Korean J Physiol Pharmacol.  2013 Dec;17(6):517-523. 10.4196/kjpp.2013.17.6.517.

Cytotoxicity and Structure-activity Relationships of Naphthyridine Derivatives in Human Cervical Cancer, Leukemia, and Prostate Cancer

• Hwang YJ
• Chung ML
• Sohn UD
• Im C

• KMID: 2285479
• DOI: http://doi.org/10.4196/kjpp.2013.17.6.517

Abstract

Naphthyridine compounds are important, because they exhibit various biological activities including anticancer, antimicrobial, and anti-inflammatory activity. Some naphthyridines have antimitotic effects or demonstrate anticancer activity by inhibiting topoisomerase II. These compounds have been investigated as potential anticancer agents, and several compounds are now part of clinical trials. A series of naphthyridine derivatives were evaluated for their in vitro cytotoxic activities against human cervical cancer (HeLa), leukemia (HL-60), and prostate cancer (PC-3) cell lines using an MTT assay. Some compounds (14, 15, and 16) were more potent than colchicine against all three human cancer cell lines and compound (16) demonstrated potency with IC50 values of 0.7, 0.1, and 5.1 microM, respectively. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used for quantitative structure-activity relationship (QSAR) molecular modeling of these compounds. We obtained accurate and predictive three-dimensional QSAR (3D-QSAR) models as indicated by the high PLS parameters of the HeLa (q2, 0.857; r2, 0.984; r2pred, 0.966), HL-60 (q2, 0.777; r2, 0.937; r2pred, 0.913), and PC-3 (q2, 0.702; r2, 0.983; r2pred, 0.974) cell lines. The 3D-QSAR contour maps suggested that the C-1 NH and C-4 carbonyl group of the naphthyridine ring and the C-2 naphthyl ring were important for cytotoxicity in all three human cancer cell lines.

Keyword

Cytotoxicity; Naphthyridine; SAR

MeSH Terms

Antineoplastic Agents
Cell Line
Colchicine
DNA Topoisomerases, Type II
Humans*
Inhibitory Concentration 50
Leukemia*
Models, Molecular
Naphthyridines
Prostate*
Prostatic Neoplasms*
Quantitative Structure-Activity Relationship
Structure-Activity Relationship*
Uterine Cervical Neoplasms*
Antineoplastic Agents
Colchicine
DNA Topoisomerases, Type II
Naphthyridines

Figure

• 

  Fig. 1 Structures of anticancer agents.

• 

  Fig. 2 Correlation plots between the experimental and predicted activities for training and test set compounds. (A) Human cervical cancer cell line (HeLa), (B) leukemia cell line (HL-60), and (C) prostate cancer cell line (PC-3). The IC50 values were transformed into pIC50 (-log IC50) values (● : training set molecules, ▲ : test set molecules).

• 

  Fig. 3 Three-contour maps for the CoMSIA models. (A) Cervical cancer cell line (HeLa), (B) leukemia cell line (HL-60), and (C) prostate cancer cell line (PC-3). Compound (16) is shown within the fields (blue, favorable positive charge; red, favorable negative charge; yellow, favorable hydrophobicity; white, unfavorable hydrophobicity; cyan, favorable hydrogen bond donor; purple, unfavorable hydrogen bond donor).

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