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Revision as of 17:06, 13 January 2011 editCheMoBot (talk | contribs)Bots141,565 edits Updating {{chembox}} (changes to verified fields - updated 'UNII_Ref', 'KEGG_Ref') per Chem/Drugbox validation (report errors or [[user talk:CheMoBot|bugs← Previous edit Latest revision as of 12:34, 2 October 2024 edit undoDankedaniel (talk | contribs)31 editsm bracket fungus Fomitopsis betulina added and wiki-linkedTag: Visual edit 
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{{chembox {{chembox
| Verifiedfields = changed | Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 401927653 | verifiedrevid = 407684511
| ImageFile = Betulinic acid structure.png | ImageFile = Betulinic acid.svg
| ImageSize = 200px | ImageSize =
| IUPACName = (3β)-3-Hydroxy-lup-20(29)-en-28-oic acid | IUPACName = 3β-Hydroxylup-20(29)-en-28-oic acid
| SystematicName = (1''R'',3a''S'',5a''R'',5b''R'',7a''R'',9''S'',11a''R'',11b''R'',13a''R'',13b''R'')-9-Hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-1-yl)icosahydro-3a''H''-cyclopentachrysene-3a-carboxylic acid
| OtherNames = Betulic acid<br />Mairin | OtherNames = Betulic acid<br />Mairin
| Section1 = {{Chembox Identifiers |Section1={{Chembox Identifiers
| IUPHAR_ligand = 3945
| Abbreviations = | Abbreviations =
| InChIKey = QGJZLNKBHJESQX-FZFNOLFKBI | InChIKey = QGJZLNKBHJESQX-FZFNOLFKBI
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| CASNo_Ref = {{cascite|correct|CAS}} | CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 472-15-1 | CASNo = 472-15-1
| ChEMBL_Ref = {{ebicite|changed|EBI}} | UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 4G6A18707N
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 269277 | ChEMBL = 269277
| ChEBI_Ref = {{ebicite|changed|EBI}}
⚫ | EINECS =
⚫ | ChEBI = 3087
⚫ | EINECS = 207-448-8
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID=58496 | ChemSpiderID =58496
| PubChem = 64971 | PubChem = 64971
| SMILES = O=C(O)54(3(1((2(C)(CC1)C(C)(C)(O)CC2)CC3)C)(C)CC4)(C(=C)\C)CC5 | SMILES = O=C(O)54(3(1((2(C)(CC1)C(C)(C)(O)CC2)CC3)C)(C)CC4)(C(=C)C)CC5
| InChI = 1/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 | InChI = 1/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
| RTECS = | RTECS =
| MeSHName = | MeSHName =
⚫ | ChEBI =
| KEGG_Ref = {{keggcite|correct|kegg}} | KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = | KEGG =
}}
| ATCCode_prefix =
⚫ |Section2={{Chembox Properties
| ATCCode_suffix =
| C=30 | H=48 | O=3
| ATC_Supplemental =}}
⚫ | Section2 = {{Chembox Properties
| Formula = C<sub>30</sub>H<sub>48</sub>O<sub>3</sub>
| MolarMass = 456.7 g/mol
| Appearance = | Appearance =
| Density = | Density =
| MeltingPt = 316-318 °C | MeltingPtC = 316 to 318
| MeltingPt_notes =
| Melting_notes =
| BoilingPt = | BoilingPt =
| Boiling_notes = | BoilingPt_notes =
| Solubility = | Solubility =
| SolubleOther = | SolubleOther =
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| pKa = | pKa =
| pKb = }} | pKb = }}
| Section7 = {{Chembox Hazards |Section7={{Chembox Hazards
| EUClass =
| EUIndex =
| MainHazards = | MainHazards =
| NFPA-H = | NFPA-H =
| NFPA-F = | NFPA-F =
| NFPA-R = | NFPA-R =
| NFPA-O = | NFPA-S =
| RPhrases =
| SPhrases =
| RSPhrases =
| FlashPt = | FlashPt =
| Autoignition = | AutoignitionPt =
| ExploLimits = | ExploLimits =
| PEL = }} | PEL =
}}
}} }}


