Assessment of genetic integrity, splenic phagocytosis and cell death potential of (Z)-4-((1,5-dimethyl-3-oxo-2-phenyl-2,3dihydro-1H-pyrazol-4-yl) amino)-4-oxobut-2-enoic acid and its effect when combined with commercial chemotherapeutics

Abstract

The increased incidence of cancer and its high treatment costs have encouraged the search for new compounds to be used in adjuvant therapies for this disease. This study discloses the synthesis of (Z)-4-((1,5-dimethyl-3-oxo-2-phenyl-2,3dihydro-1H-pyrazol-4-yl) amino)-4-oxobut-2-enoic acid (IR-01) and evaluates not only the action of this compound on genetic integrity, increase in splenic phagocytosis and induction of cell death but also its effects in combination with the commercial chemotherapeutic agents doxorubicin, cisplatin and cyclophosphamide. IR-01 was designed and synthesized based on two multifunctionalyzed structural fragments: 4-aminoantipyrine, an active dipyrone metabolite, described as an antioxidant and anti-inflammatory agent; and the pharmacophore fragment 1,4-dioxo-2-butenyl, a cytotoxic agent. The results indicated that IR-01 is an effective chemoprotector because it can prevent clastogenic and/or aneugenic damage, has good potential to prevent genomic damage, can increase splenic phagocytosis and lymphocyte frequency and induces cell death. However, its use as an adjuvant in combination with chemotherapy is discouraged since IR-01 interferes in the effectiveness of the tested chemotherapeutic agents. This is a pioneer study as it demonstrates the chemopreventive effects of IR-01, which may be associated with the higher antioxidant activity of the precursor structure of 4-aminoantipyrine over the effects of the 1,4-dioxo-2-butenyl fragment.

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

“…However, our results are not sufficient to predict how the IR-04 ester interfered in each mechanism of action and also presented a pattern of chemoprevention in combination with the chemotherapeutics. Our results are distinct from those presented by Oliveira et al (2018). The authors evaluated the IR-01 acid, derived from the same pharmacophoric groups as IR-04, and did not find a pattern of chemopreventive response, which suggested interference in the mechanisms of action of the chemotherapeutic agents.…”

“…On the other hand, even though observing a decrease in DNA damage (antigenotoxic effect, reported in this study) we need to consider that cancer cells can be more susceptible than their normal correspondents when exposed to anti-cancer drugs (Oberley and Buettner, 1979; Cebrian et al , 2006). Such difference is due, for example, to tumor cells containing less antioxidant enzymes, as is the case for superoxide dismutate, GSH peroxidase, and GSH reductase (Oliveira et al , 2018).…”

“…IR-01 was synthesized according to Oliveira et al (2018). Briefly, a sealed tube coupled to a microwave reactor containing 4-aminoantipyrine (10.20 mmol) and maleic anhydride (10.20 mmol) was subjected to 150 W microwave irradiation at 90 °C for 10 s. Then, the tube was cooled and the product was recrystallized with ethyl acetate.…”

“…Antipyrines are possible starting points for the synthesis of antitumor molecules (Khanduja et al , 1984; Nishio et al , 2005; Berno et al , 2016; Oliveira et al , 2018). In the present study, 4-aminoantipyrine was used (Jain et al , 2006) due to its antioxidant (Teng and Liu, 2013; Ghorab et al , 2014), analgesic (Costa et al , 2006), anti-inflammatory (Burdulene et al , 1999), antipyretic, and antiviral (Evstropov et al , 1992) effects.…”

“…Several previous studies of biological activity indicated that the addition of 4-aminoantipyrine to a chemical structure can enhance its biological response (Teng and Liu, 2013; Ghorab et al , 2014; Aly et al , 2011; Oliveira et al , 2018). Thus, the ester ( Z )-methyl 4-((1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazol-4-yl)amino)-4-oxobut-2-enoate (IR-04) was synthesized from 4-aminoantipyrine via the carbonyl addition of a maleimide (1,4-dioxo-2-butenyl).…”