TSAB NTAWV

Melanogenesis yog txheej txheem los tsim cov melanin, uas yog lub luag haujlwm tseem ceeb rau cov pigmentation ntawm tib neeg cov tawv nqaij, qhov muag, thiab plaub hau. Txawm hais tias muaj ntau yam enzymatic catalyzed thiab tshuaj lom neeg cov tshuaj tiv thaiv tau koom nrog hauv cov txheej txheem melanogenesis, cov enzymes xws li tyrosinase thiab tyrosinase-related protein-1 (TRP-1) thiab TRP-2 ua lub luag haujlwm tseem ceeb hauv melanin. synthesis. Tshwj xeeb, tyrosinase yog ib qho tseem ceeb enzyme, uas catalyzes tus nqi-txheej theem ntawm melanin synthesis, thiab downregulation ntawm tyrosinase yog qhov tseem ceeb tshaj plaws mus kom ze rau txoj kev loj hlob ntawm melanogenesis inhibitors. Yog li ntawd, ntau tus inhibitors uas lub hom phiaj tyrosinase tau tsim nyob rau hauv xyoo tas los no. Kev tshuaj xyuas tsom mus rau qhov kev tshawb pom tsis ntev los no ntawm tyrosinase inhibitors uas cuam tshuam ncaj qha rau hauv inhibition ntawm tyrosinase catalytic kev ua haujlwm thiab kev ua haujlwm los ntawm txhua qhov chaw, suav nrog kev sim cov txheej txheem hluavtaws, cov khoom ntuj tsim, kev tshuaj xyuas virtual, thiab cov qauv kev tshawb fawb molecular docking.

Raws li cov kev tshawb fawb cuam tshuam, cistanche yog ib hom tshuaj ntsuab uas hu ua "cov tshuaj ntsuab muaj txuj ci uas ua rau lub neej ntev". Nws lub ntsiab tivthaiv yog cistanoside, uas muaj ntau yam teebmeem xws li antioxidant, tiv thaiv kev mob, thiab kev tiv thaiv kev ua haujlwm. Cov txheej txheem ntawm cistanche thiab tawv nqaij dawb yog nyob rau hauv cov nyhuv antioxidant ntawm cistanche glycosides. 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-dawb radicals nyob rau hauv lub cev ua ib qho tseem ceeb cuam tshuam rau melanin ntau lawm. Cistanche muaj 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.

Nyem rau Yuav Siv Cistanche li cas

Yog xav paub ntxiv:

david.deng@wecistanche.com WhatApp:86 13632399501

KEYWORDS

tib neeg tyrosinase; inhibitors; Tus kab mob Parkinson; qauv-kev sib raug zoo; daim tawv nqaij whitening agents

Taw qhia

Nws kwv yees kwv yees li ntawm 15 feem pua ​​​​ntawm cov pej xeem hauv ntiaj teb tau nqis peev pab rau cov neeg ua kom tawv nqaij dawb nrog rau Asia tau ua tus thawj coj 1. Cov kws tshuaj ntsuam xyuas kev lag luam thoob ntiaj teb (GIA) tau kwv yees tias kev lag luam thoob ntiaj teb rau cov tawv nqaij lighteners yuav ncav cuag $ 23 nphom los ntawm 2020, tau tsav los ntawm cov lag luam tshiab hauv Asia, tshwj xeeb yog Is Nrias teb, Nyiv, thiab Tuam Tshoj2. Raws li SIRONA biochem report1, kwv yees li ntawm $ 13 nphom tau siv rau cov khoom tu tawv nqaij thiab tshuaj pleev ib ce hauv Asia Pacific. Hauv Is Nrias teb ib leeg, nws kwv yees tias $ 432 lab tau siv hauv xyoo 2010 rau cov tshuaj pleev tawv nqaij thiab cov tshuaj tu tawv nqaij. Kev tshawb fawb tsis ntev los no tau qhia tias 80 feem pua ​​​​ntawm cov txiv neej Khab siv cov tshuaj pleev kom ncaj ncees thiab cov neeg siv khoom tau nce 18 feem pua ​​​​txhua xyoo. Lub molecular mechanism ntawm cov tawv nqaij-lightening agents yog txo melanin, uas yog lub hauv paus ntawm daim tawv nqaij xim.

