BETULINIC ACID

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C30H48O3
Molecular Weight	456.7003
Optical Activity	UNSPECIFIED
Defined Stereocenters	10 / 10
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

[H][C@]12[C@@H](CC[C@@]1(CC[C@]3(C)[C@]2([H])CC[C@]4([H])[C@@]5(C)CC[C@H](O)C(C)(C)[C@]5([H])CC[C@@]34C)C(O)=O)C(C)=C

InChI

InChIKey=QGJZLNKBHJESQX-FZFNOLFKSA-N

InChI=1S/C30H48O3/c1-18(2)19-10-15-30(25(32)33)17-16-28(6)20(24(19)30)8-9-22-27(5)13-12-23(31)26(3,4)21(27)11-14-29(22,28)7/h19-24,31H,1,8-17H2,2-7H3,(H,32,33)/t19-,20+,21-,22+,23-,24+,27-,28+,29+,30-/m0/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/19325847 | https://www.ncbi.nlm.nih.gov/pubmed/12118187 | https://www.ncbi.nlm.nih.gov/pubmed/27748864 | https://www.ncbi.nlm.nih.gov/pubmed/8176401 | https://www.ncbi.nlm.nih.gov/pubmed/9810272

Betulinic acid (BA) is a plant-derived pentacyclic triterpenoid that exerts potent anti-cancer effects in vitro and in vivo. It`s anticancer property is linked to its ability to induce apoptotic cell death in cancer cells by triggering the mitochondrial pathway of apoptosis. In contrast to the cytotoxicity of betulinic acid against a variety of cancer types, normal cells and tissue are relatively resistant to betulinic acid, pointing to a therapeutic window. Compounds that exert a direct action on mitochondria present promising experimental cancer therapeutics, since they may trigger cell death under circumstances in which standard chemotherapeutics fail. Thus, mitochondrion-targeted agents such as betulinic acid hold great promise as a novel therapeutic strategy in the treatment of human cancers. Betulinic acid has antiretroviral, antimalarial, and anti-inflammatory properties. Betulinic acid exerts its inhibitory effect by preventing topoisomerase I-DNA interaction as a result of which the 'cleavable complex' is not formed. In consequence, it also acts as an antagonist to camptothecin-mediated cleavage. The antitumor pharmacological effects of BA consist of triggering apoptosis via the mitochondrial pathway, regulating the cell cycle and the angiogenic pathway via factors, including specificity protein transcription factors, cyclin D1 and epidermal growth factor receptor, inhibiting the signal transducer and activator of transcription 3 and nuclear factor‑κB signaling pathways, preventing the invasion and metastasis of tumor cells, and affecting the expression of topoisomerase I, p53 and lamin B1. Betulinic Acid has also been used in trials studying the treatment of Dysplastic Nevus Syndrome. Betulinic acid acts as anti-melanoma agent through inhibiting aminopeptidase N activity with IC50 of 7.3 uM. Betulinic acid is an inhibitor of HIV-1 with EC50 of 1.4 uM.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
DNA topoisomerase 1 16 Target ID: CHEMBL1075164 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12118187	Inhibitor 8297	5.0 µM [IC50]
Apoptosis 155 Target ID: map04210 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26535952 \| https://www.ncbi.nlm.nih.gov/pubmed/19325847	Activator 1430
Human immunodeficiency virus 1 33 Target ID: CHEMBL378 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8176401	Inhibitor 8297	1.4 µM [EC50]
Aminopeptidase N 3 Target ID: CHEMBL1907 Sources: https://www.ncbi.nlm.nih.gov/pubmed/9810272	Inhibitor 8297	7.3 µM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Cancer 592 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12118187 https://www.ncbi.nlm.nih.gov/pubmed/19325847 https://www.ncbi.nlm.nih.gov/pubmed/24821543	Primary		Preclinical	Unknown Approved Use Unknown
Malignant melanoma 22 Sources: http://adisinsight.springer.com/drugs/800017884 https://clinicaltrials.gov/ct2/show/NCT00346502 https://www.ncbi.nlm.nih.gov/pubmed/10771474	Primary		Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
25.1 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:		BETULINIC ACID plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
25.1 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104	200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:		BETULINIC ACID plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
382.9 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104	200 mg single, oral dose: 200 mg route of administration: Oral experiment type: SINGLE co-administered:		BETULINIC ACID plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED
1113.7 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104	200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:		BETULINIC ACID plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
62.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/17596104	200 mg 1 times / day multiple, oral dose: 200 mg route of administration: Oral experiment type: MULTIPLE co-administered:		BETULINIC ACID plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
0.01% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/12955738			BETULINIC ACID plasma	Mus musculus population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
250 mg single, oral Highest studied dose Dose: 250 mg Route: oral Route: single Dose: 250 mg Sources: https://pubmed.ncbi.nlm.nih.gov/17638699 Page: p.3577	unhealthy, ADULT Health Status: unhealthy Condition: HIV infection Age Group: ADULT Sex: M Food Status: UNKNOWN Sources: https://pubmed.ncbi.nlm.nih.gov/17638699 Page: p.3577	Sources: https://pubmed.ncbi.nlm.nih.gov/17638699 Page: p.3577
200 mg 1 times / day multiple, oral Studied dose Dose: 200 mg, 1 times / day Route: oral Route: multiple Dose: 200 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/17596104 Page: p.594	healthy, ADULT n = 6 Health Status: healthy Age Group: ADULT Sex: M Food Status: FASTED Population Size: 6 Sources: https://pubmed.ncbi.nlm.nih.gov/17596104 Page: p.594	Sources: https://pubmed.ncbi.nlm.nih.gov/17596104 Page: p.594