'''Betulinic acid''' is a naturally occurring pentacyclic ] which has ], anti-]l, and ] properties, as well as a more recently discovered potential as an anticancer agent, by inhibition of ].<ref name="Chowdhury">{{cite journal |author=Chowdhury AR, Mandal S, Mittra B, Sharma S, Mukhopadhyay S, Majumder HK |title=Betulinic acid, a potent inhibitor of eukaryotic topoisomerase I: identification of the inhibitory step, the major functional group responsible and development of more potent derivatives |journal=Medical Science Monitor |volume=8 |issue=7 |pages=BR254–65 |year=2002 |month=July |pmid=12118187 |url=http://www.medscimonit.com/fulltxt.php?ICID=13614}}</ref> It is found in the ] of several species of plants, principally the ] (''Betula pubescens'')<ref name="Tan">{{cite journal |author=Tan Y, Yu R, Pezzuto JM |title=Betulinic acid-induced programmed cell death in human melanoma cells involves mitogen-activated protein kinase activation |journal=Clinical Cancer Research |volume=9 |issue=7 |pages=2866–75 |year=2003 |month=July |pmid=12855667 |url=http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=12855667}}</ref> from which it gets its name, but also the ] tree (''Ziziphus mauritiana''), selfheal (]), the ] ] '']'' and '']'', '']'' a member of the ] family, '']'', the jambul ('']''),<ref name="Zuco">{{cite journal |author=Zuco V, Supino R, Righetti SC, ''et al.'' |title=Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells |journal=Cancer Letters |volume=175 |issue=1 |pages=17–25 |year=2002 |month=January |pmid=11734332 |doi=10.1016/S0304-3835(01)00718-2}}</ref> flowering quince ('']''),<ref name="Gao">{{cite journal |author=Gao H, Wu L, Kuroyanagi M, ''et al.'' |title=Antitumor-promoting constituents from Chaenomeles sinensis KOEHNE and their activities in JB6 mouse epidermal cells |journal=Chemical & Pharmaceutical Bulletin |volume=51 |issue=11 |pages=1318–21 |year=2003 |month=November |pmid=14600382 |doi=10.1248/cpb.51.1318}}</ref> '''Betulinic acid''' is a naturally occurring pentacyclic ] which has ], anti]l, and ] properties, as well as a more recently discovered potential as an anticancer agent, by inhibition of ].<ref name="Chowdhury">{{cite journal | vauthors = Chowdhury AR, Mandal S, Mittra B, Sharma S, Mukhopadhyay S, Majumder HK | title = Betulinic acid, a potent inhibitor of eukaryotic topoisomerase I: identification of the inhibitory step, the major functional group responsible and development of more potent derivatives | journal = Medical Science Monitor | volume = 8 | issue = 7 | pages = BR254–65 | date = July 2002 | pmid = 12118187 | url = http://www.medscimonit.com/fulltxt.php?ICID=13614 }}</ref> It is found in the ] of several species of plants, principally the ] (''Betula pubescens'')<ref name="Tan">{{cite journal | vauthors = Tan Y, Yu R, Pezzuto JM | title = Betulinic acid-induced programmed cell death in human melanoma cells involves mitogen-activated protein kinase activation | journal = Clinical Cancer Research | volume = 9 | issue = 7 | pages = 2866–75 | date = July 2003 | pmid = 12855667 | url = http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=12855667 }}</ref> from which it gets its name, same as the ] '']'', but also the ber tree ('']''), selfheal ('']''), the ] ] '']'' and '']'', '']'', a member of the ] family, '']'', the jambul (''] formosanum''),<ref name="Zuco">{{cite journal | vauthors = Zuco V, Supino R, Righetti SC, Cleris L, Marchesi E, Gambacorti-Passerini C, Formelli F | title = Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells | journal = Cancer Letters | volume = 175 | issue = 1 | pages = 17–25 | date = January 2002 | pmid = 11734332 | doi = 10.1016/S0304-3835(01)00718-2 }}</ref> flowering quince ('']'', former ''Chaenomeles sinensis KOEHNE''),<ref name="Gao">{{cite journal | vauthors = Gao H, Wu L, Kuroyanagi M, Harada K, Kawahara N, Nakane T, Umehara K, Hirasawa A, Nakamura Y | title = Antitumor-promoting constituents from Chaenomeles sinensis KOEHNE and their activities in JB6 mouse epidermal cells | journal = Chemical & Pharmaceutical Bulletin | volume = 51 | issue = 11 | pages = 1318–21 | date = November 2003 | pmid = 14600382 | doi = 10.1248/cpb.51.1318 | doi-access = free }} (''Chaenomeles sinensis KOEHNE'' is now named '']'')</ref>
],<ref name="Abe">{{cite journal |author=Abe F, Yamauchi T, Nagao T, ''et al.'' |title=Ursolic acid as a trypanocidal constituent in rosemary |journal=Biological & Pharmaceutical Bulletin |volume=25 |issue=11 |pages=1485–7 |year=2002 |month=November |pmid=12419966 |doi=10.1248/bpb.25.1485}}</ref> ],<ref name="Abe">{{cite journal | vauthors = Abe F, Yamauchi T, Nagao T, Kinjo J, Okabe H, Higo H, Akahane H | title = Ursolic acid as a trypanocidal constituent in rosemary | journal = Biological & Pharmaceutical Bulletin | volume = 25 | issue = 11 | pages = 1485–7 | date = November 2002 | pmid = 12419966 | doi = 10.1248/bpb.25.1485 | doi-access = free }}</ref>
and '']''.<ref name="Ji">{{cite journal |author=Ji ZN, Ye WC, Liu GG, Hsiao WL |title=23-Hydroxybetulinic acid-mediated apoptosis is accompanied by decreases in bcl-2 expression and telomerase activity in HL-60 Cells |journal=Life Sciences |volume=72 |issue=1 |pages=1–9 |year=2002 |month=November |pmid=12409140 |doi=10.1016/S0024-3205(02)02176-8}}</ref> and '']''.<ref name="Ji">{{cite journal | vauthors = Ji ZN, Ye WC, Liu GG, Hsiao WL | title = 23-Hydroxybetulinic acid-mediated apoptosis is accompanied by decreases in bcl-2 expression and telomerase activity in HL-60 Cells | journal = Life Sciences | volume = 72 | issue = 1 | pages = 1–9 | date = November 2002 | pmid = 12409140 | doi = 10.1016/S0024-3205(02)02176-8 }}</ref>


==Anti-tumor activity== ==Antitumor activity==
{{more medical citations needed|Section|date=September 2014}}
In 1995, betulinic acid was reported as a selective ] of human ].<ref name="Pisha">{{cite journal |author=Pisha E, Chai H, Lee IS, ''et al.'' |title=Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis |journal=Nature Medicine |volume=1 |issue=10 |pages=1046–51 |year=1995 |month=October |pmid=7489361 |doi=10.1038/nm1095-1046}}</ref>
Then it was demonstrated, that betulinic acid induces ] in human melanoma ] and ] model systems.<ref name="Schmidt">{{cite journal |author=Schmidt ML, Kuzmanoff KL, Ling-Indeck L, Pezzuto JM |title=Betulinic acid induces apoptosis in human neuroblastoma cell lines |journal=European Journal of Cancer |volume=33 |issue=12 |pages=2007–10 |year=1997 |month=October |pmid=9516843 |doi=10.1016/S0959-8049(97)00294-3}}</ref> Currently it is undergoing development with assistance from the ] program of the ].<ref name="Tan"/> In 1995, betulinic acid was reported as a selective ] of human ].<ref name="Pisha">{{cite journal | vauthors = Pisha E, Chai H, Lee IS, Chagwedera TE, Farnsworth NR, Cordell GA, Beecher CW, Fong HH, Kinghorn AD, Brown DM | title = Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis | journal = Nature Medicine | volume = 1 | issue = 10 | pages = 1046–51 | date = October 1995 | pmid = 7489361 | doi = 10.1038/nm1095-1046 | s2cid = 24752850 }}</ref>
