천연 화합물의 후성 유전적 활성(HDAC Inhibitors)

New Insights into the Epigenetic Activities of Natural Compounds

2018

http://www.lidsen.com/journals/genetics/genetics-02-03-029

 

Table 1 Screening results.

Sirt activation is denoted by a minus sign.

 

DNMT: DNA methylation transferase; SAM: S-adenosyl-methionine; SAH: S-Adenosyl-L-homocysteine; BRET: Bioluminescent resonance energy transfer; HDAC: Histone deacetylase; Sirt: Sirtuin; me3H3K9 and me3H3K27: trimethylated histone H3 lysine 9 and 27.

Compounds Underlined when screened for HDAC6 (11)		Biological Activity (viability as IC50 in MCF7)					HDAC inhibition (BRET)	HDAC inhibition (% of control at 100 µM) (HeLa nuclear extract)		Sirt inhibition (% of control at 60 µM)	Plants which contain the compound
5-Aza-cytidine		DNMT1 control (0.13 μM ± 0.05)					(-)
Zebularine		DNMT1 control (426 µM ± 21)					(-)
SGI-1027		DNMT1 control, IC50 for DNMT1: 6 μM, DNMT3A: 8 μM and DNMT3B: 7.5 μM (4.8 µM ± 0.21)					(-)
BIX-01294		KDM control, IC50: G9a: 2.7 μM and G9a-like protein: 0.7 µM (5.44 µM ± 0.20)					(-)
DZNep		KDM control: IC50 for EZH2: 0.8–0.24 µM (SAH) (0.0153 µM ± 0)					(-)
Chaetocin		KDM control IC50 for Su(var)3-9: 0.8 μM (0.8 μM ± 0.03)					(-)
Entinostat MS275		HDAC control, IC50 for HDAC1: 0.368 μM, HDAC3: 1.7 μM and HDAC8: 63.4 μM (0.4 µM ± 0.01)					+
Tacedinaline CI994		HDAC control, IC50 for HDAC1: 18.22 ± 2.45 µM, HDAC2: 3.85 ± 0.11 µM, HDAC3 and HDAC6: > 100 µM (0.5 µM±0.02)					+	42 ± 0.9
Tubastatin A		HDAC control, IC50 for HDAC6,: 34.9 ± 1.4 μM and HDAC8: >200 µM (15 µM ± 0.5)					(-)
Vorinostat SAHA		HDAC control, IC50 for HDAC1: 0.35 ± 0.04 µM, HDAC2:0.55 ± 0.08 µM, HDAC3: 0.14 ± 0.01 µM and HDAC6: 0.05 ± 0.01 µM (0.75 µM ± 0.03)					+	100 ± 1.5		Sirt2: 12 ± 1
Trichostatin TSA		HDAC control, IC50 for HDAC 1: 15.7 ± 1.5 µM, HDAC3: 0.0015 ± 0.1 µM and HDAC 6: 16.0 ± 0.74 µM (0.052 µM ± 0.002)					+	59.3 ± 4.4
Valproic acid		HDAC 1 inhibitor, IC50: 400 µM (20 mM ± 0.9)					+
Sodium butyrate		HDACI 1 and 3 Control (IC50: 300 µM both) (8 mM ± 0.35)					+
Sirtinol		Sirt control, IC50 for Sirt1: 131 μM and Sirt2 and Sirt3: 8 μM (30 µM ± 1.2)					(-)			Sirt2: 92.57 ± 5
Tenovin 6		Sirt Control, IC50 for Sirt1:21 μM, Sirt2: 10 μM and Sirt3: 67 μM (6 µM ± 0.25)					(-)			Sirt1:73.9 ± 1.3 and Sirt2: 94.9 ± 0.4
Cambinol		Sirt Control, IC50 for Sirt1: 59.5 ± 1.1 μM and Sirt2: 51.9 ± 1.2 μM (4.8 µM ± 2.3)					(-)			Sirt1: 59.5 ± 1.0 and Sirt2: 51.9 ± 1
Anacardic acid B		HAT inhibitor, IC50 for PCAF: 5 µM and 8.5 µM for p300 (85 µM ± 4.1)					(-)				Cashews and mango
Scutellarin		Flavone (15 µM ± 0.7)					+	100 ± 2.5 HDAC1: 42.2 ± 2.4 HDAC2: >100 HDAC3: 18.0 ± 7.9			Scutellaria lateriflor and Asplenium belangeri
Apigenin		Flavone (3 µM ± 0.12)					+	79.11±2.4 HDAC3: 31.2±10.6 µM		Sirt1: 2.1 ± 7.4 and Sirt2: 32.8 ± 1.2	Parsley, celery, Chinese cabbage, garlic, apples, olive oil and chamomile tea
Chrysin		Flavone (35 µM ± 1.6)					(-)	14.9 ± 5.7			Passiflora caerulea, Pleurotus ostreatus and Oroxylum indicum
Isorhoifolin		Flavone					(-)				Peppermint and olives
Diosmetin		Flavone (>150 µM)					(-)			Sirt2: 19.8 ± 5	Vicia
