Thiourea derivatives

Raws li cov kev tshawb fawb cuam tshuam,cistancheyog ib hom tshuaj ntsuab uas hu ua "cov tshuaj ntsuab miracle uas ua rau lub neej ntev". Nws lub ntsiab tivthaiv yogcistanoside, uas muaj ntau yam teebmeem xws li antioxidant, anti-inflammatory, thiab kev tiv thaiv kev ua haujlwm nce qib. Lub mechanism ntawm cistanche thiabtawv nqaijntxuav hniav dawblus dag hauvantioxidantcov nyhuv cistancheglycosides. Melanin nyob rau hauv tib neeg daim tawv nqaij yog tsim los ntawm oxidation ntawm tyrosine catalyzed los ntawm tyrosinase, thiab cov tshuaj tiv thaiv oxidation yuav tsum muaj kev koom tes ntawm oxygen, yog li cov pa oxygen dawb radicals nyob rau hauv lub cev ua ib qho tseem ceeb cuam tshuam rau melanin ntau lawm.Cistanchemuaj cistanoside, uas yog ib qho antioxidant thiab tuaj yeem txo qhov tsim ntawm cov dawb radicals hauv lub cev, yog li inhibiting melanin ntau lawm.

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Phenylthiourea (PTU) yog ib qho ntawm cov paub zoo tshaj plaws tyrosinase inhibitors kawm hauv cov ntaub ntawv 89–91. Cov sulfur atom ntawm PTU khi rau ob qho tib si tooj liab ions ntawm qhov chaw nquag ntawm tyrosinase thiab thaiv cov enzyme kev ua haujlwm. Professor Jung et al. Tsis ntev los no tshawb nrhiav SAR ntawm PTU derivatives ntawm nceb tyrosinase92,93. Txawm hais tias cov teebmeem ntawm PTU derivatives feem ntau raug soj ntsuam rau lawv cov melanogenesis inhibition hauv B16 melanoma hlwb, tom qab ntawd nws tau lees paub tias nws yog vim inhibition ntawm tyrosinase kev ua. Cov kev tshawb fawb SAR tau qhia txog cov txheej txheem tseem ceeb rau ob qho tib si melanogenesis thiab tyrosinase inhibition (Daim duab 9(a)): (i) kev sib txuas ncaj qha ntawm p-planar qauv rau thiourea (24a-24b), (ii) hydrophobic hloov ntawm para- los yog meta-txoj hauj lwm ntawm lub nplhaib phenyl raug lees txais (24c–24d), hloov pauv ntawm ortho-txoj hauj lwm tsis tau zam (24e), qhia tias C2- hloov phenyl tuaj yeem cuam tshuam txoj kev tsim ntawm thiourea nrog tooj liab ions ntawm lub active site ntawm tyrosinase. Ntxiv mus, (iii) pub dawb 3-amino hydrogens yog ib qho tseem ceeb rau tyrosinase inhibition tab sis tsis yog rau melanogenesis inhibition ntawm B16 hlwb, 1,3-disubstituted derivatives pom muaj zog dua nyob rau hauv melanogenesis inhibition (24f). Cov kev tshawb pom no tau pom tias 1,3-disubstituted derivatives ua los ntawm txoj kev sib txawv ntawm tyrosinase catalytic kev ua si los tiv thaiv melanogenesis. Molecular docking tsom xam ntawm 1-phenylthiourea thiab 1,3,-diphenyl thiourea qhia tias kev sib txuas ncaj qha ntawm planar phenyl mus rau thiourea unit thiab dawb 3-NH2 yog qhov yuav tsum tau ua ua ntej rau kev ua tyrosinase (Daim duab 10).

Ntawm qhov tod tes, Crinton thiab al tau tshaj tawm cov xov xwm ntawm N-hydroxy-N0 -phenyl urea derivatives, hloov cov sulfur nrog oxygen thiab 3-NH2 nrog N-hydroxylamine hauv PTU91. Cov txiaj ntsig tau pom tias cov txiaj ntsig tau tshaj tawm muaj zog dua, tshwj xeeb tshaj yog, N-hydroxy-N0 -phenyl urea (25a) tau pom 6 npaug ntau dua li PTU. Hauv qhov sib piv, N-hydroxy-N0 -phenylthiourea (25b) derivatives qhia tsis muaj kev cuam tshuam, qhia tias lub peev xwm chelating ntawm N-hydroxyurea yog qhov tseem ceeb rau tyrosinase inhibition (Daim duab 9(a)).

