Betulinic acid

Betulinic acid
Names
IUPAC name
(3β)-3-Hydroxy-lup-20(29)-en-28-oic acid
Other names
Betulic acid
Mairin
Identifiers
472-15-1 YesY
3D model (Jmol) Interactive image
ChEBI CHEBI:3087 N
ChEMBL ChEMBL269277 YesY
ChemSpider 58496 YesY
ECHA InfoCard 100.006.773
3945
PubChem 64971
Properties
C30H48O3
Molar mass 456.71 g·mol−1
Melting point 316 to 318 °C (601 to 604 °F; 589 to 591 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YesYN ?)
Infobox references

Betulinic acid is a naturally occurring pentacyclic triterpenoid which has antiretroviral, antimalarial, and anti-inflammatory properties, as well as a more recently discovered potential as an anticancer agent, by inhibition of topoisomerase.[1] It is found in the bark of several species of plants, principally the white birch (Betula pubescens)[2] from which it gets its name, but also the ber tree (Ziziphus mauritiana), selfheal (Prunella vulgaris), the tropical carnivorous plants Triphyophyllum peltatum and Ancistrocladus heyneanus, Diospyros leucomelas, a member of the persimmon family, Tetracera boiviniana, the jambul (Syzygium formosanum),[3] flowering quince (Pseudocydonia sinensis, former Chaenomeles sinensis KOEHNE),[4] rosemary,[5] and Pulsatilla chinensis.[6]

Antitumor activity

In 1995, betulinic acid was reported as a selective inhibitor of human melanoma.[7] Then it was demonstrated to induce apoptosis in human neuroblastoma in vitro and in vivo in model systems.[8] At one time, it was undergoing drug development with assistance from the Rapid Access to Intervention Development program of the National Cancer Institute.[2] Also, betulinic acid was found active in vitro against neuroectodermal (neuroblastoma, medulloblastoma, Ewing's sarcoma[9]) and malignant brain tumors,[3][10] ovarian carcinoma,[3] in human leukemia HL-60 cells,[6] and malignant head and neck squamous cell carcinoma SCC25 and SCC9 cell lines.[11] In contrast, epithelial tumors, such as breast, colon, small cell lung and renal cell carcinomas, as well as T-cell leukemia cells, were completely unresponsive to treatment with betulinic acid.[9]

Mode of action

Regarding the mode of action of betulinic acid, little is known about its antiproliferative and apoptosis-inducing mechanisms. In neuroectodermal tumor cells, betulinic acid–induced apoptosis is accompanied by caspase activation, mitochondrial membrane alterations and DNA fragmentation.[9][11] Caspases are produced as inactive proenzymes, 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 endonucleases such as caspase-activated DNAase (CAD). After activation, CAD contributes to DNA degradation.[11] Betulinic acid induces apoptosis by direct effects on mitochondria, leading to cytochrome-C release, which in turn regulates the "downstream" caspase activation.[11] Betulinic acid bypasses resistance to CD95 and doxorubicin-mediated apoptosis, due to different molecular mechanism of betulinic acid-induced apoptosis.

The role of p53 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.[9] The suggestion is supported by study of Raisova.[12] Alternatively,Rieber suggested betulinic acid exerts its inhibitory effect on human metastatic melanoma partly by increasing p53.[13]

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.[13] Comparing betulinic acid with other treatment modes, Zuco demonstrated it was less than 10% as potent as 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.[3] 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.[3] The effect of betulinic acid on melanoma cell lines is stronger than its growth-inhibitory effect on primary melanocytes.[14] A study of a combination of betulinic acid with γ-irradiation showed clearly additive effects, and indicated they differ in their modes of action.[14]

C-3 esterification of betulinic acid led to the discovery of bevirimat (PA-457), the novel 3,28-disubstituted derivative 2, 3"2,3"2-dimethylsuccinylbetulinic acid (DSB), a potent HIV-1 maturation inhibitor patented by Rhone-Poulenc (now Sanofi-Aventis). The clinical development, however, was stopped due to poor pharmacodynamic properties of the antiviral triterpenoid drug candidate.[15]

Anticancer derivatives

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 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 et al. obtained the 28-O-β-D-glucopyranoside of betulinic acid by microbial transformation with Cunninghamella 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.[16] A source of soluble and ingestible betulinic acid (and its precursor, betulin) is the chaga (Inonotus obliquus),[17] a slow-growing medicinal fungus found as a parasite on birch trees in the coldest regions of the Northern Hemisphere. This mushroom converts the betulin present in the bark of the birch into a soluble and ingestible form of betulinic acid. Using a proper extraction protocol (alcohol/ethanol extraction) will make the compounds available for oral consumption. The slow-growing nature of the fungus (7–10 years minimum) and because it cannot be cultivated without losing most of its properties make this an unreliable source, though.

