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Kim, Kim, Chung, and Im: Cytotoxic Activity and Three-Dimensional Quantitative Structure Activity Relationship of 2-Aryl-1,8-naphthyridin-4-ones
Original Article

Korean J Physiol Pharmacol 2009;13(6):511-516.

Published online: 18 February 2009

DOI: https://doi.org/10.4196/kjpp.2009.13.6.511

Cytotoxic Activity and Three-Dimensional Quantitative Structure Activity Relationship of 2-Aryl-1,8-naphthyridin-4-ones

Yong Jin Kim, Eun Ae Kim, Mi Lyang Chung, Chaeuk Im

College of Pharmacy, Chung-ang University, Seoul 156-756, Korea

Corresponding to: Chaeuk Im, College of Pharmacy, Chung-ang University, Heuksuk-dong, Dongjak-gu, Seoul 156-756, Korea. (Tel) 82-2-820-5603, (Fax) 82-2-816-7338, (E-mail) Chaeukim@cau.ac.kr

Received 25 November 2009       Revised 3 December 2009       Accepted 17 December 2009

Copyright © 2009 Korean J Physiol Pharmacol

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

A series of substituted 2-arylnaphthyridin-4-one analogues, which were previously synthesized in our laboratory, were evaluated for their in vitro cytotoxic activity against human lung cancer A549 and human renal cancer Caki-2 cells using MTT assay. Some compounds (11, 12, and 13) showed stronger cytotoxicity than colchicine against both tumor cell lines, and compound 13 exhibited the most potent activity with IC50 values of 2.3 and 13.4 μM, respectively. Three-dimensional quantitative structure activity relationship (3D-QSAR) studies of comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed. Predictive 3D-QSAR models were obtained with q2 values of 0.869 and 0.872 and r2ncv values of 0.983 and 0.993 for CoMFA and CoMSIA, respectively. These results demonstrate that CoMFA and CoMSIA models could be reliably used in the design of novel cytotoxic agents.

Keywords: CoMFA, CoMSIA, Cytotoxicity, MTT, QSAR

References

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Fig. 1.
Scatter plot of actual activities versus predicted activities against A549 (A) and Caki-2 (B) tumor cell lines (: training set molecules, ▴: test set molecules).
kjpp-13-511f1.tif
Fig. 2.
Contour maps of steric and electrostatic fields in lung cancer A549 (A) and renal cancer Caki-2 (B) cells. Compound 13 is shown inside the field. Color-coding is as follows: Green indicates regions where bulky groups increase activity, whereas yellow indicates regions where bulky groups decrease activity. Blue indicates that positive charge favors high activity, whereas red indicates that negative charge favors high activity.
kjpp-13-511f2.tif
Table 1.
In vitro cytotoxic activity of 2-aryl-1,8-naphthyridin-4-ones compared with colchicines
kjpp-13-511f3.tif
Table 2.
Statistical data of CoMFA and CoMSIA for two tumor cell lines
Fielda q2b Nc SEPd r2ncve SEEf Fg Contributionsa
S E D A
Lung cancer A549                    
CoMFA                    
S 0.869 3 0.240 0.983 0.091 118.709 1      
E 0.266 1 0.514 0.962 0.138 50.095   1    
SE 0.820 3 0.281 0.983 0.092 115.575 0.843 0.157    
CoMSIA                    
S 0.863 3 0.245 0.977 0.107 83.623 1      
E 0.255 1 0.518 0.950 0.158 37.767   1    
D 0.806 2 0.277 0.940 0.173 31.115     1  
A 0.306 4 0.586 0.956 0.148 43.137       1
SE 0.577 4 0.457 0.977 0.108 83.536 0.491 0.509    
DA 0.799 2 0.282 0.931 0.184 27.051     0.413 0.587
Renal cancer Caki-2                    
CoMFA                    
S 0.412 1 0.338 0.989 0.054 184.305 1      
E 0.838 4 0.208 0.984 0.064 126.912   1    
SE 0.715 3 0.260 0.992 0.046 248.683 0.637 0.363    
CoMSIA   1 0.372 0.976 0.080 81.450        
S 0.287           1      
E 0.827 3 0.202 0.985 0.062 135.235   1    
D 0.538 2 0.314 0.946 0.120 35.053     1  
A 0.485 4 0.371 0.948 0.118 36.104       1
SE 0.872 3 0.174 0.993 0.042 305.023 0.319 0.681    
DA 0.619 3 0.301 0.916 0.150 21.837     0.323 0.677

a Fields used, S, steric; E, electrostatic; D, H-bond donor; A, H-bond acceptor;

b q2, cross-validated correlation coefficient from leave-one-out(LOO);

c N, optimum number of components;

d SEP, standard error of prediction;

e r2ncv, non-crossvalidated correlation coefficient;

f SEE, standard error of estimate;

g F, F-test value.

Table 3.
Actual and predicted activity (pIC50) of training set
Compound A549 Caki-2
Actual Predicted Residual Actual Predicted Residual
1 3.71 3.78 -0.07 3.56 3.64 -0.08
2 3.94 3.86 0.08 3.74 3.69 0.05
3 3.98 3.90 0.08 3.86 3.82 0.04
4 4.59 4.59 0.00 3.89 3.89 0.00
5 4.07 4.16 –0.09 3.94 3.94 0.00
6 4.01 3.94 0.07 3.83 3.82 0.01
7 4.00 4.08 –0.08 3.94 3.96 –0.02
8 3.99 3.94 0.05 3.95 3.92 0.03
9 4.19 4.29 –0.10 3.99 4.01 –0.02
10 3.85 3.81 0.04 4.30 4.29 0.01
11 5.03 5.09 -0.06 4.72 4.76 –0.04
12 4.96 5.00 -0.04 4.76 4.76 0.00
13 5.64 5.53 0.11 4.87 4.84 0.03
  Average   0.07     0.03
Table 4.
Actual and predicted activity (pIC50) of test set
Compound A549 Caki-2
Actual Predicted Residual Actual Predicted Residual
T1 4.02 3.85 0.17 3.91 3.94 -0.03
T2 4.16 4.00 0.16 3.95 4.01 -0.06
T3 4.03 3.95 0.08 4.00 4.39 -0.39
  Average   0.14     0.16
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