Sib nrug los ntawm cov khoom siv hluavtaws lossis ntuj tsim, kev tshuaj ntsuam xyuas yog lwm txoj hauv kev los nrhiav cov inhibitors tshiab. Feem ntau kev tshuaj xyuas cov tshuaj uas tau txais kev pom zoo hauv tsev kho mob tau nce ntxiv rau ntau lub hom phiaj lom neeg. Cov ntaub ntawv cuam tshuam nrog cov tshuaj uas twb muaj lawm yuav txo lub sijhawm thiab tus nqi cuam tshuam nrog cov cai kev txawj ntse los tsim cov tshuaj tshiab. Txoj kev no muaj ntau yam zoo; suav nrog kev muaj, tus nqi qis, thiab kev nyab xeeb / kev zam. Phenylthiourea tau ntev tau paub tias yog tyrosinase inhibitor89–91,94. Cov tshuaj lom neeg zoo sib xws tau ua los ntawm ligand-based virtual lossis HTS kev tshuaj ntsuam xyuas ethionamide (26a) thiab nws cov analogs (26c–26e), suav nrog prothionamide (26b), raws li tyrosinase inhibitors95 (Daim duab 9(a)). Ethionamide yog ib qho tshuaj tiv thaiv kab mob thib ob uas pom zoo siv rau kev kho mob ntawm ntau cov tshuaj tiv thaiv kab mob. Nyob rau hauv sib piv, isoniazid, ib tug qauv analogue, thiab thawj-kab tshuaj antituberculosis yog ib tug tsis zoo inhibitor ntawm tyrosinase. Hauv B16 hlwb, inhibitors pyridine-2-carbothioamide thiab thiobenzamide txo cov ntsiab lus melanin los ntawm 44 feem pua ​​thiab 37 feem pua. Tom qab kev txheeb xyuas cov qauv dav dav, SAR cov ntaub ntawv qhia tias carbothioamide yog lub hauv paus moiety rau kev txhim kho cov tshiab thiab muaj zog tyrosinase inhibitors.

Hauv kev tshawb fawb tsis ntev los no, cov kws tshawb fawb tau khaws cov tshuaj thiourea-derived hauv kev siv tshuaj kho mob thiab tshawb xyuas lawv cov txiaj ntsig ntawm tyrosinase cov dej num los ntawm kev siv enzyme- thiab cell-based assays96. Nws tau pom tias cov tshuaj tiv thaiv kab mob methimazole 27a, 97 carbimazole 27b, 97 thiouracils 27c, 97 methylthiouracil 27d97, thiab propylthiouracil 27e97 inhibited nceb tyrosinase (Daim duab 9(b)). Tsis tas li ntawd, cov kev tshawb fawb kinetic tau muab cov tshuaj thiourea uas muaj cov tshuaj uas tsis muaj kev sib tw. Cov kev tshawb fawb SAR tau piav qhia tias thiourea nws tus kheej inhibits tyrosinase enzyme kev ua haujlwm nyob rau hauv ib qho concentration-dependent yam. Qhov no qhia tau hais tias inhibitory kev ua ntawm thiourea analogs yuav tsum yog los ntawm leej faj thiab nitrogen atoms.

Hauv lwm txoj kev tshawb fawb, ib chav kawm tshiab N-aryl-N0 - hloov phenylthiourea derivatives raug soj ntsuam ntawm diphenolase kev ua ntawm nceb tyrosinase98. Cov txiaj ntsig tau pom ob peb 4,5,6,7-tetrahydro- 2-[[(phenylamino)thioxomethyl]amino]-benzo[b]thiophene-3-carboxylic acid derivatives (28a–28d, ( Daim duab 9(b))) tau nthuav tawm qhov muaj zog inhibitory ntawm diphenolase kev ua ntawm tyrosinase. Thaum lub scaffold ntawm 4,5,6,{17}}tetrahydrobenzo[b]thiophene-3-carboxylic acid raug hloov nrog 2–(1,3,4-thiadiazol-2-yl) thio acetic acid, inhibitory kev ua ntawm cov tebchaw (xws li 29a–29d, Daim duab 9(b)) 98 tiv thaiv tyrosinase tau txhim kho. Tshwj xeeb tshaj yog, 29d (IC50=6.13 lM) pom muaj zog inhibitory kev ua haujlwm ntau dua li kojic acid (IC50=33.3 lM).

Txij li thaum xyoo 1885, saccharin, 1, 2-benzisothiazole-3-ib -1, 1- dioxide yog ib qho kev paub zoo heterocyclic compound thiab siv los ua cov khoom qab zib hauv daim ntawv ntawm nws cov ntsev ntsev. . Tsis tas li ntawd, nws tau tshaj tawm rau ntau lub hom phiaj lom neeg thiab yog li tuaj yeem raug saib raws li qhov tsim nyog scaffold. Tsis ntev los no, ib qho tshiab ntawm 6-(phenylurenyl/thionyl) conjugated saccharin derivatives raug soj ntsuam rau inhibitory cuam tshuam ntawm diphenolase kev ua ntawm txiv tsawb tyrosinase enzyme99. Cov txiaj ntsig tau pom tias tag nrho cov tshuaj tiv thaiv kev ua haujlwm tyrosinase. Ntawm lawv, 6–({10}}chlorophenylurenyl) saccharin 30a (Ki= 5.85 lM) thiab 6–(3-iodophenylthiourenyl) saccharin 30b (Ki{17}}.95 lM) tau pom tias yog cov tshuaj nquag tshaj plaws. Cov kev tshawb fawb SAR tau pom tias 6-(phenylthiourenyl) saccharin derivatives pom muaj zog inhibitory ntau dua li 6-(phenylurenyl) saccharin derivatives. Ib pawg electron rho tawm ntawm 3- txoj hauj lwm ntawm phenylurenyl/thiourenyl-ring tau nce hauv kev ua ub no, tshwj xeeb tshaj yog, cov halogen series tau pom ntau dua inhibitory kev ua ub no.