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1587	inhibitor 1767	inhibitor 1852

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
BCRP 699 UGT1A6 108 UGT1A8 36 CYP2C19 1478 P-gp 1461 OATP1B3 706 ABCB5 4 UGT1A7 21 OATP1B1 788

Drug as perpetrator

Target	Modality	Activity
CYP2C19 1553	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/30467864/	no [IC50 >50 uM]
CYP2C9 1819	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/30467864/	no [IC50 >50 uM]
CYP2D6 1891	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/30467864/	no
UGT1A7 23	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/26957994/	weak
OATP1B3 715	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29462635/	yes [IC50 0.1386 uM]
OATP1B1 803	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29462635/	yes [IC50 1.286 uM]
CYP3A4 1925	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/30467864/	yes [IC50 16.98 uM]
P-gp 1650	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29867487/	yes [IC50 20.8 uM]
ABCB5 4	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29867487/	yes [IC50 21.37 uM]
BCRP 773	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/29867487/	yes [IC50 24.06 uM]
UGT1A6 141	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/26957994/	yes
UGT1A8 48	inhibitor 3277 Sources: https://pubmed.ncbi.nlm.nih.gov/26957994/	yes

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P003ON9	https://www.1pchem.com/search?query=1P003ON9
A2B Chem	AB71109	http://a2bchem.com/prod/AB71109
AK Scientific	2267AH	https://aksci.com/item_detail.php?cat=2267AH
Alfa Chemistry	113126	http://www.alfa-chemistry.com/search.aspx?q=113126
Alfa Chemistry	ACM25488533	http://www.alfa-chemistry.com/search.aspx?q=ACM25488533
Ambeed	A200416	http://www.ambeed.com/search/Search.html?keyword=A200416
Angene	AGN-PC-0RV191	http://www.angenechemical.com/productshow/AGN-PC-0RV191.html
Apollo Scientific	BIDF1001	http://www.apolloscientific.co.uk/chemical_results.php?qstext=BIDF1001&product_group=%25&search_fieldname=header_search
Apollo Scientific	BIDF1011	http://www.apolloscientific.co.uk/chemical_results.php?qstext=BIDF1011&product_group=%25&search_fieldname=header_search
AstaTech	24063	http://astatechinc.com/CPSResult.php?CRNO=24063
BLD Pharm	BD1981	http://www.bldpharm.com/search/Search.html?keyword=BD1981
BOC Sciences	25488-53-3	http://www.bocsci.com/description.asp?cas=25488-53-3
BOC Sciences	472-15-1	http://www.bocsci.com/description.asp?cas=472-15-1
BioSynth	Q-100500	https://www.biosynth.com/en/products/life-science/other-biochemicals/products/Q-100500
Biopurify Phytochemicals	BP0271	https://www.phytopurify.com/search.do?a=s&searchtype=3&psize=10&q=BP0271&searchhtmp=simplesearch&t=1
Capot Chemical	16912	https://www.capotchem.com/search.do?q=16912
Cayman Chemical	11686	http://www.caymanchem.com/app/template/Product.vm/catalog/11686
Chem Scene	CS-1216	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-1216
Chem4Pharma	C4PB282	https://www.chem4pharma.com/product-page/C4PB282
ChemDiv	N066-0053	http://chemistryondemand.com:8080/eShop/search_results.jsp?idnumber=N066-0053
Combi-Blocks	QC-7817	http://www.combi-blocks.com/cgi-bin/find.cgi?QC-7817
Fluorochem	228218	http://www.fluorochem.co.uk/Products/Product?code=228218
Fluorochem	M01408	http://www.fluorochem.co.uk/Products/Product?code=M01408
Lab Seeker	SC-19742	http://www.labseeker.com/search.php?keywords=SC-19742&category=0
LabSeeker	SC-19742	http://www.labseeker.com/search.php?keywords=SC-19742&category=0
Matrix Scientific	90209	http://www.matrixscientific.com/090209.html
MedChem Express	HY-10529	https://www.medchemexpress.com/search.html?q=HY-10529&ft=&fa=&fp=
MolPort	MolPort-003-939-279	https://www.molport.com/shop/molecule-link/MolPort-003-939-279
MolPort	MolPort-007-980-897	https://www.molport.com/shop/molecule-link/MolPort-007-980-897
MolPort	MolPort-039-033-337	https://www.molport.com/shop/molecule-link/MolPort-039-033-337
Molnova	M14569	https://www.molnova.com/en/serch-list.html?keywords=M14569
Ryan Scientific	Genipin	https://ryansci.com/products?q=Genipin&list_q=&search_type=exact
Selleck Chemicals	S3603	http://www.selleckchem.com/search.html?searchDTO.searchParam=S3603
Specs	AK-693/21159019	http://www.specs.net/enter.php?specsid=AK-693/21159019
TargetMol	BBP00043	https://www.targetmol.com/search?keyword=BBP00043
TargetMol	T2830	https://www.targetmol.com/search?keyword=T2830
Tetrahedron	TS71989	http://www.thsci.com/search.do?q=TS71989
TimTec	ST51036120	http://www.echemstore.com/catalogsearch/result/?q=ST51036120
Toronto Research Chemicals	B330250	https://www.trc-canada.com/product-detail/?CatNum=B330250
Vitas-M Laboratory	STL570261	http://www.vitasmlab.biz/search/STL570261
W&J PharmaChem	50A119165	http://wjpharmachem.com/new/searcht.php?keyword=50A119165
eMolecules	215689303	https://orderbb.emolecules.com/search/#?query=215689303
eMolecules	27249357	https://orderbb.emolecules.com/search/#?query=27249357
eMolecules	36726865	https://orderbb.emolecules.com/search/#?query=36726865
eMolecules	42749934	https://orderbb.emolecules.com/search/#?query=42749934
eNovation Chemicals	D628751	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D628751&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-3066570238	https://mcule.com/MCULE-3066570238/
mcule	MCULE-5368790248	https://mcule.com/MCULE-5368790248/