Melanin feem ntau yog lub luag haujlwm rau cov pigmentation ntawm tib neeg cov tawv nqaij, qhov muag, thiab tawv nqaij, uas yog tsim los ntawm epidermis melanocytes nyob rau hauv ib qho piv txwv ntawm 1:36 nrog basal keratinocytes3. Hauv kev teb rau ultraviolet B (UVB)-irradiation, melanocyte synthesizes melanin los ntawm cov txheej txheem hu ua melanogenesis. Cov synthesized melanin nyob rau hauv melanosomes yog thauj mus rau cov nyob sib ze keratinocytes nyob rau hauv lub epidermis 4. Raws li ib txwm muaj lub cev nqaij daim tawv, pigmentation muaj txiaj ntsig zoo rau kev yees duab-tiv thaiv tib neeg cov tawv nqaij tiv thaiv kev raug mob UV thiab ua lub luag haujlwm tseem ceeb hauv kev camouflage thiab tsiaj mimicry5. Txawm li cas los xij, ntau dhau ntawm melanin ua rau muaj teeb meem dermatological xws li freckles, hnub ci lentigo (hnub nyoog me ntsis), thiab melasma6-9, nrog rau mob qog noj ntshav 10 thiab postinflammatory melanoderma11. Tsis tas li ntawd, tsis tu ncua UV-irradiation tuaj yeem ua rau DNA puas tsuaj, noob hloov pauv, kev txhim kho qog noj ntshav, thiab ua rau lub cev tsis muaj zog lossis photoaging12.

Kev tswj ntawm melanogenesis

Melanogenesis yog ib txoj hauv kev nyuaj uas muaj kev sib xyaw ua ke ntawm cov tshuaj enzymatic thiab tshuaj lom neeg catalyzed. Melanocytes tsim ob hom melanin: eumelanin (xim av-dub) thiab pheomelanin (liab-daj) tsim los ntawm conjugation ntawm cysteine ​​lossis glutathione (Daim duab 1) 13-15.

Cov txheej txheem melanogenesis yog pib nrog oxidation ntawm L-tyrosine rau dopaquinone (DQ) los ntawm cov enzyme tseem ceeb, tyrosinase (TYR). Qhov tshwm sim quinone yuav ua lub substrate rau synthesis ntawm eumelanin thiab pheomelanin16,17. Kev tsim ntawm DQ yog tus nqi-txheej theem hauv melanin synthesis vim tias qhov seem ntawm cov tshuaj tiv thaiv kab mob tuaj yeem ua raws li tus nqi ntawm lub cev pH ntawm 17. Tom qab tsim DQ, nws nkag mus rau intramolecular cyclization los tsim indoline, thiab leukodopachrome (cyclo-dopa). . Kev sib pauv redox ntawm leukodopachrome thiab DQ ua rau dopachrome thiab L-3, 4-dihydroxyphenylalanine (L-DOPA), uas kuj yog ib qho substrate rau TYR thiab oxidized rau DQ dua los ntawm cov enzyme. Dopachrome maj mam decomposes muab dihydroxy indole (DHI) thiab dihydroxy indole-2-carboxylic acid (DHICA). Cov txheej txheem tom kawg yog catalyzed los ntawm TRP-2, tam sim no hu ua dopachrome tautomerase (DCT). Thaum kawg, cov dihydroxy indoles (DHI thiab DHICA) yog oxidized rau eumelanin. TRP{11}} ntseeg tau tias yuav ua rau cov oxidation ntawm DHICA rau eumelanin. Ib sab, DQ hloov mus rau 5-S-cysteineyldopa lossis glutothionyldopa nyob rau hauv muaj cysteine ​​lossis glutathione. Tom qab oxidation muab benzothiazine intermediates thiab thaum kawg tsim pheomelanin. Txawm hais tias peb enzymes, TYR, TRP-1, thiab TRP{15}} koom nrog txoj hauv kev melanogenesis, tyro sinase tsuas yog tsim nyog rau melanogenesis.

