Assessment of the toxicogenic effects and cell death potential of the ester (Z)-methyl 4-((1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino)-4-oxobut-2-anoate in combination with cisplatin, cyclophosphamide and doxorubicin

Oliveira, Rodrigo Juliano; Pereira, Fabrícia Paniago Ajala Nery; Silveira, Ingridhy Ostaciana Maia Freitas da; Lima, Ricardo Vieira de; Berno, Claudia Rodrigues; Pesarini, João Renato; Antoniolli-Silva, Andréia Conceição Milan Brochado; Monreal, Antônio Carlos Duenhas; Beatriz, Adilson; Lima, Dênis Pires de; Gomes, Roberto da Silva

doi:10.1590/1678-4685-gmb-2017-0279

Cited by 5 publications

(9 citation statements)

References 38 publications

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“…Compound 2 , when associated with the CIS , DOX , and CYP , reduces the chemotherapeutic effects of these drugs because it prevents the induction of DNA damage and, indirectly, reduces the rate of cell death, which is also observed for ZIM .…”

Section: Discussionmentioning

confidence: 84%

“…It possibly occurred because activated splenic phagocytosis and the removal of damaged cells (micronucleated cells, for instance) by the spleen may have favored the homeostasis of the animals and, therefore, did not induce any change in the cell count of the blood. This fact is documented in different types of studies ,− and even in products derived from 4-AA . ,, …”

Section: Discussionmentioning

confidence: 87%

“…In addition, it causes low phagocytic activation. Even though the frequency of cell death increased . This fact suggests that the induction of death for 2 is not mediated by DNA damage.…”

Section: Discussionmentioning

confidence: 88%

“…Building on our earlier work, ,, we first synthesized ZIM , a norbornene dicarboximide based on the 1,4-dioxo-butenyl/4-aminoantipyrine scaffold. We then evaluated the synthesized ZIM in a mouse model for its genotoxic and apoptotic potential alone and in combination with three chemotherapeutic agents currently used in clinical settings (cisplatin- CIS , doxorubicin- DOX , and cyclophosphamide- CYP ).…”

Section: Introductionmentioning

confidence: 99%

“…Gray: 4-aminoantipyrine moiety; red: 1,4-dioxobutenyl moieties. Compound 1 refers to ref , and compound 2 refers to ref .…”

Section: Introductionmentioning

confidence: 99%

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

Oliveira

Silveira

Neves

et al. 2022

Chem. Res. Toxicol.

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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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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 87%

“…In addition, it causes low phagocytic activation. Even though the frequency of cell death increased . This fact suggests that the induction of death for 2 is not mediated by DNA damage.…”

Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

“…Gray: 4-aminoantipyrine moiety; red: 1,4-dioxobutenyl moieties. Compound 1 refers to ref , and compound 2 refers to ref .…”

Section: Introductionmentioning

confidence: 99%

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

Oliveira

Silveira

Neves

et al. 2022

Chem. Res. Toxicol.

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Design, synthesis and in vivo evaluation of 1,4-dioxo-2-butenyl aryl amine derivatives as a promising anti-inflammatory drug prototype

Silveira

Moslaves

Muller

et al. 2022

Bioorganic Chemistry

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Chemotherapeutic Mechanism of Action of the Synthetic Resorcinolic Methyl 3,5-dimethoxy-2-octanoylbenzoate

Correa,

das Neves,

Oliveira

et al. 2024

Chem. Res. Toxicol.

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Resorcinolic lipids are described as potential examples of selective chemotherapeutic adjuvants that can enhance the effects of cyclophosphamide (CYC) while promoting cell death without causing DNA damage. Therefore, the current study attempted to describe how the resorcinolic lipid methyl 3,5-dimethoxy-2-octanoylbenzoate (AMS35BB) interacted with DNA (DNA docking) and how this compound affected genetic toxicology models and other biological characteristics when combined with CYC. We observed that AMS35BB, used alone (7.5 and 10 mg/kg), increases the frequency of genomic damage (comet assay) but not chromosomal damage (micronuclei assay), lowers phagocytosis, and promotes cell death in Swiss male mice. When used in association with CYC, AMS35BB can reduce the risk of genomic damage by up to 33.8% as well as chromosomal damage, splenic phagocytosis, cell death, and lymphocyte frequency. Molecular docking showed that AMS35BB had a higher affinity than the active metabolite of CYC for binding to the DNA double helix major groove. As a result, AMS35BB has the potential to be both an adjuvant when used in association with CYC and a therapeutic candidate for the development of a selective chemotherapeutic drug.

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Assessment of the toxicogenic effects and cell death potential of the ester (Z)-methyl 4-((1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino)-4-oxobut-2-anoate in combination with cisplatin, cyclophosphamide and doxorubicin

Cited by 5 publications

References 38 publications

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

Design, synthesis and in vivo evaluation of 1,4-dioxo-2-butenyl aryl amine derivatives as a promising anti-inflammatory drug prototype

Chemotherapeutic Mechanism of Action of the Synthetic Resorcinolic Methyl 3,5-dimethoxy-2-octanoylbenzoate

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