Then it was demonstrated to induce ] in human neuroblastoma '']'' and '']'' in model systems.<ref name="Schmidt">{{cite journal | vauthors = Schmidt ML, Kuzmanoff KL, Ling-Indeck L, Pezzuto JM | title = Betulinic acid induces apoptosis in human neuroblastoma cell lines | journal = European Journal of Cancer | volume = 33 | issue = 12 | pages = 2007–10 | date = October 1997 | pmid = 9516843 | doi = 10.1016/S0959-8049(97)00294-3 }}</ref> At one time, it was undergoing ] with assistance from the Rapid Access to Intervention Development program of the ].<ref name="Tan"/>
Also betulinic acid was found active against neuroectodermal (], ], ]<ref name="Fulda">{{cite journal |author=Fulda S, Friesen C, Los M, ''et al.'' |title=Betulinic acid triggers CD95 (APO-1/Fas)- and p53-independent apoptosis via activation of caspases in neuroectodermal tumors |journal=Cancer Research |volume=57 |issue=21 |pages=4956–64 |year=1997 |month=November |pmid=9354463 |url=http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=9354463}}</ref>) and malignant brain tumors,<ref name="Zuco"/><ref>{{cite journal |author=Wick W, Grimmel C, Wagenknecht B, Dichgans J, Weller M |title=Betulinic acid-induced apoptosis in glioma cells: A sequential requirement for new protein synthesis, formation of reactive oxygen species, and caspase processing |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=289 |issue=3 |pages=1306–12 |year=1999 |month=June |pmid=10336521 |url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10336521}}</ref> ],<ref name="Zuco"/> in human ] HL-60 cells,<ref name="Ji"/> malignant head and neck squamous cell carcinoma SCC25 and SCC9 cell lines.<ref name="Thurnher">{{cite journal |author=Thurnher D, Turhani D, Pelzmann M, ''et al.'' |title=Betulinic acid: a new cytotoxic compound against malignant head and neck cancer cells |journal=Head & Neck |volume=25 |issue=9 |pages=732–40 |year=2003 |month=September |pmid=12953308 |doi=10.1002/hed.10231}}</ref> Also, betulinic acid was found active ''in vitro'' against neuroectodermal (], ], ]<ref name="Fulda">{{cite journal | vauthors = Fulda S, Friesen C, Los M, Scaffidi C, Mier W, Benedict M, Nuñez G, Krammer PH, Peter ME, Debatin KM | title = Betulinic acid triggers CD95 (APO-1/Fas)- and p53-independent apoptosis via activation of caspases in neuroectodermal tumors | journal = Cancer Research | volume = 57 | issue = 21 | pages = 4956–64 | date = November 1997 | pmid = 9354463 | url = http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=9354463 }}</ref>) and malignant brain tumors,<ref name="Zuco"/><ref>{{cite journal | vauthors = Wick W, Grimmel C, Wagenknecht B, Dichgans J, Weller M | title = Betulinic acid-induced apoptosis in glioma cells: A sequential requirement for new protein synthesis, formation of reactive oxygen species, and caspase processing | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 289 | issue = 3 | pages = 1306–12 | date = June 1999 | pmid = 10336521 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10336521 }}</ref> ],<ref name="Zuco"/> in human ] ]s,<ref name="Ji"/> and malignant head and neck squamous cell carcinoma SCC25 and SCC9 cell lines.<ref name="Thurnher">{{cite journal | vauthors = Thurnher D, Turhani D, Pelzmann M, Wannemacher B, Knerer B, Formanek M, Wacheck V, Selzer E | title = Betulinic acid: a new cytotoxic compound against malignant head and neck cancer cells | journal = Head & Neck | volume = 25 | issue = 9 | pages = 732–40 | date = September 2003 | pmid = 12953308 | doi = 10.1002/hed.10231 | s2cid = 24271002 }}</ref>
