Synthesis and Pharmacophore Modelling of 2,6,9-trisubstituted Purine Derivatives and Their Potential Role As Apoptosis-inducing Agents in Cancer Cell Lines

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2015 Apr 18

PMID 25884555

Citations 7

Authors

Jeannette Calderon-Arancibia

Christian Espinosa-Bustos

Alvaro Canete-Molina

Ricardo A Tapia

Mario Faundez

Maria Jose Torres

Adam Aguirre

Margot Paulino

Cristian O Salas

Affiliations

Soon will be listed here.

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.

Citing Articles

New Inhibitors of Bcr-Abl Based on 2,6,9-Trisubstituted Purine Scaffold Elicit Cytotoxicity in Chronic Myeloid Leukemia-Derived Cell Lines Sensitive and Resistant to TKIs.

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Design, Synthesis, In Silico Studies and Inhibitory Activity towards Bcr-Abl, BTK and FLT3-ITD of New 2,6,9-Trisubstituted Purine Derivatives as Potential Agents for the Treatment of Leukaemia.

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Coumarins and Gastrointestinal Cancer: A New Therapeutic Option?.

Banikazemi Z, Mirazimi S, Dashti F, Mazandaranian M, Akbari M, Morshedi K Front Oncol. 2021; 11:752784.

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A New Smoothened Antagonist Bearing the Purine Scaffold Shows Antitumour Activity In Vitro and In Vivo.

Zarate A, Espinosa-Bustos C, Guerrero S, Fierro A, Oyarzun-Ampuero F, Quest A Int J Mol Sci. 2021; 22(16).

PMID: 34445078 PMC: 8395040. DOI: 10.3390/ijms22168372.

Promising 2,6,9-Trisubstituted Purine Derivatives for Anticancer Compounds: Synthesis, 3D-QSAR, and Preliminary Biological Assays.

Salas C, Zarate A, Krystof V, Mella J, Faundez M, Brea J Int J Mol Sci. 2019; 21(1).

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References

Gray N, Wodicka L, Thunnissen A, Norman T, Kwon S, Espinoza F . Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors. Science. 1998; 281(5376):533-8. DOI: 10.1126/science.281.5376.533. View

Huang H, Liu H, Chen K, Jiang H . Microwave-assisted rapid synthesis of 2,6,9-substituted purines. J Comb Chem. 2007; 9(2):197-9. DOI: 10.1021/cc060155o. View

Aboul-Fadl T, Bin-Jubair F, Aboul-Wafa O . Schiff bases of indoline-2,3-dione (isatin) derivatives and nalidixic acid carbohydrazide, synthesis, antitubercular activity and pharmacophoric model building. Eur J Med Chem. 2010; 45(10):4578-86. DOI: 10.1016/j.ejmech.2010.07.020. View

Morales F, Ramirez A, Conejo-Garcia A, Morata C, Marchal J, Campos J . Anti-proliferative activity of 2,6-dichloro-9- or 7-(ethoxycarbonylmethyl)-9H- or 7H-purines against several human solid tumour cell lines. Eur J Med Chem. 2014; 76:118-24. DOI: 10.1016/j.ejmech.2014.02.012. View

Chang Y, Wignall S, Rosania G, Gray N, Hanson S, Su A . Synthesis and biological evaluation of myoseverin derivatives: microtubule assembly inhibitors. J Med Chem. 2001; 44(26):4497-500. DOI: 10.1021/jm010451+. View

Popowycz F, Schneider C, DeBonis S, Skoufias D, Kozielski F, Galmarini C . Synthesis and antiproliferative evaluation of pyrazolo[1,5-a]-1,3,5-triazine myoseverin derivatives. Bioorg Med Chem. 2009; 17(9):3471-8. DOI: 10.1016/j.bmc.2009.03.007. View

Vince R . Synthesis and anti-HIV activity of carbovir and related carbocyclic nucleosides. Nucleic Acids Symp Ser. 1991; (25):193-4. View

Benson C, White J, de Bono J, ODonnell A, Raynaud F, Cruickshank C . A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib (CYC202; R-Roscovitine), administered twice daily for 7 days every 21 days. Br J Cancer. 2006; 96(1):29-37. PMC: 2360206. DOI: 10.1038/sj.bjc.6603509. View

Welsch M, Snyder S, Stockwell B . Privileged scaffolds for library design and drug discovery. Curr Opin Chem Biol. 2010; 14(3):347-61. PMC: 2908274. DOI: 10.1016/j.cbpa.2010.02.018. View

10.

De Clercq E . In search of a selective antiviral chemotherapy. Clin Microbiol Rev. 1997; 10(4):674-93. PMC: 172940. DOI: 10.1128/CMR.10.4.674. View

11.

Sroka I, Heiss E, Havlicek L, Totzke F, Aristei Y, Pechan P . A novel roscovitine derivative potently induces G1-phase arrest in platelet-derived growth factor-BB-activated vascular smooth muscle cells. Mol Pharmacol. 2009; 77(2):255-61. DOI: 10.1124/mol.109.060327. View

12.

Le Tourneau C, Faivre S, Laurence V, Delbaldo C, Vera K, Girre V . Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies. Eur J Cancer. 2010; 46(18):3243-50. DOI: 10.1016/j.ejca.2010.08.001. View

13.

Ederhy S, Izzedine H, Massard C, Dufaitre G, Spano J, Milano G . Cardiac side effects of molecular targeted therapies: towards a better dialogue between oncologists and cardiologists. Crit Rev Oncol Hematol. 2011; 80(3):369-79. DOI: 10.1016/j.critrevonc.2011.01.009. View

14.

Massard C, Soria J, Anthoney D, Proctor A, Scaburri A, Pacciarini M . A first in man, phase I dose-escalation study of PHA-793887, an inhibitor of multiple cyclin-dependent kinases (CDK2, 1 and 4) reveals unexpected hepatotoxicity in patients with solid tumors. Cell Cycle. 2011; 10(6):963-70. DOI: 10.4161/cc.10.6.15075. View

15.

Saxena S, Chaudhaery S, Varshney K, Saxena A . Pharmacophore-based virtual screening and docking studies on Hsp90 inhibitors. SAR QSAR Environ Res. 2010; 21(5-6):445-62. DOI: 10.1080/1062936X.2010.501817. View

16.

Rosemeyer H . The chemodiversity of purine as a constituent of natural products. Chem Biodivers. 2006; 1(3):361-401. DOI: 10.1002/cbdv.200490033. View

17.

Vandromme L, Legraverend M, Kreimerman S, Lozach O, Meijer L, Grierson D . A Pd(0) based cross-coupling approach to the synthesis of 2-amidopurines and their evaluation as CDK inhibitors. Bioorg Med Chem. 2006; 15(1):130-41. DOI: 10.1016/j.bmc.2006.10.003. View

18.

Chang Y, Gray N, Rosania G, Sutherlin D, Kwon S, Norman T . Synthesis and application of functionally diverse 2,6,9-trisubstituted purine libraries as CDK inhibitors. Chem Biol. 1999; 6(6):361-75. DOI: 10.1016/S1074-5521(99)80048-9. View

19.

Hansen S, Skovsgaard T, Sorensen J . Treatment of small cell lung cancer with 6-mercaptopurine: a phase II study. Cancer Treat Rep. 1985; 69(5):555. View

20.

Wang X, Wang L, Wu N, Ma X, Xu J . Clinical efficacy of oral ganciclovir for prophylaxis and treatment of recurrent herpes simplex keratitis. Chin Med J (Engl). 2015; 128(1):46-50. PMC: 4837818. DOI: 10.4103/0366-6999.147808. View