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Discovery of novel 1,2,3-triazole derivatives as anticancer agents using QSAR and in silico structural modification.

Prachayasittikul V, Pingaew R, Anuwongcharoen N, Worachartcheewan A, Nantasenamat C, Prachayasittikul S, Ruchirawat S, Prachayasittikul V - Springerplus (2015)

Bottom Line: Four QSAR models were successfully constructed with acceptable predictive performance affording R CV ranging from 0.5958 to 0.8957 and RMSECV ranging from 0.2070 to 0.4526.An additional set of 64 structurally modified triazole compounds (1A-1R, 2A-2R, 7A-7R and 8A-8R) were constructed in silico and their predicted cytotoxic activities were obtained using the constructed QSAR models.The study suggested crucial moieties and certain properties essential for potent anticancer activity and highlighted a series of promising compounds (21, 28, 32, 1P, 8G, 8N and 8Q) for further development as novel triazole-based anticancer agents.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok, 10700 Thailand ; Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok, 10700 Thailand.

ABSTRACT
Considerable attention has been given on the search for novel anticancer drugs with respect to the disease sequelae on human health and well-being. Triazole is considered to be an attractive scaffold possessing diverse biological activities. Structural modification on the privileged structures is noted as an effective strategy towards successful design and development of novel drugs. The quantitative structure-activity relationships (QSAR) is well-known as a powerful computational tool to facilitate the discovery of potential compounds. In this study, a series of thirty-two 1,2,3-triazole derivatives (1-32) together with their experimentally measured cytotoxic activities against four cancer cell lines i.e., HuCCA-1, HepG2, A549 and MOLT-3 were used for QSAR analysis. Four QSAR models were successfully constructed with acceptable predictive performance affording R CV ranging from 0.5958 to 0.8957 and RMSECV ranging from 0.2070 to 0.4526. An additional set of 64 structurally modified triazole compounds (1A-1R, 2A-2R, 7A-7R and 8A-8R) were constructed in silico and their predicted cytotoxic activities were obtained using the constructed QSAR models. The study suggested crucial moieties and certain properties essential for potent anticancer activity and highlighted a series of promising compounds (21, 28, 32, 1P, 8G, 8N and 8Q) for further development as novel triazole-based anticancer agents.

No MeSH data available.


Related in: MedlinePlus

Chemical structures of tested compounds 1–32
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Fig1: Chemical structures of tested compounds 1–32

Mentions: Recently, a set of novel disubstituted 1,2,3-triazole derivatives (1–32, Fig. 1) has been reported as cytotoxic agents against four cancer cell lines i.e., HuCCA-1, HepG2, A549 and MOLT-3 by our research group (Pingaew et al. 2014a, b). Molecular docking of the tetrahydroisoquinoline-triazole derivatives 16–32 revealed that an aldo–keto reductase 1C3 (AKR1C3) has been identified to be a plausible target responsible for their anticancer activity (Pingaew et al. 2014a). In addition, the 1,2,3-triazoles (2–7, 12–13 and 15) were shown to be aromatase inhibitors (Pingaew et al. 2015). The 1,2,3-triazole ring can be synthesized using copper catalyzed azide-alkyne cycloaddition (CuAAC), known as the Click reaction. The analytical data of the reported compounds is provided in supplementary data. These triazoles were substituted by phenylsulfonyl (opened and closed chain analogs containing substituent R1) at position 1; and by R group as phenyl and phenyl(naphthalenyl/coumaryl)oxymethyl at position 4. General core structures of compounds 1–32 are summarized as opened chain (1–15) and closed chain sulfonamides (16–32) as shown in Fig. 2. Triazole and sulfonyl moieties of compounds 1–32 are substituted at 1,4-positions (para-) of the phenyl ring. For simplification, compounds 1–32 will be denoted as para-trizoles. In this study, the QSAR was employed as a tool for understanding SAR of these 1,2,3-triazole derivatives. Four QSAR models were constructed using the chemical structure of the 32 tested compounds (1–32) along with their experimental cytotoxic activity. Furthermore, the application of constructed QSAR models were extended for the prediction of cytotoxic activity of an additional set of 64 structurally modified compounds (1A–1R, 2A–2R, 7A–7R and 8A–8R, Figs. 3, 4, 5, 6) constructed in silico. Such structural modification of the compounds was rationally designed based on hydrophobic, electronic and steric effects as previously described by Topliss (1972, 1977). Therefore, the structurally modified compounds were obtained on the basis of changing groups on core structure (opened or closed chain), adding functional groups and altering the substitution positions of triazole and sulfonyl moieties on the phenyl ring (i.e., para- and meta-) to give para- and meta-triazoles, respectively (Fig. 7). A comprehensive analysis revealed important properties, crucial moieties and rigid analogs necessary for potent cytotoxic activity of the triazole compounds which would be of great benefit for guiding the design, screening and development of novel triazole anticancer drugs.Fig. 1


Discovery of novel 1,2,3-triazole derivatives as anticancer agents using QSAR and in silico structural modification.