Tyrosinase thiab nws lub luag haujlwm tseem ceeb hauv melanin synthesis

Tyrosinase (monophenol los yog o-diphenol, oxygen oxidoreductase, EC 1.14.18.1, syn. polyphenol oxidase), multifunctional membrane-bound type-3 copper-containing glycoprotein is located in the membrane of the melanosome18. Tyrosinase tsuas yog tsim los ntawm melanocyte hlwb. Tom qab nws cov khoom tsim thiab ua tiav hauv endoplasmic reticulum thiab Golgi, nws raug xa mus rau melanosomes, uas cov xim melanin yog synthesized. Los ntawm cov qauv kev pom, ob lub tooj liab ions nyob ib puag ncig los ntawm peb cov histidine residues uas yog lub luag haujlwm rau catalytic kev ua si ntawm tyrosinase (Daim duab 2) 19. Lub chaw nquag muaj peb lub xeev; oxy, ntsib, thiab deoxy cov ntaub ntawv hauv kev tsim cov pigmentation. Tshwj xeeb tshaj yog, ntawm qhov chaw ua haujlwm, ob lub tooj liab ions cuam tshuam nrog dioxygen los tsim cov tshuaj lom neeg ua haujlwm nruab nrab uas koom ncaj qha rau hauv hydroxylation ntawm monophenols rau diphenols (mycophenolate kev ua si) thiab hauv oxidation ntawm o-diphenols rau o-quinones (diphenols kev ua si. ) 20,21 Nws. Tyrosinase tseem yog catalyzing cov txheej txheem ntawm neuromelanin ntau lawm nyob rau hauv uas oxidation ntawm dopamine tsim dopaquinones. Txawm li cas los xij, ntau dhau ntawm dopaquinones ua rau muaj kev puas tsuaj neuronal thiab cell tuag. Qhov no qhia tias tyrosinase tuaj yeem ua lub luag haujlwm tseem ceeb hauv kev tsim cov neuromelanin hauv tib neeg lub hlwb thiab yog lub luag haujlwm rau cov neurodegeneration cuam tshuam nrog Parkinson's disease thiab Huntington's disease22-26. Tyrosinase kuj tau txuas mus rau browning ntawm zaub thiab txiv hmab txiv ntoo thaum lub sij hawm postharvest thiab tuav, ua rau kom ceev degradation27-29. Daim ntawv thov ntawm tyrosinase tau txuas ntxiv nyob rau hauv cov txheej txheem molting ntawm kab 30. Yog li, kev tswj hwm ntawm melanin synthesis los ntawm inhibiting tyrosinase enzyme yog ib qho kev txhawb siab loj rau cov kws tshawb fawb hauv cov ntsiab lus ntawm kev tiv thaiv hyperpigmentation.

Tyrosinase inhibitors

Txij li thaum tyrosinase yog ib qho tseem ceeb enzyme nyob rau hauv synthesizing melanin los ntawm melanogenesis, nws dhau los ua lub hom phiaj tseem ceeb tshaj plaws thiab muaj kev vam meej rau melanogenesis inhibitors uas ncaj qha inhibit tyrosinase catalytic kev ua si. Feem ntau cov tshuaj pleev ib ce los yog cov tawv nqaij ua kom pom kev ua lag luam yog cov tyrosinase inhibitors. Qhov tseeb hais tias cov inhibitors tsom tyrosinase yuav tshwj xeeb inhibit melanogenesis hauv hlwb tsis muaj kev phiv, vim tyrosinase tsuas yog tsim los ntawm melanocytes. Ntau cov tyrosinase inhibitors xws li hydroquinone (HQ) 31-34, arbutin, kojic acid35-37, azelaic acid38,39, L-ascorbic acid40-42, ellagic acid43-45, tranexamic acid46-48 tau siv los ua cov tawv nqaij dawb, nrog qee qhov tsis zoo (Daim duab 3).

HQ muaj peev xwm mutagenic rau mammalian hlwb thiab txuas rau ntau yam kev phiv xws li kev sib cuag dermatitis, irritation, transient erythema, kub hnyiab, prickling sensation, leukoderma, txiv ntseej me ntsis rau ntawm tes, hypochromic thiab ochronosis49-52. Arbutin, prodrug ntawm hydroquinone, yog ib yam khoom ntuj tsim thiab txo los yog inhibits melanin synthesis los ntawm inhibiting tyrosinase. Txawm li cas los xij, tej yam ntuj tso cov ntaub ntawv ntawm arbutin yog cov tshuaj tsis ruaj khov thiab tuaj yeem tso tawm hydroquinone uas yog catabolized rau benzene metabolites nrog lub peev xwm toxicity rau cov pob txha pob txha53. Kojic acid siv nyob rau hauv cov tshuaj pleev ib ce tau txwv, vim nws carcinogenicity thiab nws instability thaum cia54. L-Ascorbic acid yog rhiab heev rau cua sov thiab degrades yooj yim 55. Ellagic acid yog insoluble thiab yog li tsis zoo bioavailable56, thiab rau cov tranexamic acid, txoj kev melanogenic tseem undetermined 47. Yog li, nws yog ib qho tseem ceeb ntawm kev tsim tshiab tyrosinase inhibitors nrog tshuaj- zoo li khoom.

