미생물과 동물, 식물에 넓게 분포해 있는 tyrosinase는 구리를 포함하고 있는 효소이다. Tyrosinase는 L-tyrosine의 수산화 반응을 촉매하여 L-dopa로의 전환 및 L-dopa를 L-dopaquinone으로 산화시켜 멜라닌 합성을 조절한다. 피부색 결정에 관여하는 멜라닌 색소가 피부에 과량 축적되면 피부미용에 나쁜 영향을 미칠 뿐만 아니라, ...
미생물과 동물, 식물에 넓게 분포해 있는 tyrosinase는 구리를 포함하고 있는 효소이다. Tyrosinase는 L-tyrosine의 수산화 반응을 촉매하여 L-dopa로의 전환 및 L-dopa를 L-dopaquinone으로 산화시켜 멜라닌 합성을 조절한다. 피부색 결정에 관여하는 멜라닌 색소가 피부에 과량 축적되면 피부미용에 나쁜 영향을 미칠 뿐만 아니라, 피부암을 초래하기도 한다. 따라서 tyrosinase의 억제는 과색소침착을 치료하는데 중요한 역할을 할 수 있다. 이러한 점에 기초하여 tyrosinase의 천연 기질인 L-tyrosine과 L-dopa의 화학구조를 바탕으로 -phenyl-,-unsaturated carbonyl 형태의 화합물들을 설계 및 합성하고 tyrosinase 저해제로서의 효과를 평가하였다. benzylidene-2-thioxo-thiazolidinone 과 2-phenylbenzothiazole 유도체들이 강력한 tyrosinase 저해를 한다는 본 연구실의 선행 연구로부터 이들 화합물의 지용성 증가를 통해 tyrosinase 저해 효력을 높이기 위해, benzylidene-2-thioxo-thiazolidinone 구조에 phenyl 그룹이 도입된 유도체들을 합성하였으며, 2-phenylbenzothiazole의 6번 위치에 전자를 주는 methoxy 그룹으로 치환된 benzothiazole 유도체를 합성하여 tyrosinase 저해활성을 검색하였다. 또한 tyrosinase의 구리이온과 효과적인 킬레이터로 작용할 것으로 예상되는 2-mercaptoacetamide, 2-mercaptoethanethioamide, hydroxamic acid및 thiohydroxamic acid의 기능기를 가지는 유도체를 합성하고 tyrosinase 저해활성을 측정했다. 4-hydroxy(3a, 4a, 5a), 3-hydroxy-4-methoxy(3d, 4d, 5d, 6c), 3-bromo-4-hydroxy(4c, 5c), 3,4,5-trimethoxy(7j), 3-ethoxy-4-hydroxy(8g), 2,4-dihydroxy(8m), 2-mercaptoethanethioamide(10b) 및 hydroxamic acid(11b) 화합물들이 kojic acid 보다 더 우수한 tyrosinase 억제 효과를 나타냈다. 이들 화합물 중 3a와 3d의 IC50값을 측정한 결과, 각각 13.60 및 10.97 µM으로 kojic acid(38.33 M) 보다 약 3배 더 우수한 결과를 보여주었다. 이러한 결과는 화합물 3a 및 3d가 미백제로서 그리고 과색소침착 질환의 치료제로서 유망한 후보물질이 될 수 있음을 시사한다.
