Citation: Jin-Hong Liu, Zi-Fei Zhu, Jia Tang, Ai-Qin Jiang, Liu-Fang Hu, Li Chen. Novel NO-releasing derivatives of betulinic acid with antitumor activity[J]. Chinese Chemical Letters, ;2015, 26(6): 759-762. doi: 10.1016/j.cclet.2015.04.002 shu

Novel NO-releasing derivatives of betulinic acid with antitumor activity

Jin-Hong Liu ^a ,
Zi-Fei Zhu ^a ,
Jia Tang ^a ,
Ai-Qin Jiang ^b,, ,
Liu-Fang Hu ^a ,
Li Chen ^a,,

1.
a Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China;
2.
b Medical School of Nanjing University, Nanjing 210093, China

Corresponding author: Ai-Qin Jiang, Li Chen,
Received Date: 20 November 2014
Available Online: 17 March 2015

Thirteen novel NO-releasing derivatives of betulinic acid (BA) bearing two types of NO-donors (nitrates and furoxans) were synthesized and evaluated for their antitumor activity. The results showed that furoxan-based derivatives exhibited higher antitumor activity than nitrate-based derivatives, with compounds 11a and 11b displaying promising potency against B16 cell lines and HepG2 cell lines (IC₅₀ < 1 μmol/L). Wesupposed that NO-releasing amount of these derivatives which can be detected by Griess method may contribute more to their antitumor activity. As a result, furoxan-based derivatives released larger amount of NO than that of nitrate-based derivatives, which partially explained the higher anti-tumor activity of the former.
- Betulinic acid (BA),
- Derivatives,
- NO-releasing,
- Anti-tumor,
- NO donors
1. [1]
  [1] S. Moncada, Nitric oxide: discovery and impact on clinical medicine, J. R. Soc. Med. 92 (1999) 164-169.
2. [2]
  [2] P.J. Andrew, B. Mayer, Enzymatic function of nitric oxide synthases, Cardiovasc. Res. 43 (1999) 521-531.
3. [3]
  [3] J.O. Lundberg, E. Weitzberg, NO generation from nitrite and its role in vascular control, Arterioscler. Thromb. Vasc. Biol. 25 (2005) 915-922.
4. [4]
  [4] R.M. Touyz, E.L. Schiffrin, Reactive oxygen species in vascular biology: implications in hypertension, Histochem. Cell Biol. 122 (2004) 339-352.
5. [5]
  [5] J.E. Albina, J.S. Reichner, Role of nitric oxide in mediation of macrophage cytotoxicity and apoptosis, Cancer Metastasis Rev. 17 (1998) 39-53.
6. [6]
  [6] F. Dodd, M. Limoges, R.T.M. Boudreau, et al., _L-Arginine inhibits apoptosis via a NO-dependent mechanism in Nb2 lymphoma cells, J. Cell. Biochem. 77 (2000) 624-634.
7. [7]
  [7] L.A. Ridnour, K.M. Barasch, A.N. Windhausen, et al., Nitric oxide synthase and breast cancer: role of TIMP-1 in NO-mediated Akt activation, PLoS ONE 7 (2012) e44081.
8. [8]
  [8] V. Umansky, V. Schirrmacher, Nitric oxide-induced apoptosis in tumor cells, Adv. Cancer Res. 82 (2001) 107-131.
9. [9]
  [9] D.D. Thomas, M.G. Espey, L.A. Ridnour, et al., Hypoxic inducible factor 1a, extracellular signal-regulated kinase, and p53 are regulated by distinct threshold concentrations of nitric oxide, Proc. Natl. Acad. Sci. U. S. A. 101 (2004) 8894-8899.
10. [10]
  [10] L.A. Ridnour, D.D. Thomas, C. Switzer, et al., Molecular mechanisms for discrete nitric oxide levels in cancer, Nitric Oxide 19 (2008) 73-76.
11. [11]
  [11] S. Mocellin, V. Bronte, D. Nitti, Nitric oxide, a double edged sword in cancer biology: searching for therapeutic opportunities, Med. Res. Rev. 27 (2007) 317-352.
12. [12]
  [12] S. Korde Choudhari, G. Sridharan, A. Gadbail, V. Poornima, Nitric oxide and oral cancer: a review, Oral Oncol. 48 (2012) 475-483.
13. [13]
  [13] S.Y. Ryu, S.U. Choi, S.H. Lee, et al., Antitumor triterpenes from medicinal plants, Arch. Pharm. Res. 17 (1994) 375-377.
14. [14]
  [14] Y. Kashiwada, F. Hashimoto, L.M. Cosentino, et al., Betulinic acid and dihydrobetulinic acid derivatives as potent anti-HIV agents, J. Med. Chem. 39 (1996) 1016-1017.
15. [15]
  [15] F. Li, R. Goila-Gaur, K. Salzwedel, et al., PA-457: a potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing, Proc. Natl. Acad. Sci. U. S. A. 100 (2003) 13555-13560.
16. [16]
  [16] E. Pisha, H. Chai, I.S. Lee, et al., Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis, Nat. Med. 1 (1995) 1046-1051.
17. [17]
  [17] L. Fang, Y.H. Zhang, J. Lehmann, et al., Design and synthesis of furoxan-based nitric oxide-releasing glucocorticoid derivatives with potent anti-inflammatory activity and improved safety, Bioorg. Med. Chem. Lett. 17 (2007) 1062-1066.
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沈阳化工大学材料科学与工程学院沈阳 110142