Mushroom tyrosinase inhibitors

Chalcones thiab flavanone inhibitors

Hauv lwm txoj kev tshawb fawb, chalcones 2a-2d cais los ntawm Morus australis tau soj ntsuam rau lawv cov kev ua haujlwm inhibitory ntawm nceb tyrosinase siv L-tyrosine raws li substrate 58. Cov txiaj ntsig tau pom tias tag nrho plaub lub chalcone derivatives yog cov muaj zog heev inhibitors rau tyrosinase nyob rau hauv kev sib piv rau cov qauv compound. arbutin (Daim duab 5(a), 2a–2d). Tshwj xeeb tshaj yog, compound 2a yog 700-fold muaj zog inhibition hauv kev sib piv rau arbutin. Cov qauv-kev sib raug zoo kev sib raug zoo (SAR) tsom xam pom tias resorcinol kev tsim kho ntawm ob lub nplhaib A thiab lub nplhaib B tuaj yeem yog vim li cas rau qhov muaj zog tyrosinase inhibition. Tsis tas li ntawd, kev hloov pauv ntawm 30 txoj haujlwm ntawm lub nplhaib A ua lub luag haujlwm tseem ceeb hauv kev txhim kho inhibitory potency. Piv txwv li, steric bulky hloov ntawm lub nplhaib A ntawm 2c txo qhov muaj zog piv rau qhov tsis hloov pauv 2a, qhov no yog vim muaj peev xwm chelating ntawm tooj liab ions. Interestingly, compound 2d nthuav tawm muaj zog inhibitory kev ua si tshaj 2a thiab 2c, qhia tias cov 4- hydroxy{16}}pentene pawg ntawm 30 - txoj hauj lwm ntawm 2d yog lub luag hauj lwm rau kev txhim kho. Tsis tas li ntawd, cov teebmeem ntawm chalcones ntawm melanin synthesis tau sim hauv melanin-tsim B16 murine melanoma hlwb, thiab cov tebchaw 2a, 2b, thiab 2d tau muaj zog inhibited nrog me me lossis tsis muaj cytotoxicity.

Tsis ntev los no, Radhakrishnan li al., tau tshaj tawm lub tsev qiv ntawv ntawm aza chalcones thiab 59 cov teebmeem inhibitory ntawm nceb tyrosinase siv L-DOPA raws li substrate tau tshawb xyuas. Ntawm cov tshuaj ntsuam xyuas hauv kev tshawb fawb, ob lub tebchaw 3a thiab 3b, congeners (carbonyl txo) ntawm pyridyl azachalcones tau pom tias muaj zog enzyme inhibitors ntau dua kojic acid (IC50¼27.30 lM) (Daim duab 5(a), 3a–3b. ). Tsis tas li ntawd, qhov kev tshuaj ntsuam kinetic tau txheeb xyuas ob qho tib si 3a thiab 3b yog qhov sib tw inhibitors nrog Ki qhov txiaj ntsig ntawm 2.62 thiab 8.10 lM, raws li. Cov qauv-kev ua haujlwm tsom xam pom tias nitrogen atom nyob rau hauv pyridine pob txha pob txha ntawm cov inhibitors yuav complex nrog cov tooj liab ions tam sim no nyob rau hauv lub tyrosinase active site. Tib pab pawg tshawb fawb tau tshaj tawm lwm cov chalcone series nrog oxime functionality raws li ib qho inhibitor ntawm tyrosinase thiab melanin tsim nyob rau hauv melanoma B16 hlwb.60 Ob ntawm cov tebchaw (4a: IC50¼4.77 lM thiab 4b: ​​IC5057.89 lM) nthuav tawm muaj zog tyro sinase inhibitory. cov dej num (Daim duab 5(a), 4a–4b) tshaj kojic acid (IC50522.25 lM). Cov kev tshawb fawb Kinetic qhia txog kev sib tw inhibitors nrog Ki qhov txiaj ntsig ntawm 5.25 thiab 8.33 lM. Hauv ib-melanocyte-stimulating hormone (a-MSH) induced B16 melanoma hlwb, ob lub tebchaw 4a thiab 4b inhibited melanin tsim thiab tyrosinase yam tsis muaj cytotoxicity. Nyob rau hauv cov nqe lus ntawm SAR tsom xam, nws tau pom tias muaj ortho-methoxy nrog para-nitro substituents (ring B) yog lub luag hauj lwm rau muaj zog tyrosinase inhibition (4a). Tsis tas li ntawd, ib qho hluav taws xob pub dawb para-dimethyl amino nplhaib (ntiv nplhaib B) tau nthuav tawm qhov thib ob muaj zog tshaj inhibition (4b).

Hauv lwm txoj kev tshawb fawb, cov ntawv tshiab ntawm 2,3-dihydro-1H-inden-1-ib qho khoom siv zoo li chalcone tau tshaj tawm.61 Ob ntawm lawv, 5a thiab 5b, tau txheeb xyuas tias muaj zog inhibitors ntawm diphenolase kev ua ntawm tyrosinase nrog IC50 qhov tseem ceeb ntawm 12.3 thiab 8.2 lM (Daim duab 5(a)). Kev tshawb nrhiav ntxiv ntawm cov txheej txheem, ob qho tib si inhibitors 5a thiab 5b tau pom tias yuav thim rov qab thiab sib tw.