미생물과 동물, 식물에 넓게 분포해 있는 tyrosinase는 구리를 포함하고 있는 효소이다. Tyrosinase는 L-tyrosine의 수산화 반응을 촉매하여 L-dopa로의 전환 및 L-dopa를 L-dopaquinone으로 산화시켜 멜라닌 합성을 조절한다. 피부색 결정에 관여하는 멜라닌 색소가 피부에 과량 축적되면 피부미용에 나쁜 영향을 미칠 뿐만 아니라, 피부암을 초래하기도 한다. 따라서 tyrosinase의 억제는 과색소침착을 치료하는데 중요한 역할을 할 수 있다. 이러한 점에 기초하여 tyrosinase의 천연 기질인 L-tyrosine과 L-dopa의 화학구조를 바탕으로 -phenyl-,-unsaturated carbonyl 형태의 화합물들을 설계 및 합성하고 tyrosinase 저해제로서의 효과를 평가하였다. benzylidene-2-thioxo-thiazolidinone 과 2-phenylbenzothiazole 유도체들이 강력한 tyrosinase 저해를 한다는 본 연구실의 선행 연구로부터 이들 화합물의 지용성 증가를 통해 tyrosinase 저해 효력을 높이기 위해, benzylidene-2-thioxo-thiazolidinone 구조에 phenyl 그룹이 도입된 유도체들을 합성하였으며, 2-phenylbenzothiazole의 6번 위치에 전자를 주는 methoxy 그룹으로 치환된 benzothiazole 유도체를 합성하여 tyrosinase 저해활성을 검색하였다. 또한 tyrosinase의 구리이온과 효과적인 킬레이터로 작용할 것으로 예상되는 2-mercaptoacetamide, 2-mercaptoethanethioamide, hydroxamic acid및 thiohydroxamic acid의 기능기를 가지는 유도체를 합성하고 tyrosinase 저해활성을 측정했다. 4-hydroxy(3a, 4a, 5a), 3-hydroxy-4-methoxy(3d, 4d, 5d, 6c), 3-bromo-4-hydroxy(4c, 5c), 3,4,5-trimethoxy(7j), 3-ethoxy-4-hydroxy(8g), 2,4-dihydroxy(8m), 2-mercaptoethanethioamide(10b) 및 hydroxamic acid(11b) 화합물들이 kojic acid 보다 더 우수한 tyrosinase 억제 효과를 나타냈다. 이들 화합물 중 3a와 3d의 IC50값을 측정한 결과, 각각 13.60 및 10.97 µM으로 kojic acid(38.33 M) 보다 약 3배 더 우수한 결과를 보여주었다. 이러한 결과는 화합물 3a 및 3d가 미백제로서 그리고 과색소침착 질환의 치료제로서 유망한 후보물질이 될 수 있음을 시사한다.
Tyrosinase in microorganisms, animals, and plants is an enzyme that includes two copper (II) atoms. Tyrosinase regulates melanin biosynthesis by catalyzing hydroxylation reaction of L-tyrosine to L-dopa, and oxidation reaction of L-dopa to L-dopaquinone. When melanin that affects skin color accumula...
Tyrosinase in microorganisms, animals, and plants is an enzyme that includes two copper (II) atoms. Tyrosinase regulates melanin biosynthesis by catalyzing hydroxylation reaction of L-tyrosine to L-dopa, and oxidation reaction of L-dopa to L-dopaquinone. When melanin that affects skin color accumulates in the skin, it would have a negative impact on skin leading to skin cancer. Therefore, tyrosinase inhibitors play an important role in treating hyperpigmentation. -Phenyl-,-unsaturated carbonyl compounds were designed and synthesized on the basis of chemical structures of L-tyrosine and L-dopa that are the natural substrates of tyrosinase to evaluate their inhibitory effect on tyrosinase. Previous studies by our laboratory showed that benzylidene-2-thioxo-thiazolidinone and 2-phenylbenzothiazole analogues had strong tyrosinase inhibitory activity. In order to increase their efficacy through their lipophilicity enhancement, a phenyl group was introduced into the benzylidene-2-thioxo-thiazolidinone structure. Benzothiazole derivatives bearing a 6-methoxy substituent were synthesized to investigate the effect of an electron-donating group. In addition, to prepare compounds capable of acting as an effective chelator with tyrosinase copper ions, derivatives with a functional group such as mercaptoacetamide, mercaptoethanethioamide, hydroxamic acid and thiohydroxamic acid were designed, synthesized and evaluated for the inhibition effect on mushroom tyrosinase. 