Thiosemicarbazone-type inhibitors

Thiosemicarbazones nyob hauv ib qho ntawm cov chav kawm loj ntawm tyrosinase inhibitors vim lawv cov qauv txheej txheem classical thiab muaj peev xwm chelate tooj liab ions ntawm qhov chaw nquag ntawm tyrosinase enzyme. Tsis ntev los no, ntau tus thiosemicarbazones los ntawm ntau pawg tshawb fawb tau tshaj tawm txog 99-101 ua cov tshuaj muaj zog tyrosinase inhibitors.

Cov kev tshawb fawb SAR tau qhia tias thiosemicarbazide scaffold yog ib qho tseem ceeb rau kev txiav txim siab tyrosinase inhibitory kev ua haujlwm vim tias nws muaj peev xwm ua tau zoo rau ob qho tib si tooj liab ions ntawm qhov chaw nquag ntawm tyrosinase. Txhawm rau txhim kho cov haujlwm, cov koob ntawm 4/3-aminoacetophenones thiab muab tau los ntawm thiosemicarbazones tau tshaj tawm rau lawv cov haujlwm inhibitory ntawm nceb tyrosinase102. Cov txiaj ntsig tau los ntawm kev soj ntsuam lom neeg, cov tshuaj acylamino (31a–31g, Daim duab 11) pom muaj zog tyrosinase inhibitors ntau dua li kojic acid (IC50=28.5 lM), thiab qhov sib piv, cov aminophenol (31 h thiab 31i) tau pom. ua kom cov haujlwm ntawm tyrosinase. Compound 31d tau pom tias yog cov tshuaj nquag tshaj plaws nrog IC50 tus nqi ntawm 0.291 lM. Cov kev tshawb fawb nrog SAR tsom xam kuj tau qhia tias pawg thiosemicarbazide tau ua lub luag haujlwm tseem ceeb hauv tyrosinase inhibition, acylamino moieties tseem ceeb rau kev txhim kho tyrosinase inhibitory kev ua thiab acylamide hloov pauv ntawm 4- txoj hauj lwm ntawm lub nplhaib phenyl nce tyrosinase inhibitory potency. Ntxiv mus, qhov inhibition mechanism thiab kinetics txoj kev tshawb fawb qhia tau hais tias compound 31a yog reversible thiab ib tug noncompetitive inhibitor.

Hauv kev txuas ntxiv mus tshawb nrhiav cov tshuaj muaj zog ua cov tshuaj tiv thaiv tyrosinase ua tau zoo, thiab nkag siab txog SARs ntawm thiosemicarbazone compounds, series ntawm cov tshiab {{0}}alkoxy- thiab 4-acyloxy-phenyl ethylene thiosemicarbazone analogs (32a -32i, Daim duab 11) tau tsim thiab tshuaj xyuas rau tyrosinase inhibitory kev ua 103. Cov txiaj ntsig tau pom tias feem ntau ntawm cov inhibitors tau nthuav tawm qhov muaj txiaj ntsig zoo tshaj plaws hauv inhibiting tyrosinase nrog tus nqi IC50 qis dua 1.0 lM. Hauv particular, compound 32d tau nthuav tawm qhov zoo tshaj plaws tyrosinase inhibitory potency piv rau lwm cov analogs ntawm cov koob no. Cov kev tshawb fawb SAR tau qhia tias thiosemicarbazone moiety ua lub luag haujlwm tseem ceeb hauv kev txiav txim siab tyrosinase inhibitory kev ua. Qhov ntev ntawm methylene txuas ntawm lub nplhaib phenyl thiab thiosemicarbazone moiety (32f-g) tsis cuam tshuam rau tyrosinase inhibitory potency. Kev taw qhia ntawm thiocarbonohydrazide moiety (32 h-32i) tsis zoo rau kev ua haujlwm tyrosinase inhibitory.

Peptide yam inhibitors

Txhawm rau nrhiav pom cov tyrosinase inhibitors tshiab, tsis ntev los no tau txais kev saib xyuas rau kev siv peptide sequences rau tyrosinase inhibition. Ob peb tyrosinase inhibitory peptides xws li dipeptides104, cyclic peptides105, luv-sequence oligopeptides106, thiab kojic acid tripeptide compounds107, tau raug tshawb xyuas. Tshwj xeeb, oligopeptides tau ua pov thawj tias muaj txiaj ntsig zoo tyrosinase inhibitors. Ob oligopeptides P3, ib qho octapeptide (Arg-Ala-Asp-ser-Arg-Ala-Asp-Cys), thiab decapeptide P4 (Tyr-Arg-ser-Arg-Lys-Tyr-Ser-Ser-Trp-Tyr) tau qhia. Kev cuam tshuam loj heev ntawm cov nceb thiab tib neeg tyrosinase nrog IC50 tus nqi ntawm 123 thiab 40 lM, piv nrog hydroquinone. Cov oligopeptides no tsis pom muaj kev cuam tshuam rau melanocyte cytotoxicity108. Tom qab ua tiav kev tsim cov tshuaj pleev ib ce thiab cov txiaj ntsig zoo hauv kev kho mob, ib qho decapeptide P4 tseem hu ua decapeptide-12 tau raug coj mus muag ua cov khoom tseem ceeb hauv cov khoom siv tawv nqaij109.

