Process development for the total synthesis of the novel drug metabolite Carboxy toremifene as a standard reference material along with characterization and purity assessment for the Antidoping quality Control Purposes.

Tamoxifen and toremifene are two selective estrogen receptor modulators (SERMs) commonly used to treat breast cancer in women. Toremifene is well-known as a triphenylethylene derivative. Carboxy toremifene is a common metabolite of toremifene and tamoxifen. Since 2005, the World Anti-Doping Agency (WADA) has banned the SERMs category during in and out of competition. These substances are in the S4 category in the WADA prohibited list as "agents with anti-oestrogenic activity." However, there is no commercially accessible carboxy toremifene reference material in the market. This research highlights the novel synthetic procedure, the development of a carboxy toremifene HPLC method, and validation, along with detailed characterization using advanced analytical techniques using 1 H NMR, HRMS, FT-IR-ATR and UV-visible spectroscopy. RP-HPLC-DAD method was developed and validated to assess the purity of carboxy toremifene. Developed reference material has shown 100% purity. Therefore, we recommend that this synthesized carboxy toremifene may be used as reference material to strengthen the WADA-accredited lab to maintain a clean sports mission during sports competitions.

Non-permitted food colorants induced neurotoxicity in cerebellum of rat brain.

Food colorants are important food additives that not only enhance the appearance of food but also appetite. These can be obtained from natural and synthetic sources, but synthetic sources are more popular, efficient, and potential. Non-permitted food colorants (NPFCs) are banned, but their injudicious use in developing countries associated with various adverse health effects. They have potentially toxic effects on the body organs like the brain, liver, kidney, spleen, gut, etc. In view of their toxicity pattern, the present study aims to investigate the effect of three NPFCs (MY: Metanil yellow; MG: Malachite green; SIII: Sudan III) on oxidative stress, mitochondrial complexes, neurochemicals, and histological changes in the cerebellum of rats. Rats treated with MY (430 mg/kg), MG (13.75 mg/kg), SIII (250 mg/kg), and their mixtures (YGR) (MY 143.33 + MG 4.52 + SIII 83.33 mg/kg) p.o. for 60 days showed a significant increase in lipid peroxidation and decreased level of reduced glutathione, superoxide dismutase, and catalase activity as compared to controls. An increase in the activity of acetylcholinesterase (AChE) and a significant decrease in the activity of monoamine oxidase-B (MAO-B) and mitochondrial complex I and II was also observed in NPFCs treated rats as compared to controls. Further, the histological study also revealed the loss of Purkinje neurons in the cerebellum of the rat brain. The results of the present study indicate that NPFCs exposure to rats enhances oxidative stress and alters the activity of neurochemicals and mitochondrial complexes which could further lead to neuronal loss and behavioral dysfunctions.

Neuroprotective effects of mitochondria-targeted curcumin against rotenone-induced oxidative damage in cerebellum of mice.

The present study investigated the protective effect of curcumin and mitochondrial-targeted curcumin (MTC) in rotenone-induced cerebellar toxicity in mice. Treatment of rotenone in mice significantly shortened the stride length for both forelimb and hind-limb and increased fore-paws and hind-limb base width. Co-treatment of curcumin and MTC with rotenone improved the walking pattern. A significant increase in lipid peroxidation, nitric oxide and decreased activity of AChE, reduced glutathione, superoxide dismutase and catalase were observed in rotenone-treated mice while co-treatment of curcumin and MTC with rotenone significantly increased AChE activity and protected against rotenone-induced oxidative damage. Rotenone exposed mice showed irregular, damaged Purkinje cells and perineuronal vacuolation while co-treatment of curcumin and MTC with rotenone protected against rotenone-induced cellular damage in these cells. The result exhibits that both curcumin and MTC showed protective effects against rotenone-induced cerebellar toxicity in mice and MTC is more effective than curcumin.