In contrast, epithelial tumors, such as ], ], ] and ] as well as ] cells were completely refractory to treatment with betulinic acid.<ref name="Fulda"/> In contrast, epithelial tumors, such as ], ], ] and ]s, as well as ] cells, were completely unresponsive to treatment with betulinic acid.<ref name="Fulda"/>

The effects of betulinic acid as an anticancer agent in breast cancer is found to be ] dependent. Betulinic acid behaves as a ] ] and ] ].<ref>{{cite journal | vauthors = Liu X, Jutooru I, Lei P, Kim K, Lee SO, Brents LK, Prather PL, Safe S | title = Betulinic acid targets YY1 and ErbB2 through cannabinoid receptor-dependent disruption of microRNA-27a:ZBTB10 in breast cancer | journal = Molecular Cancer Therapeutics | volume = 11 | issue = 7 | pages = 1421–31 | date = July 2012 | pmid = 22553354 | pmc = 4924623 | doi = 10.1158/1535-7163.MCT-12-0026 }}</ref>


==Mode of action== ==Mode of action==
Regarding the ] of betulinic acid, little is known about its ] and ]-inducing mechanisms. In neuroectodermal tumor cells betulinic acid–induced apoptosis is accompanied by ] activation, ]l membrane alterations and ] fragmentation.<ref name="Fulda"/><ref name="Thurnher"/> Caspases are produced as inactive ]s, which are proteolytically processed to their active forms. These proteases can cooperate in proteolytic cascades, in which caspases activate themselves and each other. The initiation of the caspases cascade may lead to the activation of ]s like caspase-activated DNAase (CAD). After activation CAD contributes to DNA degradation.<ref name="Thurnher"/> Regarding the ] of betulinic acid, little is known about its ] and ]-inducing mechanisms. In neuroectodermal tumor cells, betulinic acid–induced apoptosis is accompanied by ] activation, ]l membrane alterations and ] fragmentation.<ref name="Fulda"/><ref name="Thurnher"/> Caspases are produced as inactive ]s, which are proteolytically processed to their active forms. These proteases can cooperate in proteolytic cascades, in which caspases activate themselves and each other. The initiation of the caspases cascade may lead to the activation of ]s such as caspase-activated DNAase (CAD). After activation, CAD contributes to DNA degradation.<ref name="Thurnher"/>
Betulinic acid induces apoptosis by direct effects on mitochondria, leading to cytochrome-c release, which in turn regulates the "downstream" caspase activation.<ref name="Thurnher"/> Betulinic acid induces apoptosis by direct effects on mitochondria, leading to ] release, which in turn regulates the "downstream" caspase activation.<ref name="Thurnher"/>
Betulinic acid bypasses resistance to CD95 and ]-mediated apoptosis, due to different molecular mechanism of betulinic acid-induced apoptosis. Betulinic acid bypasses resistance to ] and ]-mediated apoptosis, due to different molecular mechanism of betulinic acid-induced apoptosis.