Hauv kev tshawb fawb tsis ntev los no, Hsiao et al. pom tias dipeptide-zoo li compound (A5) thiab tripeptides RCY thiab CRY zoo inhibit qhov kev ua haujlwm tyrosinase109. Tshwj xeeb tshaj yog, ib qho tshiab tripeptide CRY tau pom qhov muaj zog tshaj plaws inhibitory tiv thaiv nceb tyrosinase (IC50=6.16 lM). Cov tripeptide no muaj zog dua li cov paub oligopeptides thiab piv nrog kojic acid-tripeptides. CRY thiab RCY tau siv thiol pab pawg ntawm cysteine ​​residue los koom tes nrog Cu ions ntawm qhov chaw nquag ntawm tyrosinase, yog li qhia txog kev ua haujlwm tyrosinase qis. Hauv lwm txoj kev tshawb fawb, cov cysteine-muaj dipeptides tau tshaj tawm tias inhibit qhov kev ua haujlwm tyrosinase hauv ib qho txiaj ntsig zoo 110. Cov kws sau ntawv tau hais tias cov cysteine-muaj dipeptides tuaj yeem cuam tshuam ncaj qha rau qhov chaw nquag ntawm tyrosinase thiab yog li ua rau muaj zog inhibition. Tshwj xeeb, N-terminal cysteine-muaj dipeptides ua tau zoo tshaj qhov C-terminal thiab cov cysteine-muaj dipeptides, CE, CS, CY, thiab CW qhia txog kev sib piv bioactivities thiab tyrosine-muaj dipeptides yog substrate-zoo li inhibitors. Tsis tas li ntawd, cov dipeptides no tsis qhia cytotoxicity hauv melanocytes, thiab CA thiab PD attenuated 5.6 thiab 16.5 feem pua ​​​​melanin cov ntsiab lus, feem, ntawm 100 lM (Table 1).

Li et al. qhia txog cov txheej txheem ntawm hydroxypyridinone-L-phenylalanine conjugates (33a thiab 33b) pib los ntawm kojic acid (Daim duab 12) 111 rau lawv cov haujlwm inhibitory ntawm tyrosinase. Kev ntsuam xyuas tawm tsam tyrosinase kev ua haujlwm tau qhia tias ib qho ntawm cov khoom sib txuas ((S)-(5-(benzyloxy)-1-octyl-4-oxo{{10}},{{11 }} dihydropyridine-2-yl)methyl 2-amino-3- phenylpropionate, (33b) pom IC50 qhov tseem ceeb 12.6 thiab 4.0 lM rau mycophenolate thiab diphenolase kev ua ub no, ntsig txog. Ntxiv mus, cov conjugates no tau sib xyaw inhibitors, qhia tias lawv tuaj yeem khi rau ob qho tib si dawb enzyme thiab cov enzyme-substrate complexes.

Hauv lwm txoj kev tshawb fawb, hydroxypyridinone-L-amino acid conjugates tau tsim thiab tshuaj xyuas rau lawv cov haujlwm inhibitory ntawm nceb tyrosinase112. Ntawm cov tshuaj tshawb nrhiav, tsuas yog ob lub tebchaw nthuav tawm ob qho tib si mycophenolate (34, IC50=1.95 lM; 35, IC50=2.79 lM) thiab diphenolase inhibitory (34, IC{10}}.97 lM; 35, IC50=26.20 lM) kev ua ntawm tyrosinase (Daim duab 12). Ntxiv mus, cov tebchaw 34 thiab 35 tau txheeb xyuas kom rov qab tau thiab sib xyaw hom inhibitors.

Lwm yam nceb tyrosinase inhibitors

Tsis ntev los no, cov extracts thiab cais cov tebchaw los ntawm tej yam ntuj tso tau attracted ntau xim raws li tyrosinase inhibitors thiab tau txais raws li nrov ntawm daim tawv nqaij whitening agents113-123. Txhawm rau nrhiav cov tshuaj dawb huv thiab ua tau zoo, Chen li al., tau tshuaj xyuas ntau yam khoom ntuj tsim los ntawm cov nroj tsuag tshuaj ntsuab thiab cov tshuaj sib cais 36 thiab 37 los ntawm rhizome ntawm Gastrodia elata, xws li nceb tyrosinase inhibitors124. Cov kev tshawb fawb SAR tom qab tau txheeb xyuas cov analogs 38–40 (Daim duab 13). Bis (4-hydroxy benzyl) sulfide 36 tau pom zoo inhibitory potency tiv thaiv tyrosinase nrog IC50 tus nqi ntawm 0.5 lM thiab Ki tus nqi ntawm 58 nM. Lub compound 37 txuas los ntawm kev sib txuas ntawm ether qhia tau hais tias qhov 713-fold txo qis hauv qhov muaj peev xwm inhibitory (IC50=378.11 lM) qhia tias leej faj atom yog qhov tseem ceeb hauv chelating nrog cov tooj liab ions thiab pab txhawb ntau dua. inhibition tyrosinase kev ua haujlwm. Ntawm qhov tod tes, shortening cov carbon linker, uas txuas cov sulfur rau benzene rings, ua rau nruab nrab tyrosinase inhibition ntawm 38. Kev tshem tawm ntawm pawg hydroxyl, 39 ua rau tsis zoo tyrosinase inhibition, qhia tias ob pawg hydroxyl tseem ceeb. Nrog rau kev hloov methoxy, ib qho analog ntawm 36, txo qhov muaj zog rau IC50 tus nqi ntawm 40.02 lM, qhia tias kev sib cuam tshuam ntawm hydrogen tau zoo dua li cov kev sib cuam tshuam hydrophobic muab los ntawm pawg methoxide.