Wang et al. cais dihydrochalcones (Daim duab 5(a), 6a–6c) thiab flavanones (Daim duab 5(b), 7a–7c) los ntawm Flemingia philippinensis thiab tshawb xyuas rau lawv cov haujlwm inhibitory ntawm tyrosinase62. Cov txiaj ntsig tau pom tias lawv inhibit mycophenolate (IC50¼1.01 txog 18.4 lM) thiab diphenols (IC50¼5.22 txog 84.1 lM) kev ua ntawm tyrosinase. Hauv particular, dihydrochalcone (6c) zoo inhibited ob qho tib si mycophenolate thiab diphenols kev ua ub no ntawm tyrosinase nrog IC50 qhov tseem ceeb ntawm 1.28 thiab 5.22 lM, feem. Kev tsom xam SAR yog qhov nthuav heev vim tias cov tshuaj pharmacophore tsis cuam tshuam nrog tyrosinase inhibition thiab nws tsis muaj qhov a, b-unsaturated ketone motif uas muaj nyob rau hauv feem ntau ntawm cov inhibitors. Nyob rau hauv cov ntaub ntawv ntawm flavanones, cov tebchaw uas muaj resorcinol pawg (7a) muaj kev sib tw thiab muaj zog inhibited mycophenolate (IC50¼1.79 lM) thiab diphenols (IC50¼7.48 lM) ntawm tyrosinase.

Hauv kev tshawb nrhiav tshiab tyrosinase inhibitors, nws tau pom tias cov extracts ntawm Camylotropis hirtella qhia tyrosinase inhibition63. Tom qab ua tiav kev ua kom huv huv thiab kev sib cais ntawm kaum plaub lub tebchaw, plaub lub tebchaw (Daim duab 5(b), 8a–8d) tau pom muaj zog inhibitory kev ua ub no tiv thaiv tyrosinase. Cov tshuaj muaj zog tshaj plaws tau pom tias yog neorauflavane 8c nthuav tawm IC50 qhov tseem ceeb ntawm 30 thiab 500 nM tiv thaiv monophenolase thiab diphenolase kev ua ntawm tyrosinase. Tsis tas li ntawd, piv nrog kojic acid (13.2 lM), 8c yog 400-fold muaj zog tshaj tawm tsam mycophenolate kev ua ntawm tyrosinase. Qhov thib ob muaj zog tshaj plaws compound yog geranylated isoflavone 8a inhibited mycophenolate thiab diphenols nrog IC50 qhov tseem ceeb 2.9 thiab 128.2 lM, raws li, thiab tau txheeb xyuas tias yog kev sib tw thiab thim rov qab inhibitor. Tsis tas li ntawd, cov tshuaj 8a thiab 8c tau txo qis melanin cov ntsiab lus hauv a-MHS-induced B16 melanoma hlwb, tsis muaj kev cuam tshuam ntawm cell viability. Los ntawm cov qauv kev pom, qhov txo qis ntawm geranyl sab saw txhim kho tyrosinase inhibitory kev ua haujlwm.

Cov analogues ntawm Resveratrol

Resveratrol (3,5,{2}}trihydroxy-trans-stilbene, 9) ib tug dav faib stilbenoid nyob rau hauv cov xwm xws li nyob rau hauv txiv hmab txiv ntoo, nthuav tawm lub inhibitory kev ua si tiv thaiv nceb tyrosinase los ntawm lub mechanism ntawm Kcat (suicide substrate) hom inhibition64. Nyob rau hauv vitro tsom xam nyob rau hauv a-MSH-stimulated B16 murine melanoma hlwb, resveratrol inhibited cellular melanin ntau lawm los ntawm kev tsub zuj zuj ntawm melanogenesis-txog cov proteins xws li tyrosinase, TRP-1, TRP-2, thiab microphthalmia-cuam tshuam transcription factor (MITF) expression65 yam tsis muaj cytotoxicity txog 200 lM.64 Cov teebmeem inhibitory ntawm resveratrol tau raug lees paub nyob rau hauv ib qho qauv hauv vivo siv UVB-irradiated brownish guinea npua. Nyob rau hauv txoj kev tshawb no, kev kho mob ntawm resveratrol nrog UVB-irradiated dorsal daim tawv nqaij ntawm guinea npua visually txo cov hyperpigmentation.

