cpd
route
dose
Tmax
Cmax
AUC
T1/2
(hr)
1.55
0.3
F
(%)
-
Acknowledgments
(mg/kg) (hr) (ng/ml) (h*ng/ml)
Authors are thankful to the Small and Medium Business
Administration (SMBA) in Korea for the financial assistance for
this project (S2321935).
UAa
UAb
iv
po
po
0.5
25
25
0.08
0.25
1.46
378.0
1.9
114.3
0.6
< 0.01
2.3
NX-
201b
30.3
132.2
4.72
References and notes
a0.5 mg/ml, DMSO:PEG 300:water = 2:4:1
b0.5% CMC water suspension
1. (a) Jäger, S.; Trojan, H.; Kopp, T.; Laszczyk, M. N.; Scheffler, A.
Molecules 2009, 14, 2016; (b) Babalola, I. T.; Shode, F. O. J. J.
Pharmacogn. Phytochem. 2013, 2, 21.
Anticancer in vivo efficacy14 of NX-201 was tried by using
typical pancreatic cancer model, a SCID mouse bearing PANC-1
xenograft to provide evidence for pancreatic cancer drug. Figure
3 shows the comparison of test groups in the tumor size for four
weeks.
2. (a) Kashyap, D.; Tuli, H. S.; Sharma, A. K. Life Sci. 2016, 146,
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H.; Sethi, G.; Bishayee, A. Biochem. Pharmacol. 2013, 83, 1579;
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2013, 75, 59; (d) Gupta, A.; Sheth, N. R.; Pandey, S.; Shah, D. R.;
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Esperandim, V. R.; Toldo, M. P. A.; Kuehn, C. C.; Prado Jr., J. C.;
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R. K.; Adams, C. M. Cell Metab. 2011, 13, 627.
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H. Biomed. Res. Int. 2015, article number 809714.
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Figure 3. In vivo test in PANC-1 xenograft SCID mouse
model
(Groups: G1 = negative control; G2 = positive control,
gemcitabine, 40 mg/kg, iv, 2 times/week; G3 = NX-201, 25
mg/kg, po, daily; G4 = NX-201, 50 mg/kg, po, daily; G5 = NX-
201, 100 mg/kg, po, daily; G6 = UA, 50 mg/kg, po, daily; G7 =
combination of NX-201 (50 mg/kg, iv, daily) and gemcitabine
(40 mg/kg, po, 2 times/week))
10. 1H NMR (DMSO-d6, 500MHz) δ 4.76~5.00 (2H, dd, J = 14Hz,
medoxomil methylene), 5.16 (1H, t, J = 1.75Hz, C12), 4.27 (1H, d,
J = 5Hz, hydroxyl), 2.96 ~ 3.01 (1H, m, C3), 2.15 (1H, d, C18),
2.11 (3H, s, medoxomil methyl), 1.04 (3H, s, C27), 0.92 (3H, d, J
= 6Hz, C30), 0.89 (3H, s, C23), 0.84 (3H, s, C25), 0.81 (3H, d, J =
6.5Hz, C29), 0.67 (3H, s, C26), 0.56 (3H, s, C24); 13C NMR
(CDCl3, 500MHz) δ 177.04 (C28), 152.25 (medoxomil carbonyl),
139.91 (medoxomil), 137.66 (C13), 133.84 (medoxomil), 126.05
(C12), 78.96 (C3), 55.20 (medoxomil methylene), 53.35 (C15),
52.87 (C18), 48.43 (C7), 47.45 (C9), 42.05 (C14), 39.50 (C8),
39.02 (C1), 38.82 (C4), 38.73 (C19), 38.60 (C20), 36.92 (C22),
36.61 (C10), 33.03 (C7), 30.54 (C21), 28.15 (C23), 27.82 (C2),
27.20 (C15), 24.12 (C16), 23.47 (C11), 23.24 (C27), 21.12 (C30),
18.28 (C6), 16.94 (C26), 16.63 (C24), 15.63 (C25), 15.40 (C26),
9.38 (medoxomil methyl); MALDI-TOF m/z [M+Na] calcd for
C35H52O6Na 591.37, found 591.34; IR(cm-1) 2918, 1882, 1686,
Repeated administration of single NX-201 (G3-G5) for 4
weeks resulted in the decrease of tumor growth rate dose-
dependently. In case of UA (G6), no significant change in tumor
size occurred as expected, that suggests the evidence of enhanced
absorption of NX-201 by oral administration route. At 100 mg/kg
dose of NX-201 (G5) tumor growth rate decreased on a similar
level of gemcitabine, and this reflects the potent anticancer effect
considering its low bioavailability. A noteworthy point is that the
combination of NX-201 and gemcitabine (G7) even reduced
tumor size after 3 weeks administration. In terms of body weight
every test groups showed no significant change.
1720, 1455, 1383, 1219, 1186, 1044, 1029; mp 188~192℃.
11. (a) Testa, B.; Kramer, S. D. Chem. Biodivers. 2009, 6, 591; (b)
Ishizuka, T.; Fujimori, I.; Kato, M.; Sakikawa, C. N.; Saito, M.;
Yoshige, Y.; Kubota, K.; Kurihara, A.; Izume, T.; Ikeda, T.;
Okazaki, O. J. Biol. Chem. 2010, 285, 11892.
12. (a) Jeon, D. W.; Kim, Y. H.; Kim, H. H.; Ji, H. Y.; Yoo, S. D.;
Choi, W. R.; Lee, S. M.; Han, C.; Lee, H. S. Biopharm. Drug.
Dispos. 2007, 28, 51; (b) Chen, Q.; Luo, S.; Zhang, Y.; Chen, Z.
Anal. Bioanal. Chem. 2011, 399, 2877.
13. Sample collection and analysis condition about PK test of UA and
NX-201(>99% purity on HPLC): (a) Blood samples (0.6 ml) were
collected prior to serve as a control, and collection points are 5
min, 15 min, 30 min, 45 min, 1 hr, 2 hr, 4 hr, 8 hr and 12 hr after
drug administration; (b) HPLC/MS/MS (Agilent 1200 series LC
system) analysis condition: detector = AB API4000 LC/MS,
column = Phenomenex Luna C18 column (50 mm * 2.0 mm, 3
In conclusion, conversion of UA to ester-type prodrug, NX-
201, ensured a high probability of new pancreatic cancer therapy.
And furthermore, UA prodrugs including NX-201 can be utilized
in the field of various cancer and other intractable diseases based
on the previous reports about UA’s pharmacological efficacies.
Since UA has been well-known for very low-toxic natural
product, it can be said that UA prodrugs have great potentials in
many respects. In the view of anticancer drugs, combination of
NX-201 and other currently prescribed drugs can be highly
beneficial in the management of incurable cancer patients. In
near future, our research team is planning to broaden the
therapeutic applications in parallel with the development of
anticancer drug.
µm), mobile phase = 10 mM ammonium acetate : methanole, 10 :
90 (v/v), flow rate = 0.3 ml/min, injection volumn = 5.0 µL,
MRM = ursolic acid (m/z 455.4).
14. In vivo test: (a) This study was performed in accordance with the
Animal Experimentation Policy of KNOTUS Co., Ltd. for animal
experimentation ethics (b) Animal model = NOD, DB17 SCID