Synthesis of asiatic acid derivatives and their cytotoxic activity
- 16 Downloads
Twenty-eight compounds, including 24 new (4–22, 25–26, and 28–30) and four known (2, 23, 24, and 27) have been synthesized starting from asiatic acid (1), which was isolated from Centella asiatica. The preparation procedure included the acetylation, hydrolyzation on the 2-, 3-, 23-, and the side chain hydroxyl, amino groups, as well as the amidation of the 28-carboxylic group. All the synthesized derivatives were structurally confirmed by 1H, 13C NMR, and MS spectra. Besides, they were evaluated for their cytotoxicity against three cancer cell lines: KB (human carcinoma in the mouth), HepG2 (human hepatocellular carcinoma), and SK-LU-1 (human lung carcinoma). Eleven of the tested compounds, including nine newly synthesized and two known ones showed very strong activity against three tested cell lines with the IC50 values ranging from 0.67 to 37.39 µM. Three compounds showed good activity against KB and HepG2 cell lines with the IC50 values ranging from 1.95 to 32.12 µM. The activity against the KB and HepG2 cell lines was in general higher than that against the SK-LU-1 cell line. The acetylation of the hydroxyl groups in the A-ring and the OH or NH groups in the amide side chains strongly enhanced the activity of the compounds. In addition, five potent compounds (9, 12, and 15–17) were also evaluated for apoptosis-inducing activities. The ratio of apoptosis and necrotic cells increased when lung cancer cells were treated with these compounds. On the other hand, compound 9 increased caspase 3 activities (P < 0.05). Thus, these compounds induced lung cancer cell death by apoptosis and necrosis.
KeywordsApoptosis Asiatic acid derivatives Acetylation Amidation Cytotoxicity
This research is funded by Vietnam National Foundation for Science and Technology Development (NAFOSTED) under grant number 104.01-2012.33.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- Do HB, Dang QC, Bui XC, Nguyen TD, Do TD, Phan VH, Vu NL, Pham DM, Phan KM, Doan TN, Nguyen T, Tran T (2003) Cây thuốc và động vật làm thuốc ở Việt Nam (Vietnamese medicinal plants and animals). Publishing House for Science and Technology, Hanoi, Part II, pp 582–586Google Scholar
- Jew SS, Kim HD, Jung JH, Park JH, Seo SK, Nam TG, Hahn DK, Park JH, Sim PJ, Lim MJ, Lin KH (1998a) Asiatic acid derivatives, its manufacturing method and dermatological agent containing it. US5834437 A, Filled 1 Dec 1995, issued 10 Nov 1998Google Scholar
- Jew SS, Park HG, Kim HD, Joung HJ, Kim JC, Kim HP, Lee MK, Choi HS, Lee ES, Yoo CH, Lim DY, Kim JH, Seo SK, Nam TG, Han D, Shim PJ, Jung JE, Beom HJ (1998b) Asiatic acid dervatives having modified A-ring. WO1998023575 A1, Filled 27 Nov 1997, issued 4 Jun 1998Google Scholar
- Jing Y, Wang G, Ge Y, Xu M, Gong Z (2015) Synthesis, anti-tumor and anti-angiogenic activity evaluations of asiatic acid amino acid derivatives. Molecules 20:3709–3724Google Scholar
- Lavrik IN, Krammer PH (2009) Life and death decisions in the CD95 system: main proand anti-apoptotic modulators. Acta Nat 1:80–83Google Scholar
- Lv J, Sharma A, Zhang T, Wu Y, Ding X (2018) Pharmacological review on asiatic acid and its derivatives: a potential compound. SLAS Technol: 1–17. https://doi.org/10.1177/2472630317751840
- Orhan IE (2012) Centella asiatica (L.) urban: from traditional medicine to modern medicine with neuroprotective potential. Evid Based Complement Altern Med 2012:8pp, Article ID 946259. https://doi.org/10.1155/2012/946259
- Tabassum R, Vaibhav K, Shrivastava P, Khan A, Amed ME, Javed H, Islam F, Amad S, Siddiqui MS, Salhi MM, Islam F (2013) Centella asiatica attenuates the neuro behavioral, neuro chemical and histological changes in transient focal middle cerebral artery occlusion rats. Neuro Sci 34:925–933CrossRefGoogle Scholar