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

Abstract

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.

Metabolomic profiling of Medicago sativa-derived fungal endophytes and evaluation of their biological activities

“…39 The natural product kojic acid [9] produced by the fungus Aspergillus , Penicillium , and Acetobacter 40 exhibited a wide range of biological activities, including powerful tyrosine-inhibiting capabilities, antioxidant, and anticancer activities. 41,42 Kojic acid [9] could act as an immunomodulatory agent by promoting the differentiation of monocytes into macrophages. 43 Group IV (Fig.…”

Anticancer Activity of Mannich Bases: A Review of Recent Literature

“…Mannich bases 51 (R = Cl or H) of chlorkojic acid and allomaltol, along with bis-aminomethyl derivatives of 3-hydroxypyran-4-one 52 (Figure 7) were shown to be more cytotoxic than the substrates from which they derive against A375 human malignant melanoma, and they were also more potent (11 μM < IC 50 < 68 μM) than some of the currently approved drugs for the treatment of this type of cancer, with the exception of vemurafenib. [63] In a second study by the same authors, [64] the most cytotoxic compounds 51 (R = Cl, R 1 = 4-Cl; R = OH, R 1 = 3-Cl) against human malignant melanoma were, however, approximately sevenfold less potent (IC 50 ~80 μM) than the best kojic acid-based anticancer agents identified in the previous paper. In a collection of ten bisaminomethyl derivatives of 3-hydroxypyran-4-one, two compounds 52 (R 1 = 2-F-4-Br, NR 2 = piperidin-1-yl or pyrrolidin-1-yl) (Figure 7) had IC 50 values of approximately 35 μM against HepG2 hepatocellular carcinoma cells, and the use of the piperidine Mannich bases in investigating its mechanism of action showed that it triggered apoptosis by increasing the levels of intracellular ROS, induction of TP53 gene, and activation of caspase 3/7.…”

“…Mannich bases 51 (R=Cl or H) of chlorkojic acid and allomaltol, along with bis‐aminomethyl derivatives of 3‐hydroxypyran‐4‐one 52 (Figure 7) were shown to be more cytotoxic than the substrates from which they derive against A375 human malignant melanoma, and they were also more potent (11 μM < IC 50 <68 μM) than some of the currently approved drugs for the treatment of this type of cancer, with the exception of vemurafenib [63] . In a second study by the same authors, [64] the most cytotoxic compounds 51 (R=Cl, R 1 =4‐Cl; R=OH, R 1 =3‐Cl) against human malignant melanoma were, however, approximately sevenfold less potent (IC 50 ∼80…”

Pengujian Ekstrak Etanol Daun Manggu Leuweung (Garcinia celebica L.) terhadap Proliferasi Lini Sel CCL-171

“…Pada penelitian ini, digunakan kojic acid yang merupakan senyawa organik berupa asam organik polifungsional yang merupakan senyawa aktif antioksidan, sehingga mampu mencegah terjadinya stres oksidatif yang disebabkan karena ketidakseimbangan radikal bebas dan antioksidan di dalam tubuh. 24 Pada penelitian sebelumnya, telah ditemukan bahwa asam kojat memiliki efek non toksik pada monosit. Asam kojat juga dapat menginduksi perubahan morfologi pada monosit seperti meningkatkan ukuran sel dan meningkatkan diferensiasi monosit menjadi makrofag sehingga mampu bertindak sebagai agen imunomodulator.…”