Kojic acid derivatives as potential anticancer agents: Synthesis and cytotoxic evaluation on A375 human malignant melanoma cells
Kojic acid derivatives as potential anticancer agents: Synthesis and cytotoxic evaluation on A375 human malignant melanoma cells
Malignant melanoma is a serious type of skin cancer with high mortality rates, arising from melanocytic cells responsible for the pigmentation of the skin. Besides, the excessive accumulation of melanin pigment can lead to many other hyperpigmentation disorders. Kojic acid is used as a skin lightening agent of medicinal and cosmetic products used in hyperpigmentation and sunburn cases. In the present study, substituted halogen containing benzylpiperazine derivatives of kojic acid (compounds 1-9) were synthesized via Mannich reaction in mild conditions. Afterwards, the cyclic amine derivatives (compounds 10-26) were obtained as a result of nucleophilic substitutions. Cytotoxic effects of all the compounds on A375 human malignant melanoma cell lines were explored by sulphorhodamine B assay and efficacies has been compared to those of anticancer FDA-approved drugs dacarbazine, temozolomide, and lenalidomide, currently used in the treatment of malignant melanoma. Also, the most active two compounds were also tested on healthy cell lines (HGF-1 and MRC-5 cell lines). These compounds have shown highest activity (IC50: 71.27 for compound 9 and 73.74 µM for compound 1) than temozolomide (IC50: 95.6 µM) and lenalidomide (IC50: 143.1 µM) against A375 cells though giving less harm to non-cancerous cell lines. In conclusion, these compounds stand out as promising anticancer agents for further studies.
___
- Veselinovic JB, Veselinovic AM, Ilic-Tomic T, Davis R, O’Connor K, Pavic A, Nikodinovic-Runic J. Potent antimelanogenic activity and favorable toxicity profile of selected 4-phenyl hydroxycoumarins in the zebrafish model and the computational molecular modeling studies. Bioorg Med Chem. 2017; 25(24): 6286-6296. [CrossRef]
- McCourt C, Dolan O, Gormley G. Malignant Melanoma: A Pictorial Review. Ulster Med J. 2014; 83(2): 103-110.
- Eugeniu B, Andreea Z, Serban A, Rares B, Liliana R, Codrina BA. Dynamic Changes of Molecular Markers during Natural History in Metastatic Melanoma: Ethical Issues and Lessons to Learn. J Integr Oncol. 2016; 5(3): E1000176. [CrossRef]
- Hanaizi Z, van Zwieten-Boot B, Calvo G, Lopez AS, van Dartel M, Camarero J, Abadie E, Pignatti F. The European Medicines Agency review of ipilimumab (Yervoy) for the treatment of advanced (unresectable or metastatic) melanoma in adults who have received prior therapy: summary of the scientific assessment of the Committee for Medicinal Products for Human Use. Eur J Cancer. 2012; 48(2): 237-242. [CrossRef]
- da Rocha Dias S, Salmonson T, van Zwieten-Boot B, Jonsson B, Marchetti S, Schellens JH, Giuliani R, Pignatti F. The European Medicines Agency review of vemurafenib (Zelboraf) for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma: summary of the scientific assessment of the Committee for Medicinal Products for Human Use. Eur J Cancer. 2013; 49(7): 1654-1661. [CrossRef]
- Bommareddy PK, Patel A, Hossain S, Kaufman HL, Talimogene laherparepvec (T-VEC) and other oncolytic viruses for the treatment of melanoma. Am J Clin Dermatol. 2017; 18(1): 1-15. [CrossRef]
- Mann T, Gervat W, Batzer J, Eggers K, Scherner C, Wenck H, Stab F, Hearing VJ, Röhm K-H, Kolbe L. Inhibition of Human Tyrosinase Requires Molecular Motifs Distinctively Different from Mushroom Tyrosinase. J Invest Dermatol. 2018; 138(7): 1601-1608. [CrossRef]
- Parvez S, Kang M, Chung H-S, Bae H. Naturally Occurring Tyrosinase Inhibitors: Mechanism and Applications in Skin Health, Cosmetics and Agriculture Industries. Phytother Res. 2007; 21: 805-816. [CrossRef]
- Sharma KV, Davids LM. Depigmentation in melanomas increases the efficacy of hypericin-mediated photodynamicinduced cell death. Photodiagnosis Photodyn Ther. 2012; 9: 156-163. [CrossRef]
- Tugrak M, Gul H, Sakagami H. Synthesis and cytotoxicities of 2-[4-hydroxy-(3,5-bis-aminomethyl)-benzylidene]indan-1-ones. Lett Drug Des Discov. 2015; 12: 806-812. [CrossRef]
- Aytemir, M.D., Karakaya, G. Kojic acid derivatives. In: Medicinal Chemistry and Drug Design; Deniz Ekinci, Ed.; InTech; Rijeka, 2012; Chapter 1, pp. 1-26.
