Natural Product (NP) Details

General Information of the NP (ID: NP0395)
Name
Nobiletin
Synonyms
Hexamethoxyflavone; 3',4',5,6,7,8-Hexamethoxyflavone; 5,6,7,8,3',4'-Hexamethoxyflavone; UNII-D65ILJ7WLY; 2-(3,4-Dimethoxyphenyl)-5,6,7,8-tetramethoxy-4H-1-benzopyran-4-one; 2-(3,4-dimethoxyphenyl)-5,6,7,8-tetramethoxychromen-4-one; NSC-76751; D65ILJ7WLY; 2-(3,4-dimethoxyphenyl)-5,6,7,8-tetramethoxy-4H-chromen-4-one; CHEMBL76447; Nobiletin (Hexamethoxyflavone); CHEBI:7602; NSC76751; MFCD03273560; Flavone, 5,6,7,8,3',4'-hexamethoxy; 4H-1-Benzopyran-4-one, 2-(3,4-dimethoxyphenyl)-5,6,7,8-tetramethoxy-; SMR000156231; CCRIS 9012; NSC 76751; CPD000156231; Nobiletin, >=97%; Spectrum2_001697; Spectrum3_000921; Spectrum4_001020; KBioGR_001519; MLS000574877; MLS000759462; MLS000877030; MLS001424129; Nobiletin, analytical standard; SCHEMBL244029; SPECTRUM1505268; SPBio_001654; MEGxp0_000930; ACon1_000921; KBio3_001922; DTXSID30197275; 2-(3,4-dimethoxyphenyl)-5,6,7,8-tetramethoxy-chromen-4-one; HMS2051D09; HMS2234A09; HMS3373C14; HMS3393D09; HMS3651G20; HY-N0155; ZINC1531669; 3'4'5,6,7,8-Hexamethoxyflavone; 3,4,5,6,7,8-Hexamethoxyflavone; ANW-42631; BDBM50338976; CCG-38781; CN0043; LMPK12111468; NSC618903; STL565829; AKOS015965334; NOBILETIN, 20% (Technical Grade); AC-1023; CS-5518; MCULE-1015144950; NC00186; NSC-618903; SDCCGMLS-0066776.P001; NCGC00095703-01; NCGC00095703-02; NCGC00169228-01; 5,6,7,8,3'',4''-hexamethoxyflavone; AK168175; AS-17452; NCI60_041691; DB-050181; FT-0686667; N0871; N1311; S2333; SW197566-2; V0181; C10112; SR-01000712262; Q-100511; Q2402963; SR-01000712262-5; BRD-K06753942-001-02-0; 2-(3,4-Dimethoxy-phenyl)-5,6,7,8-tetramethoxy-chromen-4-one; 4H-1-Benzopyran-4-one,4-dimethoxyphenyl)-5,6,7,8-tetramethoxy-; 2-(3,4-Dimethoxyphenyl)-5,6,7,8-tetramethoxy-4H-1-benzopyran-4-one, 9CI; 3 inverted exclamation mark ,4 inverted exclamation mark ,5,6,7,8-HEXAMETHOXYFLAVONE; 4H-1-Benzopyran-4-one, 2-(3,4-dimethoxyphenyl)-5,6,7,8-tetramethoxy- (9CI)
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Species Origin Ageratum conyzoides ...     Click to Show/Hide
Ageratum conyzoides
Kingdom: Viridiplantae
Phylum: Streptophyta
Class: Magnoliopsida
Order: Asterales
Family: Asteraceae
Genus: Ageratum
Species: Ageratum conyzoides
Disease Breast cancer [ICD-11: 2C60] Investigative [1]
Structure
Click to Download Mol
2D MOL

3D MOL

ADMET Property
Absporption
Caco-2 Permeability
 -4.492
 
MDCK Permeability
 -4.537
 
PAMPA
 - - -
 
HIA
 - - -
 
Distribution
VDss
 -0.161
 
PPB
 94.6%
 
BBB
 - - -
 
Metabolism
CYP1A2 inhibitor
 ++
CYP1A2 substrate
 ++
CYP2C19 inhibitor
 -
CYP2C19 substrate
 ++
CYP2C9 inhibitor
 +
CYP2C9 substrate
 - - -
CYP2D6 inhibitor
 - - -
CYP2D6 substrate
 +++
CYP3A4 inhibitor
 +
CYP3A4 substrate
 +++
CYP2B6 inhibitor
 ++
CYP2B6 substrate
 - - -
CYP2C8 inhibitor
 +++
HLM Stability
 +
 
