Synthesis and selective in vitro anti-melanoma effect of enantiomeric ??-methyl- and ??-ethyl-4-S-cysteaminylphenol

Yukitake, Jun; Otake, Hiromi; Inoue, Shigeki; Wakamatsu, Kazumasa; Olivares, Concepción; Solano, Francisco; Hasegawa, Kiyokazu; Ito, Shosuke

doi:10.1097/00008390-200312000-00010

Cited by 6 publications

(6 citation statements)

References 25 publications

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“…Our data on increased GSH are in agreement with others', 1,9) who reported on the important role of GSH in the inhibition of melanogenesis through its ability to dampen the formation of melanosomes from premelanosomes.…”

Section: Fig 2 Effect Of 44ј-bp On Camp In Msh-untreated and -Treasupporting

confidence: 93%

“…Results are reported as pmol/7ϫ10 pothesis was that 44Ј-BP inhibits the melanin biosynthesis process through a reductive power shown by others. 1,9) In addition, we examined whether 44Ј-BP reduces cAMP content, thereby suppressing the activation of PKA and melanocyte-specific transcription factor (MITF), which led to the suppression of tyrosinase protein levels, and subsequently resulted in melanogenesis inhibitory activity.…”

Section: Fig 2 Effect Of 44ј-bp On Camp In Msh-untreated and -Treamentioning

confidence: 99%

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Inhibition of Melanogenic Activity by 4,4'-Dihydroxybiphenyl in Melanoma Cells

Kim²,

Lee

et al. 2006

Biological & Pharmaceutical Bulletin

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It has been reported that the melanogenic activity can be inhibited by antioxidants, like a-tocopherol and hydrocoumarins, 1) and that reduced glutathione (GSH), an important biological reductant, plays a role in the modulation of the melanogenic process. 2)Melanogenesis, which is catalyzed enzymatically by the key enzyme, tyrosinase, is also influenced by other non-enzymatic factors such as ultraviolet rays and a-melanocytestimulating hormone (a-MSH).3) In the case of a-MSH-induced melanogenesis, the enhancement of tyrosinase activity, tyrosinase mRNA, and intracellular cyclic AMP (cAMP) were observed. 4)The requirement of cAMP for melanogenesis is quite clear for pigmentation. cAMP also increases tyrosinase mRNA and promotes increased microphthalmia transcription factor (MITF) expression. MITF is a melanocyte-specific transcription factor crucial for melanocyte survival, development and differentiation through the activation of protein kinase A (PKA).5) PKA is a serine/threonine kinase that is an inactive tetramer consisting of two regulatory subunits and two catalytic subunits, and its activation occurs by the binding of cAMP to its regulatory subunits and then releasing its catalytic subunits from the regulatory subunits. 6)Recently, we reported that 4,4Ј-dihydroxybiphenyl (44Ј-BP) has a melanogenesis inhibitory effect through the inhibition of tyrosinase and reduction of melanin content.7) However, the underlying process by which tyrosinase activity and melanogenesis were inhibited by 44Ј-BP was not elucidated. In this current study, we attempted to investigate the effect of 44Ј-BP on major cellular regulators involved in melanogenesis in B16 melanoma cells (B16 cells). The analysis was carried out by quantifying amounts of tyrosinase and MITF proteins, cAMP levels, phosphorylated PKA, and GSH and oxidized glutathione (GSSG) levels. Cell Culture System B16 cells (from Korean Cell Line Bank) were cultured in DMEM with 10% fetal bovine serum (FBS; Gibco) and penicillin/streptomycin (100 IU/50 mg/ml) in a humidified atmosphere containing 5% CO 2 in air at 37°C. B16 cells were cultured in 24-well plates for each assay. MATERIALS AND METHODS MaterialsAll the experiments were determined in triplicate and repeated three times to ensure reproducibility.GSH and GSSG Assay Assays for GSH and GSSG were carried out by the method of Pandey and Katiyar. 8)Twenty-five percent of the meta-phosphoric acid-added cell pellets were centrifuged at 12000 rpm for 10 min, and the supernatant was taken for assay. For GSH, 1 mM EDTA-50 mM phosphate buffer was added to the supernatant followed by ophthaladehyde. After 20 min at room temperature, the fluorescence was measured at excitation wavelength of 360 nm and emission wavelength of 460 nm. GSSG was assayed after preincubated with N-ethylmaleimide for 20 min and 0.1 M NaOH was substituted for 1 mM EDTA-50 mM phosphate buffer.Quantitation of cAMP To measure intracellular cAMP levels, an enzyme immunoassay kit was used. In brief, B16 cells (7ϫ10 4 ) were lyzed in 0.1 M of HCl to inh...