4-Hydroxy (3a, 4a and 5a), 3-hydroxy-4-methoxy (3d, 4d, 5d 6c, and 8e), 3-bromo-4-hydroxy (4c and 5c), 3,4,5-trimethoxy (7j), 3-ethoxy-4-hydroxy (8g), 2,4-dihydroxy (8m), 2-mercaptoethanethioamide (10b) and hydroxamic acid (11b) derivatives had more potent inhibitory effect on mushroom tyrosinase than kojic acid, a well-known tyrosinase inhibitor. Among the derivatives, IC50 values of compounds 3a and 3d showing significant mushroom tyrosinase inhibition were measured. IC50 values of compounds 3a and 3d are 13.60 µM and 10.97 µM, respectively, indicating that both compounds are about 3-fold more potent than kojic acid (IC50 = 38.33 µM) on mushroom tyrosinase inhibition effect. This result suggests that (E)-3-(4-hydroxyphenyl)-1-(thiophen-2-yl)prop-2-en-1-one (3a) and (E)-3-(3-hydroxy-4-methoxyphenyl)-1-(thiophen-2-yl)prop-2-en-1-one (3d) should be promising candidates for the development of a whitening agent and a medicine for treating hyperpigmentation.
Tyrosinase in microorganisms, animals, and plants is an enzyme that includes two copper (II) atoms. Tyrosinase regulates melanin biosynthesis by catalyzing hydroxylation reaction of L-tyrosine to L-dopa, and oxidation reaction of L-dopa to L-dopaquinone. When melanin that affects skin color accumulates in the skin, it would have a negative impact on skin leading to skin cancer. Therefore, tyrosinase inhibitors play an important role in treating hyperpigmentation. -Phenyl-,-unsaturated carbonyl compounds were designed and synthesized on the basis of chemical structures of L-tyrosine and L-dopa that are the natural substrates of tyrosinase to evaluate their inhibitory effect on tyrosinase. Previous studies by our laboratory showed that benzylidene-2-thioxo-thiazolidinone and 2-phenylbenzothiazole analogues had strong tyrosinase inhibitory activity. In order to increase their efficacy through their lipophilicity enhancement, a phenyl group was introduced into the benzylidene-2-thioxo-thiazolidinone structure. Benzothiazole derivatives bearing a 6-methoxy substituent were synthesized to investigate the effect of an electron-donating group. In addition, to prepare compounds capable of acting as an effective chelator with tyrosinase copper ions, derivatives with a functional group such as mercaptoacetamide, mercaptoethanethioamide, hydroxamic acid and thiohydroxamic acid were designed, synthesized and evaluated for the inhibition effect on mushroom tyrosinase. 4-Hydroxy (3a, 4a and 5a), 3-hydroxy-4-methoxy (3d, 4d, 5d 6c, and 8e), 3-bromo-4-hydroxy (4c and 5c), 3,4,5-trimethoxy (7j), 3-ethoxy-4-hydroxy (8g), 2,4-dihydroxy (8m), 2-mercaptoethanethioamide (10b) and hydroxamic acid (11b) derivatives had more potent inhibitory effect on mushroom tyrosinase than kojic acid, a well-known tyrosinase inhibitor. Among the derivatives, IC50 values of compounds 3a and 3d showing significant mushroom tyrosinase inhibition were measured. IC50 values of compounds 3a and 3d are 13.60 µM and 10.97 µM, respectively, indicating that both compounds are about 3-fold more potent than kojic acid (IC50 = 38.33 µM) on mushroom tyrosinase inhibition effect. This result suggests that (E)-3-(4-hydroxyphenyl)-1-(thiophen-2-yl)prop-2-en-1-one (3a) and (E)-3-(3-hydroxy-4-methoxyphenyl)-1-(thiophen-2-yl)prop-2-en-1-one (3d) should be promising candidates for the development of a whitening agent and a medicine for treating hyperpigmentation.
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