Login Register Cart 0
Generic placeholder image

Current Bioactive Compounds

Editor-in-Chief

ISSN (Print): 1573-4072
ISSN (Online): 1875-6646

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

One-pot Synthesis of Some New Betulinic Acid Derivatives with Cytotoxicity Against Human Pancreatic Cancer Cells

Author(s): Muhammad Shaiq Ali*, Ghafoor Ahmed, Huma Rasheed, Samiya Kainat, Itrat Fatima and Azra Akbar

Volume 20, Issue 2, 2024

Published on: 04 October, 2023

Article ID: e050723218451 Pages: 7

DOI: 10.2174/1573407219666230705160027

Price: $65

conference banner
Abstract

Background: One-pot synthesis of new and biologically important betulinic acid derivatives has been designed and efficiently achieved in this work.

Methods: The utilization of the carboxylic and hydroxyl moieties of betulinic acid has resulted in the development of a one-pot strategy towards the synthesis of some target compounds.

Results: One-pot synthesis of new betulinic acid derivatives 3-9 has been achieved in moderate to high yields by way of esterification of the carboxylic functionality with a variety of alkylating agents. These were fully characterized by spectroscopic techniques.

Conclusion: The synthesized new derivatives of betulinic acid were screened for their cytotoxic effect against human pancreatic cancer cells.

Keywords: Betulinic acid, new derivatives, one-pot synthesis, spectroscopy, characterization, cytotoxicity, human pancreatic cancer cells.

