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. 2015 Apr 15;20(4):6808-26.
doi: 10.3390/molecules20046808.

Synthesis and pharmacophore modelling of 2,6,9-trisubstituted purine derivatives and their potential role as apoptosis-inducing agents in cancer cell lines

Jeannette Calderón-Arancibia  1 , Christian Espinosa-Bustos  2 , Álvaro Cañete-Molina  3 , Ricardo A Tapia  4 , Mario Faúndez  5 , Maria Jose Torres  6 , Adam Aguirre  7 , Margot Paulino  8 , Cristian O Salas  9
Affiliations

Synthesis and pharmacophore modelling of 2,6,9-trisubstituted purine derivatives and their potential role as apoptosis-inducing agents in cancer cell lines

Jeannette Calderón-Arancibia et al. Molecules. .

Abstract

A series of 2,6,9-trisubstituted purine derivatives have been synthesized and investigated for their potential role as antitumor agents. Twelve compounds were obtained by a three step synthetic procedure using microwave irradiation in a pivotal step. All compounds were evaluated in vitro to determine their potential effect on cell toxicity by the MTT method and flow cytometry analysis on four cancer cells lines and Vero cells. Three out of twelve compounds were found to be promising agents compared to a known and effective anticancer drug, etoposide, in three out of four cancer cell lines assayed with considerable selectivity. Preliminary flow cytometry data suggests that compounds mentioned above induce apoptosis on these cells. The main structural requirements for their activity for each cancer cell line were characterized with a preliminary pharmacophore model, which identified aromatic centers, hydrogen acceptor/donor center and a hydrophobic area. These features were consistent with the cytotoxic activity of the assayed compounds.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structures of 2,6,9-trisubstituted purines with biological properties.
Scheme 1
Scheme 1
Synthesis of target compounds 4a–l.
Figure 2
Figure 2
Structures of compounds 2b and 2b' and key HMBC correlations.
Figure 3
Figure 3
2D representation of 4e and numbering used to identify the pharmacophoric features.
Figure 4
Figure 4
Elucidated pharmacophoric model for 2,6,9-trisubstituted purines against each cancer cell lines: (a) Hela; (b) H1975 and (c) HTC116.
Figure 5
Figure 5
Viability assays of compounds 4f, 4j and 4k on cancer cell lines.
See this image and copyright information in PMC

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