Excretion
CLplasma
 6.976
 
T1/2
 1.705
Toxicity
DILI
 ++
 
Rat Oral Acute Toxicity
 -
 
FDAMDD
 -
 
Respiratory
 ++
 
Human Hepatotoxicity
 -
 
Ototoxicity
 - -
 
Drug-induced Nephrotoxicity
 - -
 
Drug-induced Neurotoxicity
 +
 
Hematotoxicity
 +
 
Genotoxicity
 - - -
 
Tips: 1. For the classification endpoints, the prediction probability values are transformed into six symbols: 0-0.1 (- - -), 0.1-0.3 (- -), 0.3-0.5 (-), 0.5-0.7 (+), 0.7-0.9 (++), and 0.9-1.0 (+++). 2. Additionally, the corresponding relationships of the three labels are as follows: excellent; medium; poor.
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    Click to Show/Hide the Molecular Information and External Link(s) of This Natural Product
Formula
C21H22O8
PubChem CID
72344
Canonical SMILES
COC1=C(C=C(C=C1)C2=CC(=O)C3=C(O2)C(=C(C(=C3OC)OC)OC)OC)OC
InChI
1S/C21H22O8/c1-23-13-8-7-11(9-15(13)24-2)14-10-12(22)16-17(25-3)19(26-4)21(28-6)20(27-5)18(16)29-14/h7-10H,1-6H3
InChIKey
MRIAQLRQZPPODS-UHFFFAOYSA-N
CAS Number
CAS 478-01-3
Herb ID
HBIN037171
ETMC ID
1348
SymMap ID
SMIT00234
TCMSP ID
MOL005828
Combinatorial Therapeutic Effect(s) Validated Clinically or Experimentally
    α. A List of Drug(s) Whose Efficacy can be Enhanced by This NP
          Sorafenib      Renal cell carcinoma     Click to Show/Hide the Molecular Data of This Drug
                 Achieving Therapeutic Synergy     Click to Show/Hide
                    Representative Experiment Reporting the Effect of This Combination [2]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Molecule(s)
                    Regulation		 Up-regulation Expression BAX  Molecule Info 
Pathway MAP
Up-regulation Expression CDKN1A  Molecule Info 
Pathway MAP
Up-regulation Expression RB1  Molecule Info 
Pathway MAP
                    In-vitro Model PC-3 CVCL_0035 Prostate carcinoma Homo sapiens
                    Experimental
                    Result(s)		 NOB and SOR combination was more effective than SOR and NOB alone and reduced the exposure time for SOR and NOB in PC-3 cells. NOB and SOR combination significantly caused much more apoptotic cell death and cell cycle arrest at G0/G1 phase by up-regulation of Bax, Rb1, and CDKN1A levels in PC-3 cells.
Target and Pathway
Target(s) Apoptosis mediating surface antigen FAS (FAS)  Molecule Info  [3]
Apoptosis regulator BAX (BAX)  Molecule Info  [4]
Protein kinase B alpha (AKT1)  Molecule Info  [5]
KEGG Pathway MAPK signaling pathway Click to Show/Hide
2 ErbB signaling pathway
3 Ras signaling pathway
4 Rap1 signaling pathway
5 cGMP-PKG signaling pathway
6 cAMP signaling pathway
7 Chemokine signaling pathway
8 HIF-1 signaling pathway
9 FoxO signaling pathway
10 Sphingolipid signaling pathway
11 mTOR signaling pathway
12 PI3K-Akt signaling pathway
13 AMPK signaling pathway
14 Apoptosis
15 Adrenergic signaling in cardiomyocytes
16 VEGF signaling pathway
17 Osteoclast differentiation
18 Focal adhesion
19 Tight junction
20 Signaling pathways regulating pluripotency of stem cells
21 Platelet activation
22 Toll-like receptor signaling pathway
23 Jak-STAT signaling pathway
24 T cell receptor signaling pathway
25 B cell receptor signaling pathway
26 Fc epsilon RI signaling pathway
27 Fc gamma R-mediated phagocytosis
28 TNF signaling pathway
29 Neurotrophin signaling pathway
30 Cholinergic synapse
31 Dopaminergic synapse
32 Insulin signaling pathway
33 Progesterone-mediated oocyte maturation
34 Estrogen signaling pathway
35 Prolactin signaling pathway
36 Thyroid hormone signaling pathway
37 Adipocytokine signaling pathway
38 Glucagon signaling pathway
39 Regulation of lipolysis in adipocytes
40 Non-alcoholic fatty liver disease (NAFLD)
41 Carbohydrate digestion and absorption
42 Chagas disease (American trypanosomiasis)
43 Toxoplasmosis
44 Tuberculosis
45 Hepatitis C
46 Hepatitis B
47 Measles
48 Influenza A
49 HTLV-I infection
50 Epstein-Barr virus infection
51 Pathways in cancer
52 Proteoglycans in cancer
53 Colorectal cancer
54 Renal cell carcinoma