Graphical Abstract

[1]
Fulda, S. Betulinic acid for cancer treatment and prevention. Int. J. Mol. Sci., 2008, 9(6), 1096-1107.
[http://dx.doi.org/10.3390/ijms9061096] [PMID: 19325847]
[2]
Schühly, W.; Heilmann, J.; Çalis, I.; Sticher, O. New triterpenoids with antibacterial activity from Zizyphus joazeiro. Planta Med., 1999, 65(8), 740-743.
[http://dx.doi.org/10.1055/s-1999-14054] [PMID: 10630117]
[3]
Gauthier, C.; Legault, J.; Lebrun, M.; Dufour, P.; Pichette, A. Glycosidation of lupane-type triterpenoids as potent in vitro cytotoxic agents. Bioorg. Med. Chem., 2006, 14(19), 6713-6725.
[http://dx.doi.org/10.1016/j.bmc.2006.05.075] [PMID: 16787747]
[4]
Lee, S.Y.; Kim, H.H.; Park, S.U. Recent studies on betulinic acid and its biological and pharmacological activity. EXCLI J., 2015, 14, 199-203.
[http://dx.doi.org/10.17179/excli2015-150] [PMID: 26648812]
[5]
Fulda, S.; Scaffidi, C.; Susin, S.A.; Krammer, P.H.; Kroemer, G.; Peter, M.E.; Debatin, K.M. Activation of mitochondria and release of mitochondrial apoptogenic factors by betulinic acid. J. Biol. Chem., 1998, 273(51), 33942-33948.
[http://dx.doi.org/10.1074/jbc.273.51.33942] [PMID: 9852046]
[6]
Huang, Q.X.; Chen, H.F. Luo, X Structure and anti-HIV activity of betulinic acid analogues. Curr. Med. Sci., 2018, 38(3), 387-397.
[http://dx.doi.org/10.1007/s11596-018-1891-4 ] [PMID: 30074203]
[7]
Koehn, F.E.; Carter, G.T. The evolving role of natural products in drug discovery. Nat. Rev. Drug Discov., 2005, 4(3), 206-220.
[http://dx.doi.org/10.1038/nrd1657 ] [PMID: 15729362]
[8]
Gundoju, N.; Bokam, R.; Yalavarthi, N.R.; Azad, R.; Ponnapalli, M.G. Betulinic acid derivatives: A new class of α-glucosidase inhibitors and LPS-stimulated nitric oxide production inhibition on mouse macrophage RAW 264.7 cells. Nat. Prod. Res., 2019, 33(18), 2618-2622.
[http://dx.doi.org/10.1080/14786419.2018.1462182] [PMID: 29683341]
[9]
Mullauer, F.B.; Kessler, J.H.; Medema, J.P. Betulinic acid, a natural compound with potent anticancer effects. Anticancer Drugs, 2010, 21(3), 215-227.
[http://dx.doi.org/10.1097/CAD.0b013e3283357c62] [PMID: 20075711]
[10]
Fulda, S. Betulinic acid: A natural product with anticancer activity. Mol. Nutr. Food Res., 2009, 53(1), 140-146.
[http://dx.doi.org/10.1002/mnfr.200700491] [PMID: 19065582]
[11]
Walker, M.A. Anti-HIV activity of betulinic acid analogue YKFH312. Drug Discov. Today, 2001, 6(16), 859-861.
[http://dx.doi.org/10.1016/S1359-6446(01)01911-0] [PMID: 11495759]
[12]
Eiznhamer, D.A.; Xu, Z.Q. Betulinic acid: A promising anticancer candidate. IDrugs, 2004, 7(4), 359-373.
[PMID: 15057642]
[13]
Zuco, V.; Supino, R.; Righetti, S.C.; Cleris, L.; Marchesi, E.; Gambacorti-Passerini, C.; Formelli, F. Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells. Cancer Lett., 2002, 175(1), 17-25.
[http://dx.doi.org/10.1016/S0304-3835(01)00718-2] [PMID: 11734332]
[14]
Chintharlapalli, S.; Papineni, S.; Lei, P.; Pathi, S.; Safe, S. Betulinic acid inhibits colon cancer cell and tumor growth and induces pro-teasome-dependent and -independent downregulation of specificity proteins (Sp) transcription factors. BMC Cancer, 2011, 11(1), 371-383.
[http://dx.doi.org/10.1186/1471-2407-11-371] [PMID: 21864401]
[15]
Cichewicz, R.H.; Kouzi, S.A. Chemistry, biological activity, and chemotherapeutic potential of betulinic acid for the prevention and treat-ment of cancer and HIV infection. Med. Res. Rev., 2004, 24(1), 90-114.
[http://dx.doi.org/10.1002/med.10053] [PMID: 14595673]
[16]
Suresh, C.; Zhao, H.; Gumbs, A.; Chetty, C.S.; Bose, H.S. New ionic derivatives of betulinic acid as highly potent anti-cancer agents. Bioorg. Med. Chem. Lett., 2012, 22(4), 1734-1738.
[http://dx.doi.org/10.1016/j.bmcl.2011.12.102] [PMID: 22264477]
[17]
Pisha, E.; Chai, H.; Lee, I.S.; Chagwedera, T.E.; Farnsworth, N.R.; Cordell, G.A.; Beecher, C.W.W.; Fong, H.H.S.; Kinghorn, A.D.; Brown, D.M.; Wani, M.C.; Wall, M.E.; Hieken, T.J.; Das Gupta, T.K.; Pezzuto, J.M. Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis. Nat. Med., 1995, 1(10), 1046-1051.
[http://dx.doi.org/10.1038/nm1095-1046] [PMID: 7489361]
[18]
Jeong, H.J.; Chai, H.B.; Park, S.Y.; Kim, D.S.H.L. Preparation of amino acid conjugates of betulinic acid with activity against human melanoma. Bioorg. Med. Chem. Lett., 1999, 9(8), 1201-1204.
[http://dx.doi.org/10.1016/S0960-894X(99)00165-1] [PMID: 10328313]
[19]
Kim, J.Y.; Koo, H.M.; Kim, D.S.H.L. Development of C-20 modified betulinic acid derivatives as antitumor agents. Bioorg. Med. Chem. Lett., 2001, 11(17), 2405-2408.
[http://dx.doi.org/10.1016/S0960-894X(01)00460-7] [PMID: 11527742]
[20]
Deng, Y.; Snyder, J.K. Preparation of a 24-nor-1,4-dien-3-one triterpene derivative from betulin: A new route to 24-nortriterpene ana-logues. J. Org. Chem., 2002, 67(9), 2864-2873.
[http://dx.doi.org/10.1021/jo010929h] [PMID: 11975539]
[21]
Kim, D.S.H.L.; Pezzuto, J.M.; Pisha, E. Synthesis of betulinic acid derivatives with activity against human melanoma. Bioorg. Med. Chem. Lett., 1998, 8(13), 1707-1712.
[http://dx.doi.org/10.1016/S0960-894X(98)00295-9] [PMID: 9873420]
[22]
Mukherjee, R.; Jaggi, M.; Siddiqui, M.J.A.; Srivastava, S.K.; Rajendran, P.; Vardhan, A.; Burman, A.C. Synthesis and cytotoxic activity of 3-O-acyl/3-hydrazine/2-bromo/20,29-dibromo betulinic acid derivatives. Bioorg. Med. Chem. Lett., 2004, 14(15), 4087-4091.
[http://dx.doi.org/10.1016/j.bmcl.2004.05.034] [PMID: 15225732]
[23]
Mukherjee, R.; Jaggi, M.; Rajendran, P.; Srivastava, S.K.; Siddiqui, M.J.A.; Vardhan, A.; Burman, A.C. Synthesis of 3-O-acyl/3-benzylidene/3-hydrazone/3-hydrazine/17-carboxyacryloyl ester derivatives of betulinic acid as anti-angiogenic agents. Bioorg. Med. Chem. Lett., 2004, 14(12), 3169-3172.
[http://dx.doi.org/10.1016/j.bmcl.2004.04.010] [PMID: 15149668]
[24]
Ramadoss, S.; Jaggi, M.; Siddiqui, M.J.A.; Khanna, A.B. Betulinic acid derivative for inhibiting cancer growth and process for manufacturing betulinic acid. US Patent 6,670,345 B1, 2003.
[25]
Ramadoss, S.; Jaggi, M.; Siddiqui, M.J.A.; Khanna, A.B. Use of betulinic acid and its derivatives for inhibiting cancer growth and a method of monitoring this. US Patent 6,048,847, 2000.
[26]
Kvasnica, M.; Sarek, J.; Klinotova, E.; Dzubak, P.; Hajduch, M. Synthesis of phthalates of betulinic acid and betulin with cytotoxic activity. Bioorg. Med. Chem., 2005, 13(10), 3447-3454.
[http://dx.doi.org/10.1016/j.bmc.2005.03.006] [PMID: 15848757]
[27]
Shenoy, N.; Stenson, M.; Lawson, J.; Abeykoon, J.; Patnaik, M.; Wu, X.; Witzig, T. Drugs with anti-oxidant properties can interfere with cell viability measurements by assays that rely on the reducing property of viable cells. Lab. Invest., 2017, 97(5), 494-497.
[http://dx.doi.org/10.1038/labinvest.2017.18] [PMID: 28240748]
[28]
Wang, T.; Yang, S.; Petrenko, V.A.; Torchilin, V.P. Cytoplasmic delivery of liposomes into MCF-7 breast cancer cells mediated by cell-specific phage fusion coat protein. Mol. Pharm., 2010, 7(4), 1149-1158.
[http://dx.doi.org/10.1021/mp1000229] [PMID: 20438086]

Rights & Permissions Print Cite
Article Metrics
13
2
Wayfinder Image
© 2024 Bentham Science Publishers | Privacy Policy