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Section: Fig 2 Effect Of 44ј-bp On Camp In Msh-untreated and -Treasupporting

confidence: 93%

Section: Fig 2 Effect Of 44ј-bp On Camp In Msh-untreated and -Treamentioning

confidence: 99%

Inhibition of Melanogenic Activity by 4,4'-Dihydroxybiphenyl in Melanoma Cells

Kim²,

Lee

et al. 2006

Biological & Pharmaceutical Bulletin

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“…4-S-CAP and the enantiomers were taken up into B16-F1 cells at comparable rates, but showed varying rates of GSH depletion that were inversely correlated to the cytotoxicity. These results suggest that the use of enantiomers would increase the efficacy of tyrosinase-dependent cytotoxic phenols [27].…”

Section: Phenolic Aminesmentioning

confidence: 80%

“…Yukitake and coworkers examined and found most promising antimelanoma effects from 4-S-cysteaminylphenol (4-S-CAP), a phenolic amine [27]. For further improvement, they also synthesized the R-and S-enantiomers (99 % enantiomer excess) of α-methyl-4-S-cysteaminylphenol (α-Me-4-S-CAP) and α-ethyl-4-S-cysteaminylphenol (α-Et-4-S-CAP), whereas they found that enantiomers of α-Me-4-S-CAP and α-Et-4-S-CAP were better substrates for tyrosinase than the natural substrate, L-tyrosine [27]. They also studied them in vitro, which showed that all four enantiomers were highly cytotoxic to pigmented B16-F1 melanoma cells, the effect being 70-and 160-fold greater than that on nonpigmented B16-G4F melanoma cells and 3T3 fibroblasts, respectively.…”

Section: Phenolic Aminesmentioning

confidence: 99%

Molecular design of tyrosinase inhibitors: A critical review of promising novel inhibitors from synthetic origins

Khan

2007

Pure and Applied Chemistry

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The enzyme tyrosinase is known to be a multifunctional copper-containing enzyme from the oxidase superfamily, which is the key protein involved in the biosynthesis of the large biological pigment, melanin. The enzyme catalyzes two distinct reactions of melanin biosynthesis, the hydroxylation of a monophenol and the conversion of an o-diphenol to the corresponding o-quinone. Inhibitors of this protein have a huge impact on industry and economy. So a number of research groups around the world are engaged and are expending much effort in the discovery of these inhibitors. In this report, we review the importance and applications of the recently designed synthetic tyrosinase inhibitors from our and other leading laboratories of the world, which have been published in recent years. In our continuing search for tyrosinase inhibitors from natural resources to semi-and full synthetic approaches, until now we discovered and reported a large number of mild to potent inhibitors of several classes, such as phenolics, terpenes, steroids, chalcones, flavonoids, alkaloids, long-chain fatty acids, coumarins, sildenafil analogs, bipiperidines, biscoumarins, oxadiazole, tetraketones, etc. The structure-activity relationships (SARs) of different classes of synthetic tyrosinase inhibitors have also been discussed in this review.

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“…Tyrosinase can oxidize a variety of natural and synthetic phenols to produce highly reactive and cytotoxic o -quinones [ 7 , 8 ]. Thus, we designed synthetic molecules for the selective treatment of unresectable/metastatic melanoma based on the melanocyte- and melanoma-cell-specific metabolic process melanogenesis ( Table 1 ) [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ].…”

Section: Introduction: Overall View Of Melanogenesis Cascade To Devel...mentioning

confidence: 99%

Molecular Events in the Melanogenesis Cascade as Novel Melanoma-Targeted Small Molecules: Principle and Development

Wakamatsu

Ito

Tamura

et al. 2022

Cancers

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Malignant melanoma is one of the most malignant of all cancers. Melanoma occurs at the epidermo–dermal interface of the skin and mucosa, where small vessels and lymphatics are abundant. Consequently, from the onset of the disease, melanoma easily metastasizes to other organs throughout the body via lymphatic and blood circulation. At present, the most effective treatment method is surgical resection, and other attempted methods, such as chemotherapy, radiotherapy, immunotherapy, targeted therapy, and gene therapy, have not yet produced sufficient results. Since melanogenesis is a unique biochemical pathway that functions only in melanocytes and their neoplastic counterparts, melanoma cells, the development of drugs that target melanogenesis is a promising area of research. Melanin consists of small-molecule derivatives that are always synthesized by melanoma cells. Amelanosis reflects the macroscopic visibility of color changes (hypomelanosis). Under microscopy, melanin pigments and their precursors are present in amelanotic melanoma cells. Tumors can be easily targeted by small molecules that chemically mimic melanogenic substrates. In addition, small-molecule melanin metabolites are toxic to melanocytes and melanoma cells and can kill them. This review describes our development of chemo-thermo-immunotherapy based on the synthesis of melanogenesis-based small-molecule derivatives and conjugation to magnetite nanoparticles. We also introduce the other melanogenesis-related chemotherapy and thermal medicine approaches and discuss currently introduced targeted therapies with immune checkpoint inhibitors for unresectable/metastatic melanoma.

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Synthesis and selective in vitro anti-melanoma effect of enantiomeric ??-methyl- and ??-ethyl-4-S-cysteaminylphenol

Cited by 6 publications

References 25 publications

Inhibition of Melanogenic Activity by 4,4'-Dihydroxybiphenyl in Melanoma Cells

Inhibition of Melanogenic Activity by 4,4'-Dihydroxybiphenyl in Melanoma Cells

Molecular design of tyrosinase inhibitors: A critical review of promising novel inhibitors from synthetic origins

Molecular Events in the Melanogenesis Cascade as Novel Melanoma-Targeted Small Molecules: Principle and Development

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