PubMed

Title	Date	PubMed
Anti-AIDS agents 38. Anti-HIV activity of 3-O-acyl ursolic acid derivatives.	2000 Dec	11141100
Acetyl-boswellic acids are novel catalytic inhibitors of human topoisomerases I and IIalpha.	2000 Jul	10860928
Synthesis and anti-HIV activity of 3-alkylamido-3-deoxy-betulinic acid derivatives.	2000 Sep	10993248
Betulinic acid reduces ultraviolet-C-induced DNA breakage in congenital melanocytic naeval cells: evidence for a potential role as a chemopreventive agent.	2001 Apr	11333133
The Bax/Bcl-2 ratio determines the susceptibility of human melanoma cells to CD95/Fas-mediated apoptosis.	2001 Aug	11511312
[Studies on chemical constituents from Buddleja lindleyana Fert].	2001 Jan	12525118
p53-independent upregulation of KILLER/DR5 TRAIL receptor expression by glucocorticoids and interferon-gamma.	2001 Jan 15	11139340
Anthelmintic activity of the stem bark extracts of Berlina grandiflora and one of its active principles, Betulinic acid.	2001 Mar	11315752
Inhibitory effects of triterpenoids and sterols on human immunodeficiency virus-1 reverse transcriptase.	2001 May	11432464
Antimycobacterial plant terpenoids.	2001 Nov	11731906
Ethnopharmacology and bioinformatic combination for leads discovery: application to phospholipase A(2) inhibitors.	2001 Nov	11684183
New developments in anti-HIV chemotherapy.	2001 Nov	11562282
Development of C-20 modified betulinic acid derivatives as antitumor agents.	2001 Sep 3	11527742
Betulinic acid inhibits growth factor-induced in vitro angiogenesis via the modulation of mitochondrial function in endothelial cells.	2002 Apr	11985792
Isolation and structure elucidation of an isoflavone and a sesterterpenoic acid from Henriettella fascicularis.	2002 Dec	12502307
Mitochondrial involvement in tracheary element programmed cell death.	2002 Feb	11840169
Natural products inhibiting Candida albicans secreted aspartic proteases from Tovomita krukovii.	2002 Jan	11842327
[Studies on flavoniod constituents of Hedysarum multijugum].	2002 Mar	12579761
Betulinic acid sensitization of low pH adapted human melanoma cells to hyperthermia.	2002 Mar-Apr	11911485
Preparation of a 24-nor-1,4-dien-3-one triterpene derivative from betulin: a new route to 24-nortriterpene analogues.	2002 May 3	11975539
[Study on chemical constituents of rhizome of Anemone raddeana].	2002 Sep	12567896
Constituents in evening primrose oil with radical scavenging, cyclooxygenase, and neutrophil elastase inhibitory activities.	2002 Sep 25	12236675
Constituents of antibacterial extract of Caesalpinia paraguariensis Burk.	2003 Jan-Feb	12622230
A key role for caspase-2 and caspase-3 in the apoptosis induced by 2-chloro-2'-deoxy-adenosine (cladribine) and 2-chloro-adenosine in human astrocytoma cells.	2003 Jun	12761355
New cytotoxic lupane triterpenoids from the twigs of Coussarea paniculata.	2003 Mar	12662105
[Epimerization of hydroxyl group in the lupan series of triterpenes].	2003 Mar-Apr	12708322
Broncho-vasodilatory activity of fractions and pure constituents isolated from Bacopa monniera.	2003 May	12686438
Betulinic acid: a new cytotoxic compound against malignant head and neck cancer cells.	2003 Sep	12953308