Tsis ntev los no, ib tug series ntawm azo-resveratrol (13a–13e thiab 13 g) thiab azo-oxyresveratrol (13f) tau tshaj tawm (Daim duab 6) 69. Ntawm cov tebchaw, 13a thiab 13b tau nthuav tawm siab tyrosinase inhibitory kev ua ntawm 56.25 feem pua ​​thiab 72.75 feem pua. 50 lM, raws li 69. Lub 4-hydroxyphenyl moiety tau pom tias yog qhov tseem ceeb rau kev inhibition ntau dua thiab 3,5-dihydroxy phenyl lossis 3,5-dimethoxy phenyl derivatives pom zoo tyrosinase inhibition dua 2, 5-dimethoxy phenyl derivatives. Tshwj xeeb, kev taw qhia ntawm hydroxyl lossis methoxy pawg rau hauv 4-hydroxyphenyl moiety txo qis lossis txo qis nce nceb tyrosinase inhibition. Ntawm cov synthesized azo tebchaw, azo-resveratrol (13b) yog qhov muaj zog tshaj nceb tyrosinase inhibition nrog IC50 tus nqi ntawm 36.28 lM. Cov txiaj ntsig tau qhia tias azo-resveratrol nrog lub siab Log p-tus nqi yuav zoo dua rau resveratrol rau kev txhim kho cov tshuaj ntxuav hniav dawb thiab cov tshuaj siv tshuaj hauv kev kho mob hyperpigmentation.

Coumarin derivatives

Coumarins yog ib tsev neeg loj ntawm benzopyrone tebchaw muaj los ntawm lub hauv paus ntuj thiab hluavtaws nrog ntau yam tshuaj ua haujlwm70. Hauv cov kev tshawb fawb tsis ntev los no, ob peb coumarins tau ua pov thawj los cuam tshuam cov nceb tyrosinase, uas suav nrog esculetin thiab umbelliferone nrog kev muaj zog tyrosinase inhibitory kev ua 71,72. Hauv kev siv zog tas mus li, Matos li al., tau ua kom pom cov coumarin-resveratrol hybrid compounds, 3-phenyl coumarins nrog hydroxyl lossis alkoxy thiab bromo hloov pauv ntawm ntau txoj haujlwm hauv scaffold73 (Daim duab 7). Ntawm cov koob, qhov sib xyaw nrog bromo atom thiab ob pawg hydroxyl nyob rau hauv 3-phenyl coumarin moiety (14), tau txheeb xyuas tias yog tus inhibitor zoo tshaj plaws nrog IC50 tus nqi ntawm 215 lM. Cov tshuaj no yog ib qho tsis sib tw tyrosinase inhibitor nrog tus nqi Ki ntawm 0.189 mM.

Hauv lwm txoj kev tshawb fawb, cov tshuaj umbelliferone analogs tau tshaj tawm rau lawv cov teebmeem inhibitory ntawm nceb tyrosinase74. Tshwj xeeb, cov tebchaw 15a thiab 15b muaj 3,4-dihydroxy thiab 3,4,5-dihydroxy phenyl scaffold pom muaj zog inhibitory kev ua ub no ntau dua tiv thaiv nceb tyrosinase kev ua (Daim duab 7). Asthana et al. ua qauv qhia ntawm hydroxy coumarins (16a–16d) 75 (Daim duab 7). Cov kev tshawb fawb SAR tau qhia tias txoj haujlwm ntawm hydroxyl hloov pauv ntawm coumarin plays lub luag haujlwm hauv enzyme inhibition; cov tebchaw nrog aromatic hydroxylated, 6-hydroxycoumarin (16c), thiab 7-hydroxycoumarin (16d), pom tias tsis muaj zog substrates ntawm enzyme. Tshwj xeeb tshaj yog, 7-hydroxycoumarin muaj zog inhibited dopachrome concentration nyob rau hauv ib tug ntau yam ntawm 0.3 - 0.9 mM. Ntawm qhov siab tshaj plaws 7-hydroxycoumarin concentration, qhov inhibition mus txog 88 feem pua. Cov kws sau ntawv pom qhov tshwm sim yog vim qhov tshwj xeeb inhibition ntawm L-tyrosine hloov dua siab tshiab. Ntawm qhov tod tes, cov tebchaw nrog pyrone hydroxylated, 3-hydroxycoumarin (16a) thiab 4-hydroxycoumarin (16b) tsis yog substrates ntawm tyrosinase. 3-hydroxycoumarin (16a) tau pom tias inhibit tyrosinase tab sis tsis yog qhov sib xyaw nrog 4-hydroxycoumarin (16b), qhia tias lub nplhaib pyrone tsis tuaj yeem hydroxylated los ntawm tyrosinase.