Genkwanin		Flavone (9 µM ± 0.4)					(-)				Alnus glutinosa, Notholaena bryopoda and Asplenium normale
Genistein		Isoflavone (74 µM ± 3.4)					(-)	16.8 ± 2.0			Soybean, green bean, alfalfa and mung bean sprouts, red clover, chickpeas, kudzu root, peanuts and other legumes
Trihydroxy isoflavone		Isoflavone (100 µM ± 4)					+	24.7 ± 0.4			Soy, alfalfa sprouts, red clover, chickpeas, peanuts, kudzu and other legumes
Biochanin A		Isoflavone (102 µM ± 5)					(-)			Sirt1: 18.91 ± 1 and Sirt2: 10.9 ± 1	Chickpea
Biochanin B Formononetin		Isoflavone (68 µM ± 3)					(-)			Sirt1: 14.21 ± 5 and Sirt2: - 14.2 ± 0	Red clover, green beans, lima beans and soy
S- (-) Equol		Metabolite of isoflavone (100 µM ± 4)					(-)				Soybeans
Galangin		Flavonol					+	40.77 ± 2.0			Alpinia galangal and propolis
Kaempferol		Flavonol (25 µM ± 1.1)					+	87.74 ± 2.3			Tea, strawberries, gooseberries, cranberries, grapefruit, apples, peas, brassicas, chives, spinach, endive, leek and tomatoes
Morin hydrate		Flavonol (40 µM ± 1.9)					+	83 ± 2.1
Myricitrin		Flavonol (>200 µM)					+	43.6 ± 0,5			Grapes, red wine, berries and walnuts
Robinetin		Flavonol (>200 µM)					(-)				Vinca erecta and Robinia pseudoacacia
Quercetin hydrate		Flavonol (102 µM ± 4)					+	70 ± 3.0		Sirt1: 33.6 ± 1.2 and Sirt2: 52.7 ± 1.6	Onions, tea, wine, apples, cranberries, buckwheat and beans
Isoquercetin		Flavonol (102 µM ± 4.8)					+	68.6 ± 2.3			Mango and rhubarb
Ermanin		Flavonol					+	78.61 ± 5.2			Tanacetum microphyllum
Robinin		Flavonol					+	76.04 ± 3.2		Sirt1: 2.2 ± 1.7 and Sirt2: -5.4 ± -4.5	Vinca erecta and Robinia pseudoacacia
Rutin		Flavonol (>150 µM)					+	81.22 ± 6.0		Sirt1: 19.3 ± 0.3 and Sirt2: 3.8 ± 1.65	Citrus species, berries, peaches, apples, pagoda tree fruits, asparagus, buckwheat, parsley, tomatoes, apricots, rhubarb and tea
(+)-Catechin		Flavanol (>200 µM)					+	41.62 ± 4.0			Tea, grapes, wine, apple juice, cocoa, lentils and black-eyed peas
(-)-Epicatechin		Flavanol (>200 µM)					(-)	-2.5			Tea, grapes, wine, apple juice, cocoa, lentils and black-eyed peas
(–)-Epigallocatechin gallate		Flavanol (37 µM ± 1.5)					(-)				Green tea
Rhamnetin		Flavanol					(-)				Cloves
Narirutin		Flavanone					(-)				Oranges
Hesperidin		Flavanone					(-)				Citrus fruits
Pinocembrin		Flavanone					(-)			Sirt1: -10.7 ± 0 and Sirt2: 0	Damiana, ginger root and propolis
Chalcone 4 hydrate		Flavonoid					(-)
Aureusidine		Flavonoid					(-)	18.5 ± 2.3		Sirt1: -25.6 ± 5.8 and Sirt2: 1.6 ± 1.32	Garden snapdragon
Coumarin		Hydroxycinnamic acid derivative					(-)				Citrus fruits and maize
Imperatorin		Hydroxycinnamic acid derivative					(-)				Urena lobata L., Angelica archangelica and dahurica Glehnia littoralis, Saposhnikovia divaricata, Cnidium monnieri, Incarvillea younghusbandii and Zanthoxylum americanum mill
Umbelliferone		Hydroxycinnamic acid derivative					+	14.9 ± 5.7			Hydrangea macrophylla
Methoxsalen		Hydroxycinnamic acid derivative					(-)				Bergamot
Caffeic acid		Hydroxycinnamic acid derivative					(-)				Coffee, Acai berry oil, vanilla and cloves
Chlorogenic acid		Hydroxycinnamic acid derivative					+	46.16 ± 0.8		Sirt1: 5.9 ± 1 and Sirt2: 18.7 ± 7.4	Echinacea, strawberries, pineapple, coffee, sunflower seeds, blueberries
