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The binding between anticancer drugs and double-stranded DNA (dsDNA) is a key issue to understand their mechanism of action, and many chemical methods have been explored on this task. Molecular docking techniques successfully predict the affinity of small molecules into the DNA binding sites. In turn, various DNA-targeted drugs are electroactive; in this regard, their electrochemical behavior may change according to the nature and strength of interaction with DNA. A carbon paste electrode (CPE) modified with calf thymus ds-DNA (CPDE) and computational methods were used to evaluate the drug–DNA intercalation of doxorubicin (DOX), daunorubicin (DAU), idarubicin (IDA), dacarbazine (DAR), mitoxantrone (MIT), and methotrexate (MTX), aiming to evaluate eventual correlations. CPE and CPDE were immersed in pH 7 0.1 mM solutions of each drug with different incubation times. As expected, the CPDE response for all DNA-targeted drugs was higher than that of CPE, evidencing the drug–DNA interaction. A peak current increase of up to 10-fold was observed; the lowest increase was seen for MTX, and the highest increase for MIT. Although this increase in the sensitivity is certainly tied to preconcentration effects of DNA, the data did not agree entirely with docking studies, evidencing the participation of other factors, such as viscosity, interfacial electrostatic interactions, and coefficient of diffusion. [ABSTRACT FROM AUTHOR]

Dual 5-LOX/COX inhibitors are potential new dual drugs to treat inflammatory conditions. This research aimed to design, synthesis and to evaluate the anti-inflammatory and antinociceptive effects of the new compound, which is derived from nimesulide and darbufelone lead compounds. The new dual inhibitor 5-LOX/COX has the possible advantage of gastrointestinal safety. A voltammetric experiment was conducted to observe the drug's antioxidative effect. A formalin test, a hot plate test and carrageenan-induced mechanical hyperalgesia were employed to evaluate the analgesic nature of LQFM-091. To evaluate anti-inflammatory activity, we measured edema, leukocyte count, myeloperoxidase activity and cytokines levels in carrageenan-induced inflammation tests. We elucidated the underlying mechanisms by assessing the interaction the with COXs and LOX enzymes by colorimetric screening assay and molecular docking. The lethal dose (LD 50 ) was estimated using 3T3 Neutral Red Uptake assay. Our results indicate that the LQFM-091 prototype is a powerful antioxidant, as well as able to inhibit COX-1, COX-2 and LOX activities. LQFM091 was classified in GHS category 4 (300 < LD 50 < 2000 mg/Kg). This prototype showed analgesic activity in the formalin test and decreased carrageenan-induced mechanical hyperalgesia. Furthermore, LQFM-091 reduced the paw edema induced by carrageenan and reduced the leukocyte count, myeloperoxidase activity, TNF-α and IL-1β levels in the pleural exudate. Another interesting finding was the absence of gastrointestinal lesions. These data indicate that LQFM-091 produced antinociceptive and anti-inflammatory effects while maintaining gastrointestinal safety. Furthermore, this compound presented a safe toxicological profile. Blocked COXs and LOX enzymes are important targets for manipulating the mechanism of this compound. [ABSTRACT FROM AUTHOR]