Controversial is a role of ] in betulinic acid-induced apoptosis. Fulda suggested p53-independent mechanism of the apoptosis, basing on fact of no accumulation of wild-type p53 detected upon treatment with the betulinic acid, whereas wild-type p53 protein strongly increased after treatment with doxorubicin.<ref name="Fulda"/> The suggestion is supported by study of Raisova.<ref>{{cite journal |author=Raisova M, Hossini AM, Eberle J, ''et al.'' |title=The Bax/Bcl-2 ratio determines the susceptibility of human melanoma cells to CD95/Fas-mediated apoptosis |journal=The Journal of Investigative Dermatology |volume=117 |issue=2 |pages=333–40 |year=2001 |month=August |pmid=11511312 |doi=10.1046/j.0022-202x.2001.01409.x}}</ref> On the other hand Rieber suggested that betulinic acid exerts its inhibitory effect on human metastatic melanoma partly by increasing p53.<ref name="Rieber">{{cite journal |author=Rieber M, Strasberg Rieber M |title=Induction of p53 without increase in p21WAF1 in betulinic acid-mediated cell death is preferential for human metastatic melanoma |journal=DNA and Cell Biology |volume=17 |issue=5 |pages=399–406 |year=1998 |month=May |pmid=9628583 |doi=10.1089/dna.1998.17.399}}</ref> The role of ] in betulinic acid-induced apoptosis is controversial. Fulda suggested a p53-independent mechanism of the apoptosis, based on no accumulation of wild-type p53 detected upon treatment with the betulinic acid, whereas wild-type p53 protein strongly increased after treatment with doxorubicin.<ref name="Fulda"/> The suggestion is supported by study of Raisova.<ref>{{cite journal | vauthors = Raisova M, Hossini AM, Eberle J, Riebeling C, Wieder T, Sturm I, Daniel PT, Orfanos CE, Geilen CC | title = The Bax/Bcl-2 ratio determines the susceptibility of human melanoma cells to CD95/Fas-mediated apoptosis | journal = The Journal of Investigative Dermatology | volume = 117 | issue = 2 | pages = 333–40 | date = August 2001 | pmid = 11511312 | doi = 10.1046/j.0022-202x.2001.01409.x | doi-access = free }}</ref> Alternatively, Rieber suggested betulinic acid exerts its inhibitory effect on human metastatic melanoma partly by increasing p53.<ref name="Rieber">{{cite journal | vauthors = Rieber M, Strasberg Rieber M | title = Induction of p53 without increase in p21WAF1 in betulinic acid-mediated cell death is preferential for human metastatic melanoma | journal = DNA and Cell Biology | volume = 17 | issue = 5 | pages = 399–406 | date = May 1998 | pmid = 9628583 | doi = 10.1089/dna.1998.17.399 }}</ref>


The study also demonstrated preferential apoptotic effect of betulinic acid on C8161 metastatic melanoma cells, with greater DNA fragmentation and growth arrest and earlier loss of viability than their non-metastatic C8161/neo 6.3 counterpart.<ref name="Rieber"/> The study also demonstrated preferential apoptotic effect of betulinic acid on C8161 metastatic melanoma cells, with greater DNA fragmentation and growth arrest and earlier loss of viability than their nonmetastatic C8161/neo 6.3 counterpart.<ref name="Rieber"/>
Comparing the betulinic acid with other treatment modes, Zuco demonstrated that it was more than 10 times less potent than doxorubicin (IC50 4.5 μg/ml Vs IC50 0.21-034 μg/ml in doxorubicin) and showed an ''in vitro'' antiproliferative activity against melanoma and non-melanoma cell lines, including those resistant to doxorubicin. On the human normal dermatoblast cell line betulinic acid was 2-5 times less toxic than doxorubicin.<ref name="Zuco"/> Comparing betulinic acid with other treatment modes, Zuco demonstrated it was less than 10% as potent as doxorubicin<!-- (IC50 4.5 μg/ml vs IC50 0.21-034 μg/ml in doxorubicin) --> and showed an ''in vitro'' antiproliferative activity against melanoma and nonmelanoma cell lines, including those resistant to doxorubicin. On the human normal dermatoblast cell line, betulinic acid was one-half to one-fifth as toxic as doxorubicin.<ref name="Zuco"/>