Ferulic acid		Hydroxycinnamic acid derivative					(-)				Echinacea, strawberries, pineapple, coffee, sunflower seeds, blueberries
Curcumin		Hydroxycinnamic acid derivative					(-)			Sirt1: 10.7 ± 0.4 and Sirt2: 40.2 ± 12.8	Turmeric and curry powder
Trans Resveratrol		Stilbenoid (200 µM ± 9)					(-)			Sirt1: - 15.3 ± 3.9 and Sirt2: 22.4 ± 3.1	Grape, nuts, peanuts and Japanese knotweed root.
Carminic acid		Glucosidal Hydroxyl anthrapurin					(-)				Armenian and Polish cochineal
(S)- Evodiamine		Alkaloid (5.44 µM ± 3.2)					(-)			Sirt1: 4.2 ± 3.6, Sirt2: 71 ± 2.1 and Sirt3: 20 ± 2.1	Tetradium genus of plants
Brucine		Alkaloid (0.9 µM ± 0.04)					(-)	17.94 ± 0.7		Sirt1: -10.5±0.1 and Sirt2: 74.9±16	Strychnos nux-vomica
Boldine		Alkaloid (>160 µM)					(-)	14.35 ± 2.5		Sirt1: -4.3 ± 1 and Sirt2: 24.62 ± 6.65	Boldo tree and Lindera aggregata
Tabersonine		Alkaloid (>160 µM)					+	29.62 ± 2.5			Catharanthus roseus
Papaverin		Alkaloid (21 µM ± 1)					(-)				Opium poppy
Trigonelline hydrochloride		Alkaloid (<220 µM)					(-)				Fenugreek , peas, hemp seed, oats, potatoes, Stachys species, dahlia, Strophanthus species, Dichapetalum cymosum and arabica coffee
Vincamine		Alkaloid					(-)				Vinca minor
Pilocarpine		Alkaloid					(-)				Pilocarpus
Protopine		Alkaloid (400 µM ± 18)					(-)				Opium poppy, Corydalis tubers and Fumaria officinalis
Caffeine		Alkaloid					(-)				Coffee bean
Quinine		Alkaloid					(-)			Sirt1: 9.45 ± 1	Cinchona tree
Neoruscogenin		Terpenoid					(-)			Sirt1: 21.62 ± 0 and Sirt2: 26.65 ± 2.3	Butcher's broom
Marrubin		Diterpene					(-)				Lion's tail and black horehound
Cycloartenol acetate		Triterpene					(-)			Sirt1: -4.4 ± 1 and Sirt2: 0	Olive
Glycyrrhetinic acid		Triterpene					(-)				Liquorice
Cucurbitacine echinocistic acid 3 glucoside		Triterpene					(-)	6.24 ± 1.2			Pumpkins and gourds
Retinoic Acid		Terpenoid					(-)				Mango, orange, papaya, carrots, spinach, sweet potatoes and crude palm oil
Camphene		Terpenoid					(-)				Turpentine, cypress, camphor, citronella, neroli, ginger, and valerian
Emodin		Anthraquinone					+	42.6 ± 5.0			Rhubarb, buckthorn, and Japanese knotweed
Rhein		Anthraquinone					+	42.6 ± 5.0			Rhubarb
Aloin		Anthraquinone					+	72.6 ± 5.0		Sirt1: 39 ± 2.2 and Sirt2: 39.7 ± 6.9	Aloe species
Withaferin A		Steroidal lactone					(-)	6.85 ± 0.2			Indian Winter cherry
Withanone		Steroidal lactone					(-)				Indian Winter cherry
D-Glucuronic acid		Sugar acid					(-)				Gum Arabic
Plumbagin		5-Hydroxy-2-methyl-1,4-naphthoquinone					(-)			Sirt2: 41.8 ± 6.9	Plumbago
Arbutine		Glycosylated hydroquinone					(-)				Bearberry
Cymarine		Cardiac glucoside					(-)	8.73 ± 1.1		Sirt1: 3.6 ± 0.8 and Sirt2: 20.4 ± 1.5	Apocynum cannabinum and venetum
Catalpol		Iridoid glucoside					(-)				Catalpa
Lanatoside C		Cardiac glucoside					(-)				Digitalis lanata
L-Carnitine		3-Hydroxy-4-trimethylammonio-butanoate					(-)	-13.5 ± 1.1			Muscle metabolite
Vanillin alcohol		Phenolic acid					(-)				Acai berry oil, vanilla beans and cloves
Salicylic alcohol		Phenolic acid					(-)				Peppermint, liquorice, peanut and wheat