Compound 36 kho nrog 50 lM txo 20 feem pua ​​​​melanin cov ntsiab lus hauv tib neeg cov kab mob melanocytes yam tsis muaj cytotoxicity tseem ceeb. Tsis tas li ntawd, zebrafish nyob rau hauv vivo kev soj ntsuam qhia tau hais tias 36 zoo txo ​​melanogenesis tsis muaj kev phiv. Tsis tas li ntawd, txoj kev tshawb fawb mob toxicity ntawm qhov ncauj tau lees paub tias qhov sib xyaw 36 tsis muaj qhov pom tau cytotoxicity hauv nas. Yog li kev sib xyaw 36 yog tus neeg sib tw muaj peev xwm los tsim kom muaj kev nyab xeeb thiab siv tau zoo tshuaj rau cov tawv nqaij dawb. Tsis ntev los no, Ai li al., tau tshuaj xyuas lub tsev qiv ntawv tshuaj siv cov tshuaj ntsuam xyuas virtual thiab txheeb xyuas qhov sib xyaw 41 raws li cov nceb muaj zog tyrosinase inhibitor125, nrog rau IC50 tus nqi ntawm 8 lM thiab yielded 29 feem pua ​​​​± 17.64 feem pua ​​blockage ntawm melanin biosynthesis hauv B16 hlwb. ntawm ib tug concentration ntawm 0.002 feem pua ​​uas yog sib npaug rau 27.5 lathes.

Cov kev tshawb fawb SAR tau soj ntsuam nyob ib ncig ntawm cov qauv 41 tau pom qhov aromaticity ntawm lub nplhaib B ntawm compound 41 zoo nkaus li tseem ceeb rau kev ua si, raws li kev hloov ntawm lub nplhaib B nrog cyclohexyl nplhaib (compound 42b) poob qhov inhibitory kev ua ntawm melanin synthesis hauv B16 hlwb. Ntawm qhov tod tes, kev hloov pauv ntawm 4- txoj haujlwm ntawm lub nplhaib A tau ua rau muaj kev cuam tshuam tsis zoo rau kev ua haujlwm inhibitory (42a–42d). Cov tebchaw no tau noj tshuaj thiab inhibited melanin synthesis hauv B16 hlwb. Txawm li cas los xij, kev txhim kho ntxiv ntawm kev sib xyaw 41, ua rau muaj peev xwm tsim teeb meem thiab raug tshem tawm raws li tus neeg sib tw rau lub hom phiaj kom zoo nkauj. Ib qho kev soj ntsuam ntxiv ntxiv tau txheeb xyuas qhov sib xyaw 43 pom 79 feem pua ​​​​± 5.34 feem pua ​​​​ inhibition ntawm melanin biosynthesis ntawm B16 hlwb ntawm qhov concentration ntawm 0.001 feem pua ​​(33.6 lM). Ob lub tebchaw 41 thiab 43 no muaj cov khoom siv biochemical zoo thiab ua rau Lipinski "txoj cai ntawm tsib" thiab nthuav tawm cov nyhuv inhibitory ntawm melanin synthesis hauv B16 hlwb. Qhov no melanin synthesis inhibition tau pom tias tsis cuam tshuam rau cellular viability, uas ntxiv underscores lub peev xwm coj mus muag khoom siv ntawm cov tebchaw.

Nws tau tshaj tawm tias vanillin thiab vanillic acid cais tawm ntawm Origanum vulgare tuaj yeem ua tus neeg sawv cev rau antimelanogenesis126. Raws li cov keeb kwm yav dhau los no, ntau cov vanillin esters suav nrog benzoic acid, cinnamic acid, thiab piperazine tau tshaj tawm rau tyrosinase inhibitory kev ua 127. Cov txiaj ntsig tau pom tias cov tebchaw 44a-44d pom zoo rau kev ua haujlwm zoo ntawm cov nceb tyrosinase (Daim duab 14). Hauv particular, 44b tau nthuav tawm qhov muaj zog tshaj plaws inhibitory kev ua si nrog IC50 tus nqi ntawm 16.13 lM. Los ntawm cov qauv kev pom, qhov hloov cinnamic acid esters thiab hydroxyl hloov pauv tau ua lub luag haujlwm tseem ceeb hauv tyrosinase inhibition. Cov kev tshawb fawb kinetic tau qhia cov compound 44b yog ib hom sib xyaw tyrosinase inhibitor nrog Ki 13 lM thiab Ki 0 53 lM thiab tsim ib qho kev rov qab enzyme-inhibitor complex.

