considered that ZIM has chemotherapeutic potential. However, it should not be used in combination with cisplatin, doxorubicin, and cyclophosphamide as it reduces the effects of these drugs.

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