Tsis ntev los no, ib tug series ntawm phosphonic acid diamides tau soj ntsuam rau lawv tyrosinase inhibition kev ua 76. Cov txiaj ntsig tau pom tias qhov hloov pauv txuas nrog C-5 thiab stereochemistry ntawm ob lub chaw stereogenic (C-5 thiab phosphorus atom) yog qhov tseem ceeb rau tyrosinase inhibition (17a–17d). Diastereomers nrog unsubstituted phenyl tsis tau qhia ib yam dab tsi inhibitory tiv thaiv tyrosinase (17a thiab 17a0 ). Nyob rau hauv sib piv, cov tebchaw nrog ib tug hloov phenyl pom muaj ntau yam teebmeem ntawm tyrosinase kev ua, piv txwv li, compound 17b nrog p-chlorophenyl (80.65 feem pua ​​​​tyrosinase inhibition) nruab nrab inhibited tyrosinase tab sis nws diastereomer 17b0 16 .5% tyrosinase inhibition) tsis ua haujlwm. Hauv lwm qhov xwm txheej, 17c (58.54 feem pua ​​​​tyrosinase inhibition) thiab 17c0 muaj p-methyl phenyl (61.80 feem pua ​​​​tyrosinase inhibition) pom zoo tyrosinase inhibition. Cov tshuaj 17d suav nrog 2-pyridinyl (97.40 feem pua ​​​​tyrosinase inhibition) tawg tau pom tias yog qhov muaj zog tshaj plaws tyrosinase inhibitor ntawm txoj kev tshawb no saum toj no.

Inhibitors nrog b-phenyl-a, b-unsaturated carbonyl functionality

Tsis ntev los no, nws tau tshaj tawm tias benzylidene hydantoin 18a, benzylidene pyrrolidine dione 18b, thiab benzylidene thiazolidine-2, 4-dione 18c (Daim duab 8(a)) derivatives raws li cov kev tshawb fawb muaj peev xwm tyrosinase inhibitors thiab siv nyob rau hauv tau ua pov thawj tias yog ib qho zoo ntawm daim tawv nqaij whitening agents77-80. Lawv pom muaj zog inhibitory kev ua ub no tshaj kojic acid thiab arbutin. Lub compound 18a tau tsim los ntawm kev ua cov qauv tshuaj ntawm L-tyrosine thiab L-DOPA, tyrosinase substrates. Cov kev tshawb fawb SAR tau qhia tias amide NH ntawm 1- txoj hauj lwm ntawm hydantoin 18a tuaj yeem tsim hydrogen bonds nrog cov amino acids ntawm qhov chaw nquag ntawm tyrosinase. Tsis tas li ntawd, pawg imido ntawm 18a ua raws li pawg carboxylic acid ntawm cov substrates. Raws li keeb kwm no, Kim et al. tsis ntev los no tau tsim thiab tshuaj xyuas cov series ntawm 5-(hydroxyl- los yog alkoxy hloov benzylidene) thiohydantoin analogs muaj b-phenyl-a, b-unsaturated carbonyl scaffolds.81 Ntawm lawv, peb lub tebchaw, 19a-19c, nthuav tawm cov dej num inhibitory siab. tshaj kojic acid lossis resveratrol (Daim duab 8(a)). Tshwj xeeb tshaj yog, 2, 4-dihydroxybenzylidene-2-thiohydantoin 19c (IC50¼1.07 lM) tau pom tias yog qhov zoo tshaj plaws inhibitor ntawm txoj kev tshawb no. Tsis tas li ntawd, 19c inhibited cellular tyrosinase kev ua haujlwm hauv B16 hlwb yam tsis muaj cytotoxicity tseem ceeb.

Hauv kev txuas ntxiv, (E)-2-benzoyl-3-(hloov phenyl)acrylonitriles (BPA analogs) nrog cov kab tawm b-phenyl-a, b-unsaturated carbonyl scaffold tau tsim thiab ntsuas raws li qhov muaj peev xwm tyrosinase inhibitors82. Ntawm lawv, peb lub tebchaw 20a-20c tau zoo inhibited nceb tyrosinase kev ua haujlwm (Daim duab 8(a)). Tshwj xeeb tshaj yog, compound 20c ua rau txo qis melanin biosynthesis thiab inhibited intracellular tyrosinase kev ua haujlwm hauv B16 hlwb yam tsis muaj kev cuam tshuam ntawm cell viability. Kev soj ntsuam SAR tau qhia tias txhua qhov sib txuas ua haujlwm muaj 4- pawg hydroxy ntawm lub nplhaib phenyl, thiab kev hloov pauv ntawm Br ntawm 3- txoj haujlwm lossis 3 thiab 5- txoj haujlwm tau pom tias muaj kev cuam tshuam nrog lub zog tyrosinase. inhibitory kev ua haujlwm.