Hauv lwm txoj kev tshawb fawb, {{0}}hydroxytyrosol 45 (2-HT)128 tau pom tias inhibit nceb tyrosinase nrog IC50 tus nqi ntawm 13.0 lmol / L uas muaj zog sib npaug li kojic acid (IC{{ 7.8 lmol/L). Tsis tas li ntawd, 2-HT koob tshuaj-raws li inhibited tyrosinase kev ua haujlwm (IC50=32.5 lmol/L) hauv cell-free extract ntawm B16 melanoma cells thiab a-MSH-stimulated melanin tsim hauv cov hlwb B16 melanoma . Methimazole ({18}}mercapto-1-methylimidazole) derivatives tau tshaj tawm tias inhibit nceb tyrosinase129. 2-Mercaptoimidazole (46a), mercapto-1-methylimidazole (46b), thiab tert-butyl 3-methyl-2-sulfanylidene-2, 3-dihydro{ {30}}H-imidazole- 1-carboxylate (46c) cuam tshuam tyrosinase kev ua si uas nthuav tawm IC50 tus nqi ntawm 4.11 mM, thiab 1.43 mM thiab 1.45 mM, raws li, (Daim duab 14). Kinetic tsom xam qhia tias cov tebchaw 46a thiab 46b raws li kev sib tw tyrosinase inhibitors, thaum 46c yog qhov tsis sib tw tyrosinase inhibitor. Ntxiv mus, nyob rau hauv vitro tsom xam ntawm B16 hlwb, cov tebchaw ntawm 46a-46c exerted ib tug muaj zog inhibitory nyhuv ntawm intracellular melanin ntau lawm yam tsis muaj cuam tshuam lub cytotoxicity.

Ib tug series ntawm triazole Schiff lub hauv paus derivatives tau qhia rau lawv inhibitory kev ua si tiv thaiv nceb tyrosinase kev ua 130. Cov txiaj ntsig tau pom los ntawm kev soj ntsuam lom neeg uas tsuas yog peb lub tebchaw 47a-47c pom muaj zog inhibitory cuam tshuam nrog IC50 qhov tseem ceeb ntawm 12.5, 7.0, thiab 1.5 lM (Daim duab 14). Kinetic tsom xam pom tias inhibitors yog reversible thiab sib xyaw hom. Fluorescence quenching thiab tooj liab kev sib cuam tshuam kev tshawb fawb tau lees paub qhov kev cuam tshuam ntawm inhibitors nrog tyrosinase thiab chelation muaj peev xwm nrog tooj liab ions hauv qhov chaw nquag. Los ntawm cov qauv kev pom, kev hloov pauv ntawm 2- txoj hauj lwm ntawm lub nplhaib benzene pom kev ua haujlwm zoo (47c) dua li 3- txoj hauj lwm (47b). Ib qho tshiab ntawm thymol analogs suav nrog hydroxylated benzoic acids thiab cinnamic acids tau tshaj tawm tias nceb tyrosinase inhibitors131. Feem ntau, cov cinnamic acid-derived thymol derivatives pom zoo tyrosinase inhibition dua li benzoic acid derivatives, piv txwv los ntawm kev sib piv ntawm 48a (IC{18}}.20 lM) piv rau 48b (IC50 91.5 lM) .

Tsis ntev los no, cov nyhuv ntawm picrionoside A 49 cais tawm los ntawm nplooj ntawm Korean ginseng (P. ginseng CA Mayer) tau tshuaj xyuas 132 thiab nws tau inhibited nceb tyrosinase kev ua haujlwm nrog IC50 tus nqi ntawm 9.8 lM, txog 6.8 rau 10-fold siab dua. kojic acid thiab arbutin, ntsig txog (Daim duab 14). Hauv cov hlwb melan-Ab, 49 txo qis 17.1 feem pua ​​​​melanin cov ntsiab lus nyob rau hauv ib koob tshuaj uas tsis muaj kev cuam tshuam ntawm tes. Tsis tas li ntawd, Picionoside A-kho zebrafish tau pom qhov cuam tshuam zoo kawg nkaus rau lub cev pigmentation. Ua ke cov txiaj ntsig no qhia tau tias Picrionoside A tuaj yeem yog tus neeg sawv cev zoo nkauj ntawm daim tawv nqaij 133. Nyob rau hauv cov chav kawm ntawm kev tshuaj ntsuam, melanogenesis inhibitors hauv Streptomyces bikiniensis, nws tau pom tias S-(-)-10,11-dihydroxyfarnesoic acid methyl ester (dhFAME, 50), ib kab juvenile hormone tsim los ntawm Beauveria bassiana CS1029 134 ncaj qha inhibited cov haujlwm tyrosinase. Tsis tas li ntawd, 50 txo qis melanin cov ntsiab lus, inhibited cellular tyrosinase kev ua si nrog rau cov intracellular tsub zuj zuj ntawm cAMP theem nyob rau hauv melan-ib hlwb tsis inducing cell viability.