 

Diosmetin, (S)-equol, umbelliferone, papaverin 및 L-carnitine은 새로운 DNA 탈메틸화제로 확인되었습니다. 

Emodin, rhein, aloin 및 D-glucuronic acid는 새로운 히스톤 H3 탈메틸화 화합물로 확인되었습니다. 

이전에 설명되지 않은 아피제닌, 바이오카닌 B, 로비닌, 피노셈브린, 아우레시딘, 브루신 및 볼딘에 의한 Sirt 활성화도 감지되었습니다.

 

 Apigenin, galangin, scutallerein, kaempferol, ermanin, robinin, morin, myricitrin, quercetin, isoquercetin, rutin, epicatechin, catechin, chlorogenic acid, emodin, rhein 및 aloin은 두 분석 모두에서 상당한 전역 HDAC 억제 활성을 갖는 것으로 밝혀졌습니다.

 

후성유전학은 DNA 염기서열의 변화 없이 일어나는 게놈의 유전적 변화로 정의됩니다. 

후성유전학적 변형은 가역적이기 때문에 의약화학자들에게 중요한 연구 분야이다. 

몇몇 천연 영양소는 DNA의 변형, 히스톤 메틸화 및 히스톤 아세틸화뿐만 아니라 마이크로 및 긴 비암호화 RNA의 변형을 통해 후성유전체에 영향을 미치는 것으로 밝혀졌습니다