55 Pancreatic cancer
56 Endometrial cancer
57 Glioma
58 Prostate cancer
59 Melanoma
60 Chronic myeloid leukemia
61 Acute myeloid leukemia
62 Small cell lung cancer
63 Non-small cell lung cancer
64 Central carbon metabolism in cancer
65 Choline metabolism in cancer
66 Cytokine-cytokine receptor interaction
67 p53 signaling pathway
68 Natural killer cell mediated cytotoxicity
69 Type I diabetes mellitus
70 Alzheimer's disease
71 African trypanosomiasis
72 Herpes simplex infection
73 Autoimmune thyroid disease
74 Allograft rejection
75 Graft-versus-host disease
NetPath Pathway TSH Signaling Pathway Click to Show/Hide
2 IL2 Signaling Pathway
3 TCR Signaling Pathway
Panther Pathway Angiogenesis Click to Show/Hide
2 Apoptosis signaling pathway
3 EGF receptor signaling pathway
4 Endothelin signaling pathway
5 FGF signaling pathway
6 Huntington disease
7 Hypoxia response via HIF activation
8 Inflammation mediated by chemokine and cytokine signaling pathway
9 Insulin/IGF pathway-protein kinase B signaling cascade
10 Interleukin signaling pathway
11 PI3 kinase pathway
12 T cell activation
13 VEGF signaling pathway
14 p53 pathway
15 Ras Pathway
16 p53 pathway by glucose deprivation
17 p53 pathway feedback loops 2
18 CCKR signaling map ST
19 FAS signaling pathway
Pathwhiz Pathway Intracellular Signalling Through Adenosine Receptor A2a and Adenosine Click to Show/Hide
2 Intracellular Signalling Through Adenosine Receptor A2b and Adenosine
3 Fc Epsilon Receptor I Signaling in Mast Cells
4 Insulin Signalling
5 Leucine Stimulation on Insulin Signaling
Pathway Interaction Database Regulation of nuclear SMAD2/3 signaling Click to Show/Hide
2 Fc-epsilon receptor I signaling in mast cells
3 Endothelins
4 BCR signaling pathway
5 LPA receptor mediated events
6 Insulin Pathway
7 IL4-mediated signaling events
8 TCR signaling in na&#xef
9
10 Plasma membrane estrogen receptor signaling
11 CD40/CD40L signaling
12 Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met)
13 Signaling events mediated by PTP1B
14 S1P3 pathway
15 Coregulation of Androgen receptor activity
16 Reelin signaling pathway
17 Integrin-linked kinase signaling
18 TCR signaling in na&#xef
19
20 Angiopoietin receptor Tie2-mediated signaling
21 FAS (CD95) signaling pathway
22 Thromboxane A2 receptor signaling
23 Regulation of Telomerase
24 FOXA2 and FOXA3 transcription factor networks
25 Glucocorticoid receptor regulatory network
26 mTOR signaling pathway
27 CXCR4-mediated signaling events
28 IGF1 pathway
29 FoxO family signaling
30 IL2 signaling events mediated by PI3K
31 Ceramide signaling pathway
32 p75(NTR)-mediated signaling
33 E-cadherin signaling in the nascent adherens junction
34 amb2 Integrin signaling
35 Integrins in angiogenesis
36 IFN-gamma pathway
37 ErbB1 downstream signaling
38 ErbB2/ErbB3 signaling events
39 IL6-mediated signaling events
40 E-cadherin signaling in keratinocytes
41 Nephrin/Neph1 signaling in the kidney podocyte
42 Retinoic acid receptors-mediated signaling
43 IL8- and CXCR2-mediated signaling events
44 Signaling events mediated by the Hedgehog family
45 Nongenotropic Androgen signaling
46 Hedgehog signaling events mediated by Gli proteins
47 Caspase Cascade in Apoptosis
48 CXCR3-mediated signaling events
49 VEGFR1 specific signals
50 Signaling events mediated by Stem cell factor receptor (c-Kit)
51 Signaling events mediated by VEGFR1 and VEGFR2
52 a6b1 and a6b4 Integrin signaling
53 Aurora A signaling
54 Insulin-mediated glucose transport
55 Class I PI3K signaling events mediated by Akt
56 IL8- and CXCR1-mediated signaling events
57 HIF-1-alpha transcription factor network
58 p53 pathway
59 Trk receptor signaling mediated by PI3K and PLC-gamma
60 VEGFR3 signaling in lymphatic endothelium
61 FGF signaling pathway
62 p73 transcription factor network
63 Direct p53 effectors
64 HIV-1 Nef: Negative effector of Fas and TNF-alpha
65 Validated transcriptional targets of TAp63 isoforms
Reactome Activation of BAD and translocation to mitochondria Click to Show/Hide
