The parkin protein functions as a RING-type ubiquitin protein ligase. Considering the possibility that impaired ubiquitin-proteosomal system activity may impair antioxidant defenses and enhance oxidative stress, we have investigated the activity of mitochondrial respiratory enzymes in patients with parkin gene mutations. A significant decrease in the leukocyte complex I activity was found both in patients with parkin mutations (62.5%) and idiopathic PD (64.5%) compared with age-matched controls (P < 0.001). Complex IV activity was also decreased significantly in idiopathic PD patients (60%), but no difference was detected between controls and patients with parkin mutations.

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In the present study, Mannich bases of kojic acid with the structure of 2-substituted-3-hydroxy-6-hyroxymethyl/chloromethyl/methyl/morpholinomethyl/piperidinylmethyl/pyrrolidinylmethyl-4H-pyran-4-one (compounds 1-23) were synthesized by the reaction of kojic acid/chlorokojic acid/allomaltol and substituted benzylpiperazine derivatives in presence of formaline. To obtain the cyclic amine (morpholine, piperidine and pyrrolidine) derivatives of the 6th-position of chlorokojic acid derivatives, nucleophilic substitutions were carried out. Thereafter, cytotoxic effects on A375 human malignant melanoma, HGF-1 human gingival fibroblasts, and MRC-5 human lung cell lines were investigated by sulphorhodamine B assay. Efficacy of all these compounds has been compared to those of vemurafenib, dacarbazine, temozolomide, and lenalidomide, which are the commercially available drugs for the treatment of malignant melanoma. Cytotoxic action against melanoma cells was significantly more efficacious (IC50: 11.26-68.58 µM) than the FDA-approved drugs except for vemurafenib. Fourteen of the compounds were proven to have higher IC50 values for the non-cancerous cell lines, HGF-1, and MRC-5 cells. Melanogenesis inhibition assay was performed to observe the ability of the drugs to inhibit melanin production and certain compounds were shown to be capable of actively inhibiting melanin production in melanoma cells. In conclusion, Mannich bases of kojic acid derivatives may be promising therapeutic agents, since some have more potent effects on melanoma cells than previously FDA-approved drugs for the treatment of malignant melanoma.

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