Ib chav kawm tshiab ntawm cov muaj zog tyrosinase inhibitors tau txheeb xyuas los ntawm cov qauv-raws li kev tshuaj ntsuam xyuas kev kwv yees135. Cov qauv ntawm cov nceb tyrosinase (PDB ID: 2Y9X) tau siv los ua tus qauv rau kev ua kom muaj zog molecular (MD) simulation. Thaum pib, ib pawg ntawm 10 000 cov qauv siv molecular dynamics simulation tau tsim. Cov kev tshuaj ntsuam xyuas tau ua rau cov 61 molecules saum toj kawg nkaus rau kev ntsuam xyuas tawm tsam nceb tyrosinase kev ua thiab cov kev xaiv inhibitors (51a–51e) tau qhia hauv daim duab 14. Cov txiaj ntsig tau pom tias moieties ntawm tetrazole thiab triazole tuaj yeem cuam tshuam nrog di-tooj ​​liab catalytic chaw ntawm cov tyrosinase. Hauv particular, tetrazole compound 51b nthuav tawm cov haujlwm muaj zog tshaj plaws. Cov kws sau ntawv pom tau tias ntau lub tebchaw pom qhov txo qis hauv melanin hauv B16 melanoma hlwb uas tsis muaj cytotoxicity. Tshwj xeeb, thiosemicarbazone-muaj cov khoom xyaw 51e txo melanin cov ntsiab lus los ntawm 55 feem pua. Cov txiaj ntsig tau muab kev pom zoo rau kev hloov pauv ntawm cov haujlwm ntawm hom -3 tooj liab enzymes.

Captopril ([2S]-N-[3-mercapto-2-methylpropionyl]-L-proline) yog angiotensin-hloov enzyme inhibitor136,137 uas tau siv dav hauv kev kho mob ntshav siab thiab lub plawv tsis ua haujlwm. Txhawm rau txheeb xyuas qhov tshiab thiab zoo tyrosinase inhibitors, cov nyhuv inhibitory ntawm captopril (52) tau sim nrog rau kev ua haujlwm tyrosinase inhibitory. Cov txiaj ntsig tau pom tias 52 inhibited tyrosinase kev ua haujlwm nrog IC50 tus nqi ntawm 590 lg / mL (Daim duab 14) 138. Tsis tas li ntawd, kev tshawb fawb hauv vitro hauv B16 hlwb, 52 tau pom tias inhibit qhov kev ua haujlwm ntawm tyrosinase 139,140 nyob rau hauv ib koob tshuaj uas ua rau. rau inhibition ntawm melanin tsim yam tsis muaj cytotoxicity.

Tib neeg tyrosinase inhibitors

Txawm hais tias muaj ntau tus tyrosinase inhibitors muaj thiab ntau ntawm lawv nrog cov muaj zog inhibitory kev ua ub no tau tham ua ntej, yuav luag tag nrho cov inhibitors tau soj ntsuam tawm tsam nceb tyrosinase. Txhawm rau nrhiav cov tshuaj tiv thaiv tshiab tawm tsam tib neeg tyrosinase, Yoshimori thiab al ua qauv qhia thujaplicins (52–54; a, b, thiab c isomers, Daim duab 15) rau lawv cov teebmeem inhibitory ntawm cov nceb tyrosinase thiab tib neeg tyrosinase (Tyr), nrog kev sib piv 141. Cov txiaj ntsig tau pom tias hom c-thujaplicins (53 thiab 54) tau zoo inhibited tib neeg tyrosinase kev ua haujlwm nyob rau hauv koob tshuaj nrog IC50 qhov tseem ceeb ntawm 8.98 thiab 1.15 lM, feem. Tshwj xeeb, c-thujaplicin 54 tau zoo heev rau kojic acid (IC{15}} lM). Cov kev tshawb fawb SAR tau qhia txog txoj haujlwm ntawm isopropyl ntawm tropolone scaffold yog qhov txiav txim siab rau lub zog ntawm thujaplicines. Lub zog ntawm thujaplicins yog raws li hauv qab no: c> b> a-thujaplicin.

To understand the inhibitory mechanism, the binding mode of c-thujaplicin was predicted using a homology model of hTYR. It showed the carbonyl and hydroxyl group of the c-thujaplicin chelate with two copper ions at the active site of hTYR. Tropolone scaffolds of thujaplicin form stacking interaction with the imidazole ring of His367 and hydrophobic interaction with isopropyl of Val377. The isopropyl group of thujaplicin forms hydrophobic interaction with Ile368. In addition, the results from comparative studies on the inhibitory effects of the other thujaplicins (a and b) indicated that van der Waals (VdW) clashes of the isopropyl group of a-thujaplicin with Val377 and S380 might reduce the inhibitory activity against hTYR. The main reason for the higher inhibitory activity of c–thujaplicin against hTYR among thujaplicins is considered to be the hydrophobic interaction of the isopropyl group with Ile368. In contrast, in many, the Val377, and Ser380 are replaced with proline (P257) and alanine (A260), respectively, therefore it can be considered that there are little VdW clashes of the isopropyl group of a-thujaplicin with A260 and P257 (Figure 16). This explains why the inhibitory effect of a-thujaplicin against mTYR (IC50=9.53 lM) is more than two orders of magnitude stronger than hTYR (IC50>1000 LWM). Raws li, nws tau pom tias qhov sib txawv ntawm Ala260 hauv mTYR thiab Ser380 hauv hTYR cuam tshuam rau qhov inhibitory profile ntawm a-thujaplicin.

