In vivo chemotherapeutic insight of a novel isocoumarin (3-hexyl-5,7-dimethoxy-isochromen-1-one): Genotoxicity, cell death induction, leukometry and phagocytic evaluation

Abstract

Chemotherapy is one of the major approaches for the treatment of cancer. Therefore, the development of new chemotherapy drugs is an important aspect of medicinal chemistry. Chemotherapeutic agents include isocoumarins, which are privileged structures with potential antitumoral activity. Herein, a new 3-substituted isocoumarin was synthesized from 2-iodo-3,5-dimethoxy-benzoic acid and oct-1-yne in a cross-coupling Sonogashira reaction followed by a copper iodide-catalyzed intramolecular cyclization as key step using MeOH/Et3N as the solvent system. The present study also evaluated the leukometry, phagocytic activity, genotoxic potential and cell death induction of three different doses (5 mg/kg, 10 mg/kg and 20 mg/kg) of this newly synthesized isocoumarin, alone and in combination with the commercial chemotherapeutic agents cyclophosphamide (100 mg/kg) and cisplatin (6 mg/kg) in male Swiss mice. The results suggest that the isocoumarin has genotoxicity and causes cell death. Noteworthy, this new compound can increase splenic phagocytosis and lymphocyte frequency, which are related to immunomodulatory activity. When combined with either cyclophosphamide or cisplatin, chemopreventive activity led to a reduction in the effects of both chemotherapeutic drugs. Thus, the new isocoumarin is not a candidate for chemotherapeutic adjuvant in treatments using cyclophosphamide or cisplatin. Nevertheless, the compound itself is an important prototype for the development of new antitumor drugs.

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

“…According to Rundell et al (2003) , genotoxic damage is likely to undergo repair, whereas mutagenic damage is not, with changes becoming fixed in the genetic material as mutations. Such occurrence is not uncommon in preclinical chemoprevention experiments, both with natural products ( Synder and Gillies, 2002 ; Cunha et al , 2005 ; Rodeiro et al , 2006 ; Hoshina et al , 2013 ; Mendanha da Cunha et al , 2013 ; Luo et al , 2015 ) and with synthetic compounds ( Zhan et al , 2008 ; Cao et al , 2015 ; Frolova et al , 2015 ; de Araújo et al , 2017 ). Although there are significant differences in the frequency of micronuclei between the negative control group and the groups treated with IR-01, Vaz et al (2016) describes that this isolated fact does not necessarily imply in toxicogenetic damage.…”

“…These mutations lead to the altered expression or function of genes important for the maintenance of homeostasis, causing the loss of cell proliferation control ( Steward and Brown, 2013 ). The genesis of cancer can occur via mutations ( Ames et al , 1973 ); therefore, the chemopreventive and chemotherapeutic potential of synthetic compounds that are able to reduce or increase the frequency of DNA damage has been explored, yielding good models for genetic toxicology ( de Araújo et al , 2017 ).…”

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

“…Effects such as these are described for β-glucan, glutamine, , dietary fibers such as wheat, and resistant starch, among others. However, it has also been described for synthetic compounds such as isocoumarin, an acid (compound 1 , Figure ), and an ester (compound 2 , Figure ) derived from 4-AA .…”

Evaluation of the Antitumor Potential of the Resorcinolic Lipid 3-Heptyl-3,4,6-trimethoxy-3H-isobenzofuran-1-one in Breast Cancer Cells

“…In addition, AMS35AA and AMS49 did not show any toxicogenicity, considering that they do not induce micronuclei and they further potentiate the genotoxic effects of cyclophosphamide (3,4). On the other hand, isocoumarin has genotoxic action (increases comet frequency and micronuclei) and at the same time has antigenotoxic action against damage induced by cyclophosphamide and cisplatin (5). Thus, it is perceived that AMS35AA and AMS49 are candidates as new chemotherapeutics and adjuvants, which was not occurred in the isocoumarin experiment because it reduced the commercial drug effects.…”

“…Among the resorcinolic lipids those that stressed relevance are the 3-Heptyl-3,4,6-trimethoxy-3H-isobenzofuran-1-one (AMS35AA) (3), the 3-Heptyl-4,6-dihydroxy-3H-isobenzofuran-1-one (AMS49) (4) and the 3-hexyl-5,7-dimethoxyisochromen-1-one (isocoumarin) (5). These compounds share the ability to increase the frequency of apoptosis in the kidneys and liver of treated animals.…”