Betulinic acid suppresses carcinogen-induced NF-kappa B activation through inhibition of I kappa B alpha kinase and p65 phosphorylation: abrogation of cyclooxygenase-2 and matrix metalloprotease-9.	2003 Sep 15	12960358
Apoptosis of human carcinoma cells in the presence of potential anti-cancer drugs: III. Treatment of Colo-205 and SKBR3 cells with: cis -platin, Tamoxifen, Melphalan, Betulinic acid, L-PDMP, L-PPMP, and GD3 ganglioside.	2004	15454695
Betulinic acid augments the inhibitory effects of vincristine on growth and lung metastasis of B16F10 melanoma cells in mice.	2004 Apr 19	15083202
Synthesis and cytotoxic activity of 3-O-acyl/3-hydrazine /2-bromo/20,29-dibromo betulinic acid derivatives.	2004 Aug 2	15225732
Phenolic compounds obtained from stems of Couepia ulei with the potential to induce quinone reductase.	2004 Feb	15022717
Apoptosis-modulating agents in combination with radiotherapy-current status and outlook.	2004 Feb 1	14751526
Role of the ectodomain of the gp41 transmembrane envelope protein of human immunodeficiency virus type 1 in late steps of the membrane fusion process.	2004 Jan	14694113
New prenylated isoflavanones and other constituents of Lespedeza bicolor.	2004 Jan	14693230
Differential expression of three oxidosqualene cyclase mRNAs in Glycyrrhiza glabra.	2004 Jul	15256745
Betulinic acid enhances 1alpha,25-dihydroxyvitamin D3-induced differentiation in human HL-60 promyelocytic leukemia cells.	2004 Jul	15205607
Cell death induction by betulinic acid, ceramide and TRAIL in primary glioblastoma multiforme cells.	2004 Jul	15197616
New 3-O-acyl betulinic acids from Strychnos vanprukii Craib.	2004 Jun	15217281
Isolation and structure of gustastatin from the Brazilian nut tree Gustavia hexapetala.	2004 Jun	15217278
Quantitative analysis of anti-inflammatory and radical scavenging triterpenoid esters in evening primrose oil.	2004 Jun 2	15161190

Patents

Sample Use Guides

In Vivo Use Guide

Treatment will consist of four weeks of daily application of 20% BA ointment to the dysplastic nevi, after which it will be removed surgically and examined. A similar dysplastic nevi will be removed as a control. Four groups of patients will be enrolled. The first group will apply the ointment once a day, the second twice a day, the third three times a day, and the fourth four times a day.

Route of Administration: Topical

In Vitro Use Guide

Betulinic acid inhibits rat topoisomerase I in a dose dependent manner, with complete inhibition of enzyme activity achieved at 10 uM concentration. Betulinic acid at a concentration of 2.5 uM does not inhibit the enzyme activity whereas at 5 uM concentration 50% inhibition is achieved.

Name

Type

Language

BETULINIC ACID

Official Name

English

LUP-20(29)-EN-28-OIC ACID, 3.BETA.-HYDROXY-

Systematic Name

English

NSC-677578

Code

English

BETULINIC ACID [INCI]

Common Name

English

ALS-357

Code

English

BETULIC ACID

Common Name

English

.BETA.-BETULINIC ACID

Common Name

English

BETULINIC ACID [MI]

Common Name

English

LUPATIC ACID

Common Name

English

(3.BETA.)-3-HYDROXYLUP-20(29)-EN-28-OIC ACID

Common Name

English

NSC-113090

Code

English

MAIRIN

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C2139