Betulinic acid

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Betulinic acid
Names
IUPAC name
3β-Hydroxylup-20(29)-en-28-oic acid
Systematic IUPAC name
(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-Hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-1-yl)icosahydro-3aH-cyclopenta[a]chrysene-3a-carboxylic acid
Other names
Betulic acid
Mairin
Identifiers
3D model (
JSmol
)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard
 100.006.773 Edit this at Wikidata
EC Number
  • 207-448-8
IUPHAR/BPS
UNII
  • 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 checkY
    Key: QGJZLNKBHJESQX-FZFNOLFKSA-N checkY
  • 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
    Key: QGJZLNKBHJESQX-FZFNOLFKBI
  • O=C(O)[C@@]54[C@@H]([C@@H]3[C@@]([C@]1([C@@H]([C@]2(C)[C@@H](CC1)C(C)(C)[C@@H](O)CC2)CC3)C)(C)CC4)[C@H](C(=C)C)CC5
Properties
C30H48O3
Molar mass 456.711 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 checkY☒N ?)

Betulinic acid is a naturally occurring pentacyclic

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 (

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
small cell lung and renal cell carcinomas, as well as T-cell leukemia cells, were completely unresponsive to treatment with betulinic acid.[9]

The effects of betulinic acid as an anticancer agent in breast cancer is found to be

CB2 agonist.[12]

Mode of action

Regarding the

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.[13] Alternatively, Rieber suggested betulinic acid exerts its inhibitory effect on human metastatic melanoma partly by increasing p53.[14]

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.[14] 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.[15] A study of a combination of betulinic acid with γ-irradiation showed clearly additive effects, and indicated they differ in their modes of action.[15]

C-3 esterification of betulinic acid led to the discovery of

pharmacodynamic properties.[16]

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.[17]

Biosynthesis

NADPH to NADP+.[18]

Biosynthetic pathway of betulinic acid, with all of the enzymes, structures, and cofactors as described by Li et al. in "Modulating betulinic acid production in Saccharomyces cerevisiae by managing the intracellular supplies of the co-factor NADPH and oxygen".[18]

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.[19]

See also

References

  1. PMID 12118187
    .
  2. ^
    PMID 12855667
    .
  3. ^
    PMID 11734332
    .
  4. Pseudocydonia sinensis
    )
  5. PMID 12419966
    .
  6. ^
    PMID 12409140
    .
  7. S2CID 24752850
    .
  8. PMID 9516843
    .
  9. ^
    PMID 9354463
    .
  10. PMID 10336521
    .
  11. ^
    S2CID 24271002
    .
  12. PMID 22553354
    .
  13. PMID 11511312
    .
  14. ^
    PMID 9628583
    .
  15. ^
    PMID 10771474
    .
  16. ^ Novel 3,28-Disubstituted Betulinic Acid Derivatives as Potent Anti-HIV Agents Aims/Hypothesis Out-licensing. iptechex pharmalicensing, IP Technology Exchange (2013)
  17. ^ Uldis (2022-03-10). "How to use Betulinic acid in Cosmetics". NST Chemicals. Retrieved 2023-01-07.
  18. ^
    PMID 25043336
    .
  19. PMID 16787747
    .
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