Prachayasittikul V, Pingaew R, Anuwongcharoen N, Worachartcheewan A, Nantasenamat C, Prachayasittikul S, Ruchirawat S, Prachayasittikul V - Springerplus (2015)

Chemical structures of tested compounds 1–32
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4628044&req=5

Fig1: Chemical structures of tested compounds 1–32
Mentions: Recently, a set of novel disubstituted 1,2,3-triazole derivatives (1–32, Fig. 1) has been reported as cytotoxic agents against four cancer cell lines i.e., HuCCA-1, HepG2, A549 and MOLT-3 by our research group (Pingaew et al. 2014a, b). Molecular docking of the tetrahydroisoquinoline-triazole derivatives 16–32 revealed that an aldo–keto reductase 1C3 (AKR1C3) has been identified to be a plausible target responsible for their anticancer activity (Pingaew et al. 2014a). In addition, the 1,2,3-triazoles (2–7, 12–13 and 15) were shown to be aromatase inhibitors (Pingaew et al. 2015). The 1,2,3-triazole ring can be synthesized using copper catalyzed azide-alkyne cycloaddition (CuAAC), known as the Click reaction. The analytical data of the reported compounds is provided in supplementary data. These triazoles were substituted by phenylsulfonyl (opened and closed chain analogs containing substituent R1) at position 1; and by R group as phenyl and phenyl(naphthalenyl/coumaryl)oxymethyl at position 4. General core structures of compounds 1–32 are summarized as opened chain (1–15) and closed chain sulfonamides (16–32) as shown in Fig. 2. Triazole and sulfonyl moieties of compounds 1–32 are substituted at 1,4-positions (para-) of the phenyl ring. For simplification, compounds 1–32 will be denoted as para-trizoles. In this study, the QSAR was employed as a tool for understanding SAR of these 1,2,3-triazole derivatives. Four QSAR models were constructed using the chemical structure of the 32 tested compounds (1–32) along with their experimental cytotoxic activity. Furthermore, the application of constructed QSAR models were extended for the prediction of cytotoxic activity of an additional set of 64 structurally modified compounds (1A–1R, 2A–2R, 7A–7R and 8A–8R, Figs. 3, 4, 5, 6) constructed in silico. Such structural modification of the compounds was rationally designed based on hydrophobic, electronic and steric effects as previously described by Topliss (1972, 1977). Therefore, the structurally modified compounds were obtained on the basis of changing groups on core structure (opened or closed chain), adding functional groups and altering the substitution positions of triazole and sulfonyl moieties on the phenyl ring (i.e., para- and meta-) to give para- and meta-triazoles, respectively (Fig. 7). A comprehensive analysis revealed important properties, crucial moieties and rigid analogs necessary for potent cytotoxic activity of the triazole compounds which would be of great benefit for guiding the design, screening and development of novel triazole anticancer drugs.Fig. 1

Bottom Line: Four QSAR models were successfully constructed with acceptable predictive performance affording R CV ranging from 0.5958 to 0.8957 and RMSECV ranging from 0.2070 to 0.4526.An additional set of 64 structurally modified triazole compounds (1A-1R, 2A-2R, 7A-7R and 8A-8R) were constructed in silico and their predicted cytotoxic activities were obtained using the constructed QSAR models.The study suggested crucial moieties and certain properties essential for potent anticancer activity and highlighted a series of promising compounds (21, 28, 32, 1P, 8G, 8N and 8Q) for further development as novel triazole-based anticancer agents.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok, 10700 Thailand ; Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok, 10700 Thailand.

ABSTRACT
Considerable attention has been given on the search for novel anticancer drugs with respect to the disease sequelae on human health and well-being. Triazole is considered to be an attractive scaffold possessing diverse biological activities. Structural modification on the privileged structures is noted as an effective strategy towards successful design and development of novel drugs. The quantitative structure-activity relationships (QSAR) is well-known as a powerful computational tool to facilitate the discovery of potential compounds. In this study, a series of thirty-two 1,2,3-triazole derivatives (1-32) together with their experimentally measured cytotoxic activities against four cancer cell lines i.e., HuCCA-1, HepG2, A549 and MOLT-3 were used for QSAR analysis. Four QSAR models were successfully constructed with acceptable predictive performance affording R CV ranging from 0.5958 to 0.8957 and RMSECV ranging from 0.2070 to 0.4526. An additional set of 64 structurally modified triazole compounds (1A-1R, 2A-2R, 7A-7R and 8A-8R) were constructed in silico and their predicted cytotoxic activities were obtained using the constructed QSAR models. The study suggested crucial moieties and certain properties essential for potent anticancer activity and highlighted a series of promising compounds (21, 28, 32, 1P, 8G, 8N and 8Q) for further development as novel triazole-based anticancer agents.

No MeSH data available.


Related in: MedlinePlus