Tsis ntev los no, tib pab pawg tshawb fawb txuas ntxiv tshawb xyuas SAR ntawm 3-(hloov phenyl)acrylonitriles. Raws li, ib tug series ntawm (E)-2-cyano-3-(hloov phenyl)acrylamide derivatives muaj ib tug linear b-phenyl-a, b-unsaturated carbonyl scaffold pom inhibitory kev ua ub no tiv thaiv nceb tyrosinase83. Ntawm cov tebchaw, 21a thiab 21b tau ua haujlwm inhibitory tiv thaiv nceb tyrosinase (Daim duab 8(a)). Tshwj xeeb tshaj yog, compound 21a pom zoo heev inhibitory kev ua. Hauv B16 hlwb, 21a ua rau muaj kev cuam tshuam tyrosinase hauv kev siv tshuaj ntau yam yam tsis muaj kev cuam tshuam ntawm cytotoxic nyhuv. Los ntawm cov qauv kev pom, ib qho "linear" b-phenyl-a, b-unsaturated carbonyl scaffold plays lub luag haujlwm tseem ceeb hauv kev qhia txog kev tiv thaiv melanogenic los ntawm kev cuam tshuam ncaj qha ntawm tyrosinase enzyme.

0

Nws tau ntev paub tias cinnamaldehyde muaj peev xwm inhibit L-DOPA oxidation los ntawm nceb tyrosinase84. Tsis ntev los no, Cui et al. tshaj tawm ib tug series ntawm ib-siv derivatives ntawm cinnamaldehyde derivatives85. Cov kev tshawb fawb SAR tau pom tias a-bromocinnamaldehyde 22a, a-chlorocinnamaldehyde 22b, thiab a-methyl cinnamaldehyde 22c tebchaw txo cov kev ua haujlwm ntawm mycophenolate thiab diphenolase ntawm tyrosinase (Daim duab 8(a)). IC50 qhov tseem ceeb ntawm 22a–22c yog 0.075, {{20}}.140, thiab 0.440 mM ntawm mycophenolate thiab 0.049, 0.110, thiab 0.450 mM ntawm diphenols, feem. Tsis tas li ntawd, nws tau pom tias qhov hloov pauv cinnamaldehyde derivative muaj zog dua piv rau cinnamaldehyde.

Tsis ntev los no, thio / barbiturates tau txais kev saib xyuas hauv thaj tsam ntawm tyrosinase inhibitors 86, vim lawv cov qauv zoo nkauj ntawm b-phenyl-a, b-unsaturated carbonyl scaffold lub luag haujlwm rau tyrosinase inhibitory muaj nuj nqi. Nyob rau hauv cov ntaub ntawv, ob peb 5-benzylidene (thio) barbiturates nrog hydroxyl hloov ntawm 4- txoj hauj lwm ntawm lub nplhaib phenyl tau zoo heev inhibitory kev ua ub no, piv txwv li, 23a thiab 23b inhibited nrog IC50 qhov tseem ceeb ntawm 13.98 thiab 14.49 lM, raws li 87 (Daim duab 8(b)). Kev tshoov siab los ntawm txoj haujlwm no, Chen li al., tsis ntev los no tau tshawb nrhiav SAR ntawm thio / barbiturates hais txog txoj haujlwm thiab cov naj npawb ntawm hydroxyl substituents rau kev cuam tshuam ntawm tyrosinase inhibitory kev ua. Yog li ntawd, ib tug series ntawm hydroxy- lossis methoxy-hloov pauv 5-benzylidene (thio) barbiturates tau tshaj tawm rau lawv cov teebmeem inhibitory ntawm diphenols kev ua ntawm nceb tyrosinase88. Cov txiaj ntsig tau pom tias cov tebchaw (23c–23 g) muaj lub zog tyrosinase inhibitory ua haujlwm piv rau kojic acid (IC50=18.25 lM). Hauv particular, ib qho kev sib xyaw nrog 3,4-dihydroxy substituents 23e tau txheeb xyuas tias yog qhov zoo tshaj plaws inhibitor nrog tus nqi IC50 ntawm 1.52 lM. Cov kev tshawb fawb SAR tau qhia tias barbiturates muaj zog tshaj thiobarbiturates thiab 3,4-dihydroxyl pawg ntawm lub nplhaib phenyl txhim kho lub zog. Tsis tas li ntawd, cov tshuaj inhibitors tau pom rau hom rov qab.

Yog xav paub ntxiv: david.deng@wecistanche.com WhatApp:86 13632399501