Synthesis and Cytotoxic Evaluation of Kojic Acid Derivatives with Inhibitory Activity on Melanogenesis in Human Melanoma Cells

Abstract

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.

A kojic acid derivative promotes intrinsic apoptotic pathway of hepatocellular carcinoma cells without incurring drug resistance

“…As KA and its derivatives are acknowledged by their tyrosinase inhibitor effects, first of all the effects of our novel compounds were tested on A375 human malignant melanoma cell line and found to be significantly anti‐proliferative. Nonetheless, these derivative compounds were attested to be not cytotoxic within the applied doses on certain healthy cell lines (HGF‐1 human normal gingival biopsy and MRC‐5 normal human lung cell lines) (Karakaya et al, ). These findings directed us to investigate whether some of these particular KA derivative compounds reflect anti‐neoplastic properties on HCC cells pursuing a separate mechanism.…”

“…Therefore, KA is employed as an ingredient of dermocosmetics used for the treatment of hyperpigmentation of the skin (Cho et al, ; Kahn, Ben‐Shalom, & Zakin, ; Sharma & Davids, ; Wang et al, ). Numerous other studies proved that KA and its derivatives also exhibit anti‐oxidant, anti‐neoplastic, anti‐inflammatory, anti‐bacterial, anti‐viral, anti‐convulsant, anti‐tyrosinase, and anti‐aging properties (Aytemir & Calis, ; Aytemir & Ozcelik, ; Aytemir, Ozcelik, Erdogan, Karakaya, & Senol, ; Aytemir, Septioglu, & Calis, ; Dung et al, ; Karakaya, Ercan, Oncul, & Aytemir, ; Mohammadpour, Behjati, Sadeghi, & Fassihi, ; Rho et al, ; Smith & Lindsay, ; Zhang et al, ).…”

“…We previously reported their cytotoxic effects on A375 human malignant melanoma compared to HGF‐1 human gingival fibroblasts and MRC‐5 human lung cell lines. As cytotoxic activity of these compounds against melanoma cells was observed, compounds were found to be significantly more potent than the FDA‐approved drugs dacarbazine, temozolomide, and lenalidomide (Karakaya et al, ). Also, compound 1 was synthesized and patented with anti‐tyrosinase, anti‐aging, anti‐oxidant, anti‐mycobacterium, and anti‐dermatophytic activities (Aytemir et al, ).…”

“…In synthesis process, chlorokojic acid (2‐chloromethyl‐5‐hydroxy‐4 H ‐pyran‐4‐one, CKA) was obtained from commercially available kojic acid in a one‐step reaction. 2‐Substituted‐6‐(hydroxymethyl/chloromethyl)‐3‐hydroxy‐4 H ‐pyran‐4‐one (compounds 1 , 2 , 5 and 8 ) derivatives were synthesized with the reaction of appropriate substituted benzylpiperazine derivatives with KA or CKA and formaline at room temperature (Aytemir et al, ; Aytemir, Ozcelik, & Karakaya, ; Karakaya, Aytemir, Ozcelik, & Calis, ; Karakaya et al, ). Finally, Mannich bases of CKA reacted with piperidine or pyrrolidine moieties in the dimethylformamide (DMF) in presence of K 2 CO 3 to synthesize compounds with the structure of 2‐substituted‐3‐hydroxy‐6‐(piperidinylmethyl/pyrrolidinylmethyl)‐4 H ‐pyran‐4‐one (compounds 3 , 4 , 6 , 7 , 9 , and 10) (Karakaya et al, , ).…”

Kojic acid derivatives as potential anticancer agents: Synthesis and cytotoxic evaluation on A375 human malignant melanoma cells

“…To date, a large number of Mannich bases of KA were synthesized by our research group and their various biological actions including anticonvulsant, antibacterial, antifungal, anti-mycobacterial, anti-aging, antioxidant, antityrosinase and antiviral activities with cytotoxicity were evaluated [11][12][13][14][15][16][17][18]. In our recent study, the synthesis of new KA derivatives and their inhibitory activities on melanogenesis were reported [19]. Some compounds were found to be significantly more potent than the FDA-approved drugs dacarbazine, temozolomide, and lenalidomide which were used as standards.…”