See also

References

  1. ↑ Chowdhury AR, Mandal S, Mittra B, Sharma S, Mukhopadhyay S, Majumder HK (July 2002). "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". Medical Science Monitor. 8 (7): BR254–65. PMID 12118187.
  2. 1 2 Tan Y, Yu R, Pezzuto JM (July 2003). "Betulinic acid-induced programmed cell death in human melanoma cells involves mitogen-activated protein kinase activation". Clinical Cancer Research. 9 (7): 2866–75. PMID 12855667.
  3. 1 2 3 4 5 Zuco V, Supino R, Righetti SC, et al. (January 2002). "Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells". Cancer Letters. 175 (1): 17–25. doi:10.1016/S0304-3835(01)00718-2. PMID 11734332.
  4. ↑ Gao H, Wu L, Kuroyanagi M, et al. (November 2003). "Antitumor-promoting constituents from Chaenomeles sinensis KOEHNE and their activities in JB6 mouse epidermal cells". Chemical & Pharmaceutical Bulletin. 51 (11): 1318–21. doi:10.1248/cpb.51.1318. PMID 14600382. (Chaenomeles sinensis KOEHNE is now named Pseudocydonia sinensis)
  5. ↑ Abe F, Yamauchi T, Nagao T, et al. (November 2002). "Ursolic acid as a trypanocidal constituent in rosemary". Biological & Pharmaceutical Bulletin. 25 (11): 1485–7. doi:10.1248/bpb.25.1485. PMID 12419966.
  6. 1 2 Ji ZN, Ye WC, Liu GG, Hsiao WL (November 2002). "23-Hydroxybetulinic acid-mediated apoptosis is accompanied by decreases in bcl-2 expression and telomerase activity in HL-60 Cells". Life Sciences. 72 (1): 1–9. doi:10.1016/S0024-3205(02)02176-8. PMID 12409140.
  7. ↑ Pisha E, Chai H, Lee IS, et al. (October 1995). "Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis". Nature Medicine. 1 (10): 1046–51. doi:10.1038/nm1095-1046. PMID 7489361.
  8. ↑ Schmidt ML, Kuzmanoff KL, Ling-Indeck L, Pezzuto JM (October 1997). "Betulinic acid induces apoptosis in human neuroblastoma cell lines". European Journal of Cancer. 33 (12): 2007–10. doi:10.1016/S0959-8049(97)00294-3. PMID 9516843.
  9. 1 2 3 4 Fulda S, Friesen C, Los M, et al. (November 1997). "Betulinic acid triggers CD95 (APO-1/Fas)- and p53-independent apoptosis via activation of caspases in neuroectodermal tumors". Cancer Research. 57 (21): 4956–64. PMID 9354463.
  10. ↑ Wick W, Grimmel C, Wagenknecht B, Dichgans J, Weller M (June 1999). "Betulinic acid-induced apoptosis in glioma cells: A sequential requirement for new protein synthesis, formation of reactive oxygen species, and caspase processing". The Journal of Pharmacology and Experimental Therapeutics. 289 (3): 1306–12. PMID 10336521.
  11. 1 2 3 4 Thurnher D, Turhani D, Pelzmann M, et al. (September 2003). "Betulinic acid: a new cytotoxic compound against malignant head and neck cancer cells". Head & Neck. 25 (9): 732–40. doi:10.1002/hed.10231. PMID 12953308.
  12. ↑ Raisova M, Hossini AM, Eberle J, et al. (August 2001). "The Bax/Bcl-2 ratio determines the susceptibility of human melanoma cells to CD95/Fas-mediated apoptosis". The Journal of Investigative Dermatology. 117 (2): 333–40. doi:10.1046/j.0022-202x.2001.01409.x. PMID 11511312.
  13. 1 2 Rieber M, Strasberg Rieber M (May 1998). "Induction of p53 without increase in p21WAF1 in betulinic acid-mediated cell death is preferential for human metastatic melanoma". DNA and Cell Biology. 17 (5): 399–406. doi:10.1089/dna.1998.17.399. PMID 9628583.
  14. 1 2 Selzer E, Pimentel E, Wacheck V, et al. (May 2000). "Effects of betulinic acid alone and in combination with irradiation in human melanoma cells". The Journal of Investigative Dermatology. 114 (5): 935–40. doi:10.1046/j.1523-1747.2000.00972.x. PMID 10771474.
  15. ↑ Novel 3,28-Disubstituted Betulinic Acid Derivatives as Potent Anti-HIV Agents Aims/Hypothesis Out-licensing. iptechex pharmalicensing, IP Technology Exchange (2013)
  16. ↑ Gauthier C, Legault J, Lebrun M, Dufour P, Pichette A (October 2006). "Glycosidation of lupane-type triterpenoids as potent in vitro cytotoxic agents". Bioorganic & Medicinal Chemistry. 14 (19): 6713–25. doi:10.1016/j.bmc.2006.05.075. PMID 16787747.
  17. ↑ Ingram, Dr. Cass (2010). The cure is in the Forest (3rd ed.). Vernon, Ill: Knowledge House Publishers. pp. 25, 31.
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