2 GPVI-mediated activation cascade
3 PIP3 activates AKT signaling
4 Translocation of GLUT4 to the plasma membrane
5 Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation
6 AKT phosphorylates targets in the cytosol
7 AKT phosphorylates targets in the nucleus
8 Negative regulation of the PI3K/AKT network
9 eNOS activation
10 AKT-mediated inactivation of FOXO1A
11 Integrin alphaIIb beta3 signaling
12 Deactivation of the beta-catenin transactivating complex
13 CD28 dependent PI3K/Akt signaling
14 CTLA4 inhibitory signaling
15 G beta:gamma signalling through PI3Kgamma
16 KSRP (KHSRP) binds and destabilizes mRNA
17 VEGFR2 mediated vascular permeability
18 TP53 Regulates Metabolic Genes
19 Constitutive Signaling by AKT1 E17K in Cancer
20 FasL/ CD95L signaling
WikiPathways Toll-like receptor signaling pathway Click to Show/Hide
2 DNA Damage Response (only ATM dependent)
3 TCR Signaling Pathway
4 Notch Signaling Pathway
5 EPO Receptor Signaling
6 IL-2 Signaling Pathway
7 Insulin Signaling
8 Endochondral Ossification
9 EGF/EGFR Signaling Pathway
10 IL-4 Signaling Pathway
11 TGF beta Signaling Pathway
12 IL-6 signaling pathway
13 Wnt Signaling Pathway Netpath
14 Copper homeostasis
15 Extracellular vesicle-mediated signaling in recipient cells
16 Apoptosis-related network due to altered Notch3 in ovarian cancer
17 IL-3 Signaling Pathway
18 Cardiac Hypertrophic Response
19 Translocation of GLUT4 to the Plasma Membrane
20 Regulation of mRNA Stability by Proteins that Bind AU-rich Elements
21 PIP3 activates AKT signaling
22 Signal Transduction of S1P Receptor
23 T-Cell Receptor and Co-stimulatory Signaling
24 Primary Focal Segmental Glomerulosclerosis FSGS
25 Apoptosis
26 Alpha 6 Beta 4 signaling pathway
27 BDNF signaling pathway
28 Integrated Pancreatic Cancer Pathway
29 Oncostatin M Signaling Pathway
30 Corticotropin-releasing hormone
31 Interleukin-11 Signaling Pathway
32 AGE/RAGE pathway
33 TNF alpha Signaling Pathway
34 B Cell Receptor Signaling Pathway
35 Prostate Cancer
36 Signaling Pathways in Glioblastoma
37 TSLP Signaling Pathway
38 IL17 signaling pathway
39 IL-7 Signaling Pathway
40 Regulation of Microtubule Cytoskeleton
41 TWEAK Signaling Pathway
42 FSH signaling pathway
43 Leptin signaling pathway
44 TSH signaling pathway
45 RANKL/RANK Signaling Pathway
46 Integrated Breast Cancer Pathway
47 SREBP signalling
48 Integrated Cancer pathway
49 IL-1 signaling pathway
50 Metabolism of nitric oxide
51 Integrin-mediated Cell Adhesion
52 TFs Regulate miRNAs related to cardiac hypertrophy
53 MicroRNAs in cardiomyocyte hypertrophy
54 Angiogenesis
55 TOR Signaling
56 Regulation of toll-like receptor signaling pathway
57 AMPK Signaling
58 Androgen receptor signaling pathway
59 IL-5 Signaling Pathway
60 DNA Damage Response
61 Apoptosis Modulation by HSP70
62 MAPK Signaling Pathway
63 FAS pathway and Stress induction of HSP regulation
64 Adipogenesis
65 Allograft Rejection
66 Alzheimers Disease
67 Extrinsic Pathway for Apoptosis
68 Apoptosis Modulation and Signaling
69 miRNA Regulation of DNA Damage Response
References
Reference 1 Nobiletin inhibits breast cancer via p38 mitogen-activated protein kinase, nuclear transcription factor-KappaB, and nuclear factor erythroid 2-related factor 2 pathways in MCF-7 cells. Food Nutr Res. 2018 Nov 21;62.
Reference 2 Synergistic Effects of Nobiletin and Sorafenib Combination on Metastatic Prostate Cancer Cells. Nutr Cancer. 2019;71(8):1299-1312.
Reference 3 Nobiletin induces brown adipocyte-like phenotype and ameliorates stress in 3T3-L1 adipocytes. Biochimie. 2018 Mar;146:97-104.
Reference 4 Inhibitory effects of nobiletin on hepatocellular carcinoma in vitro and in vivo. Phytother Res. 2014 Apr;28(4):560-7.
Reference 5 Nobiletin, a citrus flavonoid, suppresses invasion and migration involving FAK/PI3K/Akt and small GTPase signals in human gastric adenocarcinoma AGS cells. Mol Cell Biochem. 2011 Jan;347(1-2):103-15.
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