Wang thiab cov neeg ua haujlwm tsis ntev los no tau pom cov khoom ntuj linderanolide B (55) thiab suboxide A (56) cais tawm ntawm cov stems ntawm Cinnamomum tau ua pov thawj tias muaj qhov zoo hauv vitro inhibitory muaj peev xwm ntawm nceb tyrosinase ntawm cov koob tshuaj tsawg (Daim duab 15) 142. Ob qhov sib xyaw pom cell viability ntawm tib neeg keratinocytes, melanocytes, thiab fibroblasts kho nrog ntau yam concentrations ntawm ob lub tebchaw. Kev kho mob ntawm koob tshuaj tsawg (0.01–1.0 lM) tsis pom muaj cytotoxicity tseem ceeb rau tib neeg cov tawv nqaij hlwb. Txoj kev tshawb no qhia ob lub tebchaw tuaj yeem txo 50 feem pua ​​​​ntawm tib neeg cov haujlwm tyrosinase ntawm koob tshuaj 1 lM tom qab 48-h kho thiab inhibited zoo (40 feem pua ​​​​txo) cov melanin tsim hauv HEMn-MP hlwb. Ob leeg 55 thiab 56 tau pom qhov muaj peev xwm inhibitory zoo tshaj plaws ntawm zebrafish hauv vivo pigmentation txawm tias qis dua yam tsis muaj kev soj ntsuam toxicity. Yog li ntawd, ob lub tebchaw no yog cov tshiab tyrosinase inhibitors kom raug suav hais tias yog cov neeg ua kom tawv nqaij dawb. Hauv lwm txoj kev tshawb fawb, Kolbe et al. tshuaj xyuas cov teebmeem inhibitory ntawm kojic acid, hydroquinone, thiab arbutin nrog rau lwm chav kawm paub zoo ntawm cov khoom sib xyaw 4-butyl resorcinol (57) ntawm tib neeg tyrosinase thiab inhibition ntawm kev tsim cov MelanoDermTM daim tawv nqaij qauv culture143. Xyoo 1995, 4-butyl resorcinol tau qhia txog resorcinol derivative uas muaj cov nyhuv inhibitory ntawm tyrosinase144 thiab TRP-1145,146. Cov txiaj ntsig tau pom tias 4-butyl resorcinol tau ua pov thawj tias yog ib qho zoo heev inhibitor ntawm tib neeg tyrosinase nrog IC50 tus nqi ntawm 21 lmol / L thiab ua tiav inhibition ntawm qhov siab tshaj 100 lmol / L. 4-Butyl resorcinol tau nthuav tawm 20 lub sijhawm muaj zog inhibitory kev ua haujlwm ntau dua li kojic acid, uas pom tias IC50 ntawm 500 lmol / L, thiab qhov siab tshaj plaws inhibition (89 feem pua) tau ua tiav ntawm 5.6 mmol / L concentration. Arbutin thiab hydroquinone yog cov tsis zoo inhibitors ntawm tib neeg tyrosinase nrog IC50 qhov tseem ceeb hauv millimolar ntau yam, uas yog, 6500 lmol / L rau arbutin thiab 4400 lmol / L rau hydroquinone. Txawm li cas los xij, tsis muaj ib qho ntawm ob qho tib si tau cuam tshuam tib neeg tyrosinase.

Hauv melanoDerm qauv ntawm daim tawv nqaij, arbutin pom tsuas yog qhov ua tau zoo ntawm melanin ntau lawm nrog IC5{{30}} tus nqi ntawm 500 lmol / L, thaum kojic acid inhibited nrog IC50 ntawm 400 mol / L. Interestingly, hydroquinone inhibited melanin ntau lawm nrog IC50 tus nqi qis dua 40 lmol / L, uas yog tej zaum vim txawv mechanisms ntawm tyrosinase inhibition. 4-Butyl resorcinol yog qhov muaj zog tshaj plaws inhibitor nrog IC50 ntawm 13.5 mol / L. Kev ua tau zoo hauv vivo ntawm 4-butyl resorcinol tau lees paub hauv kev tshawb fawb soj ntsuam. Cov neeg mob uas muaj hnub nyoog me ntsis ntawm lub hauv pliaj tau kho ob zaug ib hnub ob lub hnub nyoog me me nrog cov qauv uas muaj 4-n-butyl resorcinol (57), 4-hexylresorcinol (58), thiab 4-phenylethylresorcinol (59). ). Tsis pub dhau 8 lub lis piam, 4-butyl resorcinol (57) txo qis qhov pom ntawm lub hnub nyoog me ntsis thaum 4-hexylresorcinol thiab 4-phenylethylresorcinol pom muaj txiaj ntsig zoo tom qab 12 lub lis piam. Ib txoj kev tshawb fawb thib ob tau pom tias 4-butylresorcinol tau zoo dua li 4-hexylresorcinol thiab 4-phenylmethylsorcinol. Cov txiaj ntsig tau txais kev kho mob ntawm hyperpigmentation qhia tau tias 4-butyl resorcinol tuaj yeem yog ib qho tseem ceeb ntawm cov khoom siv rau kev tswj cov xim pigmentation. 4-butyl resorcinol tau siv los kho melasma. Nyob rau hauv tag nrho cov ntaub ntawv luam tawm, 4-butyl resorcinol 0.1 feem pua ​​​​cov qab zib qhia tau hais tias muaj txiaj ntsig sai, kev nyab xeeb, thiab kev ua siab ntev thaum nws siv rau kev kho melasma147,148. Ib txoj kev tshawb fawb tsis ntev los no tau tshaj tawm tias 4-butyl resorcinol 0.3 feem pua ​​​​cov qab zib muaj kev nyab xeeb, siv tau zoo, thiab ua tau zoo rau cov neeg mob Indian nrog melisma149.

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