ABSTRACT
A series of tailored novobiocin-ferrocene conjugates was prepared in moderate yields and investigated for in vitro anticancer and antiplasmodial activity against the MDA-MB-231 breast cancer line and Plasmodium falciparum 3D7 strain, respectively. While the target compounds displayed moderate anticancer activity against the breast cancer cell line with IC50 values in the mid-micromolar range, compounds 10a-c displayed promising antiplasmodial activity as low as 0.889 µM. Furthermore, the most promising compounds were tested for inhibitory effects against a postulated target, heat shock protein 90 (Hsp90). A selection of tailored novobiocin derivatives bearing the organometallic ferrocene unit were synthesized and characterized by common spectroscopic techniques. The target compounds were investigated for in vitro anticancer and antimalarial activity against the MDA-MB-231 breast cancer cell line and Plasmodium falciparum 3D7 strain, respectively.
Subject(s)
Antimalarials/pharmacology , Antineoplastic Agents/pharmacology , Ferrous Compounds/pharmacology , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Metallocenes/pharmacology , Novobiocin/pharmacology , Plasmodium falciparum/drug effects , Antimalarials/chemical synthesis , Antimalarials/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Ferrous Compounds/chemistry , HSP90 Heat-Shock Proteins/metabolism , HeLa Cells , Humans , Metallocenes/chemistry , Molecular Structure , Novobiocin/chemistry , Parasitic Sensitivity Tests , Structure-Activity RelationshipABSTRACT
This study sought to investigate the effects of kolaviron on diclofenac-induced hepatotoxicity in rats. Sixty male Wistar rats were divided into 6 groups of 10 rats each as follows: a control group that received oral propylene glycol and treatment groups that received diclofenac alone, diclofenac followed by Livolin Forte (a reference drug), or diclofenac followed by kolaviron at three different doses. At the end of the study period, five rats per group were sacrificed under ketamine hydrochloride anesthetic, 24h after treatment, while the other 5 rats in the group were allowed to recover for 2 weeks before being sacrificed. Liver enzyme activities, total bilirubin levels, and the concentrations of several pro-inflammatory cytokines were determined using plasma samples, while liver tissue samples were used for antioxidant analysis and histopathological examination. Compared with the control group, plasma liver enzyme activities, along with bilirubin levels, were higher in the groups that received diclofenac alone or diclofenac+the highest dose of kolaviron, respectively. These groups had higher plasma concentrations of pro-inflammatory cytokines than did the control group. However, the administration of Livolin Forte and kolaviron (at the lower doses) ameliorated diclofenac-induced hepatic injury by improving antioxidant status, preventing an increase in inflammatory mediators, decreasing malondialdehyde, and attenuating the adverse effect of diclofenac on hepatic tissues. In addition, there was a significant difference in the histological scores between the groups that received either diclofenac alone or diclofenac followed by the highest dose of kolaviron when compared with the other three groups (Livolin Forte or lower doses of kolaviron). In conclusion, kolaviron appears to be as effective as Livolin in attenuating DCLF-induced hepatotoxicity in rats. However, high doses of kolaviron seem to cause damage to the liver.