The ability of betulinic acid to induce two different effects (cytotoxic and cytostatic) on two clones derived from the same human melanoma metastasis suggests that the development of clones resistant to this agent will be more unlikely, than that to conventional cytotoxic drugs. Moreover in spite of the lower potency compared with doxorubicin, betulinic acid seems to be selective for tumor cells with minimal toxicity against normal cells.<ref name="Zuco"/> The effect of betulinic acid on melanoma cell lines is stronger than its growth-inhibitory effect on primary melanocytes.<ref name="Selzer">{{cite journal |author=Selzer E, Pimentel E, Wacheck V, ''et al.'' |title=Effects of betulinic acid alone and in combination with irradiation in human melanoma cells |journal=The Journal of Investigative Dermatology |volume=114 |issue=5 |pages=935–40 |year=2000 |month=May |pmid=10771474 |doi=10.1046/j.1523-1747.2000.00972.x}}</ref> Study of combination of betulinic acid with γ-irradiation showed clearly additive effects, and indicates that they differ in their mode of action.<ref name="Selzer"/> The ability of betulinic acid to induce two different effects (cytotoxic and cytostatic) on two clones derived from the same human melanoma metastasis suggests the development of clones resistant to this agent will be more unlikely, than that to conventional cytotoxic drugs. Moreover, in spite of the lower potency compared with doxorubicin, betulinic acid seems to be selective for tumor cells with minimal toxicity against normal cells.<ref name="Zuco"/> The effect of betulinic acid on melanoma cell lines is stronger than its growth-inhibitory effect on primary melanocytes.<ref name="Selzer">{{cite journal | vauthors = Selzer E, Pimentel E, Wacheck V, Schlegel W, Pehamberger H, Jansen B, Kodym R | title = Effects of betulinic acid alone and in combination with irradiation in human melanoma cells | journal = The Journal of Investigative Dermatology | volume = 114 | issue = 5 | pages = 935–40 | date = May 2000 | pmid = 10771474 | doi = 10.1046/j.1523-1747.2000.00972.x | doi-access = free }}</ref> A study of a combination of betulinic acid with γ-irradiation showed clearly additive effects, and indicated they differ in their modes of action.<ref name="Selzer"/>

C-3 esterification of betulinic acid led to the discovery of ], an HIV-1 ] patented by ] (now Sanofi-Aventis). The clinical development, however, was stopped due to poor ] properties.<ref> Aims/Hypothesis Out-licensing. iptechex pharmalicensing, IP Technology Exchange (2013)</ref>

== Use in cosmetics ==
There has been great emphasis on the use of betulinic acid as an antioxidative additive. Creams containing betulinic acid have been proven to help against highly reactive radicals that might cause skin DNA damage. Furthermore, betulinic acid was able to counteract the effects of ionizing radiation like UV. This makes betulinic acid a great additive for sunscreems and sunblocks and also creams for anti-aging purposes.<ref>{{Cite web |last=Uldis |date=2022-03-10 |title=How to use Betulinic acid in Cosmetics |url=https://nstchemicals.com/how-to-use-betulinic-acid-in-cosmetics/ |access-date=2023-01-07 |website=NST Chemicals |language=en-US}}</ref>

== Biosynthesis ==
'']'' has been engineered to produce betulinic acid from the ], with ] as an intermediate. ] is converted to ] through use of the ] (HMGR) and the bifunctional ] and ] (ERG9) and oxidation of NADPH to NADP<sup>+</sup>. This is then further oxygenated by the ] (ERG1) to squalene 2,3-epoxide. This is cyclized to ] by the '']'' ] (AtLUP1). Finally, lupeol is converted to betulinic acid through the '']'' ] (CrAO) with the oxidation of ] to NADP<sup>+</sup>.<ref name="Li2014">{{cite journal |last1=Li |first1=Jing |last2=Zhang |first2=Yansheng |title=Modulating betulinic acid production in ''Saccharomyces cerevisiae'' by managing the intracellular supplies of the co-factor NADPH and oxygen |journal=Journal of Bioscience and Bioengineering |date=June 19, 2014 |volume=119 |issue=1 |pages=77–81 |doi=10.1016/j.jbiosc.2014.06.013|pmid=25043336 }}</ref>