- Aytemir MD, Calis U. Anticonvulsant and neurotoxicity evaluation of some novel kojic acids and allomaltol derivatives. Arch Pharm. 2010; 343(3): 173-181. [CrossRef]
- Aytemir MD, Ozcelik B. A study of cytotoxicity of novel chlorokojic acid derivatives with their antimicrobial and antiviral activities. Eur J Med Chem. 2010; 45(9): 4089-4095. [CrossRef]
- Aytemir MD, Ozcelik B. Synthesis and biological activities of new Mannich bases of chlorokojic acid derivatives. Med Chem Res. 2011; 20(4): 443-452. [CrossRef]
- Karakaya G, Aytemir MD, Ozcelik B, Calis U. Design, synthesis and in vivo/in vitro screening of novel chlorokojic acid derivatives. J Enz Inh Med Chem. 2013; 28(3): 627-638. [CrossRef]
- Aytemir MD, Ozcelik B, Karakaya G. Evaluation of bioactivities of chlorokojic acid derivatives against dermatophytes couplet with cytotoxicity. Bioorg Med Chem Lett. 2013; 23(12): 3646-3649. [CrossRef]
- Aytemir MD, Özçelik B, Erdoğan İ. Orhan, Karakaya G, Şenol FS. Kojic acid-derived mannich bases with biological effect US 9,975,884 B2, May 22, 2018.
- Karakaya G, Türe A, Ercan A, Öncül S, Aytemir MD. Synthesis, Computational Molecular Docking Analysis and Effectiveness on Tyrosinase Inhibition of Kojic Acid Derivatives. Bioorg Chem. 2019; 88, 102950. [CrossRef]
- Karakaya G, Ercan A, Oncul S, Aytemir MD. Synthesis and cytotoxic evaluation of kojic acid derivatives with inhibitory activity on melanogenesis in human melanoma cells, Anticancer Agents Med Chem. 2018; 18: 2137-2148. [CrossRef]
- Ashok M, Holla BS, Poojary B. Convenient one pot synthesis and antimicrobial evaluation of some new Mannich bases carrying 4-methylthiobenzyl moiety. Eur J Med Chem. 2007; 42: 1095-1101. [CrossRef]
- Liu X, Xia W, Jiang Q, Yu P, Yue L. Chitosan oligosaccharide-N-chlorokojic acid mannich base polymer as a potential antibacterial material. Carbohydr Polym. 2018; 182: 225-234. [CrossRef]
- Ichimoto I, Ueda H, Tatsumi C, Fujii K, Sekido F, Nonomura S. Studies on Kojic Acid and its Related γ-Pyrone Compounds: Part VII. The Alkylation of kojic acid and pyromeconic acid through their Mannich base (Synthesis of Maltol-(1)) Part VIII. Synthesis of comenic acid from kojic acid (Synthesis of Maltol (2)). Agric Biol Chem. 1965; 29(2): 94-103. [CrossRef]
- Kim G, McKee AE, Ning YM, Hazarika M, Theoret M, Johnson JR, Xu QC, Tang S, Sridhara R, Jiang X, He K, Roscoe D, McGuinn WD, Helms WS, Russel AM, Miksinski SP, Zirkelbach JF, Earp J, Liu Q, Ibrahim A, Justice R, Pazdur R. FDA approval summary: vemurafenib for treatment of unresectable or metastatic melanoma with the BRAFV600E mutation. Clin Cancer Res. 2014; 20(19): 4994-5000. [CrossRef]
- Chapman PB, Robert C, Larkin J, Haanen JB, Ribas A, Hogg D, Hamid O, Ascierto PA, Testori A, Lorigan PC, Dummer R, Sosman JA, Flaherty KT, Chang I, Coleman S, Caro I, Hauschild A, McArthur GA. Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study. Ann Oncol. 2017; 28(10): 2581-2587. [CrossRef]
- Vichai V, Kirtikara K, Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc 2006; 1: 1112-1116. [CrossRef]