]


==Anticancer derivatives== ==Anticancer derivatives==
A major inconvenience for the future clinical development of betulinic acid and analogues resides in their poor solubility in aqueous media like blood serum and polar solvents used for bioassays. To circumvent this problem of hydrosolubility and to enhance pharmacological properties, many derivatives were synthesized and evaluated for cytotoxic activity. A study showed that C-20 modifications involve the loss of cytotoxicity. Another study demonstrated the importance of the presence of the COOH group since compounds substituted at this position like lupeol and methyl betulinate were less active on human melanoma than betulinic acid. Moreover, some C-28 amino acids and C-3 phthalates derivatives exhibited higher cytotoxic activity against cancer cell lines with improved selective toxicity and water solubility. Chatterjee and co-workers obtained the 28-O-β-D-glucopyranoside of betulinic acid by microbial transformation with Cunninghamella species while Baglin and co-workers obtained it by organic synthesis. This glucoside did not exhibit any significant in vitro activity on human melanoma (MEL-2) and human colorectal adenocarcinoma (HT-29) cell lines which confirms the importance of the carboxylic acid function to preserve the cytotoxicity. Recently, Gauthier and coworkers have synthesized a series of 3-''O-''glycosides of betulinic acid which exhibited a strongly potent ''in vitro'' anticancer activity against human cancer cell lines.<ref>{{cite journal |author=Gauthier C, Legault J, Lebrun M, Dufour P, Pichette A |title=Glycosidation of lupane-type triterpenoids as potent in vitro cytotoxic agents |journal=Bioorganic & Medicinal Chemistry |volume=14 |issue=19 |pages=6713–25 |year=2006 |month=October |pmid=16787747 |doi=10.1016/j.bmc.2006.05.075}}</ref> A major inconvenience for the future clinical development of betulinic acid and analogues resides in their poor solubility in aqueous media such as blood serum and polar solvents used for bioassays. To circumvent this problem of hydrosolubility and to enhance pharmacological properties, many derivatives were synthesized and evaluated for cytotoxic activity. One study showed C-20 modifications involve the loss of cytotoxicity. Another study demonstrated the importance of the presence of the -COOH group, since compounds substituted at this position, such as ] and methyl betulinate, were less active on human melanoma than betulinic acid. Moreover, some C-28 amino acids and C-3 phthalates derivatives exhibited higher cytotoxic activity against cancer cell lines with improved selective toxicity and water solubility. Chatterjee ''et al.'' obtained the 28-O-β-D-glucopyranoside of betulinic acid by microbial transformation with '']'' species, while ''Baglin et al.'' obtained it by organic synthesis. This glucoside did not exhibit any significant ''in vitro'' activity on human melanoma (MEL-2) and human colorectal adenocarcinoma (HT-29) cell lines, which confirms the importance of the carboxylic acid function to preserve the cytotoxicity. Recently, Gauthier ''et al.'' synthesized a series of 3-''O''-glycosides of betulinic acid which exhibited a strongly potent ''in vitro'' anticancer activity against human cancer cell lines.<ref>{{cite journal | vauthors = Gauthier C, Legault J, Lebrun M, Dufour P, Pichette A | title = Glycosidation of lupane-type triterpenoids as potent in vitro cytotoxic agents | journal = Bioorganic & Medicinal Chemistry | volume = 14 | issue = 19 | pages = 6713–25 | date = October 2006 | pmid = 16787747 | doi = 10.1016/j.bmc.2006.05.075 }}</ref>


==See also== == See also ==
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* Franziska B. Mullauer, Jan H. Kessler, Jan Paul Medema , 2009


== References == == References ==
{{Reflist}} {{Reflist}}


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