Biologically active carbazole derivatives: focus on oxazinocarbazoles and related compounds

Abstract

Four series of carbazole derivatives, including N-substituted-hydroxycarbazoles, oxazinocarbazoles, isoxazolocarbazolequinones, and pyridocarbazolequinones, were studied using diverse biological test methods such as a CE-based assay for CK2 activity measurement, a cytotoxicity assay with IPC-81 cell line, determination of MIC of carbazole derivatives as antibacterial agents, a Plasmodium falciparum susceptibility assay, and an ABCG2-mediated mitoxantrone assay. Two oxazinocarbazoles Ib and Ig showed CK2 inhibition with IC₅₀ = 8.7 and 14.0 µM, respectively. Further chemical syntheses were realized and the 7-isopropyl oxazinocarbazole derivative 2 displayed a stronger activity against CK2 (IC₅₀ = 1.40 µM). Oxazinocarbazoles Ib, Ig, and 2 were then tested against IPC-81 leukemia cells and showed the ability to induce leukemia cell death with IC₅₀ values between 57 and 62 μM. Further investigations were also reported on antibacterial and antiplasmodial activities. No significant inhibitory activity on ABCG2 efflux pump was detected.

• Biological activities
• carbazoles
• chemical synthesis
• oxazinocarbazoles
• screening

Acknowledgements

Dr. Z. Bouaziz and Pr. M. Le Borgne would like to gratefully thank Christine Ranquet and Dr. L. Ettouati for their assistance in the stock management of the small molecule library of EA 4446 B2C. We also would like to thank ChemAxon for providing us license to their cheminformatics software.

Declaration of interest

The authors report no declarations of interest. We acknowledge financial support to Zouhair Bouaziz and Marc Le Borgne by the “Bonus Qualité Recherche” (BQR) of the University Claude Bernard Lyon 1, by the “Cluster 5 Chimie Durable et Chimie pour la Santé” of the Region Rhône-Alpes and by the “ARC 1 Santé” of the Region Rhône-Alpes. The “Institut des Sciences Pharmaceutiques et Biologiques” (ISPB) is also gratefully acknowledged for the funding of an uHPLC/DAD/MS system.

The present work was also supported by the “Partenariat Hubert Curien” (PHC) (Campus France, Programme Aurora, Grant Agreement No. 27460VC). Pr. Marc Le Borgne also thanks the “Institut français d’Oslo” for their support via the Åsgard Programme 2010.

Dr. M. Baitiche is very grateful to the Ministry of Higher Education and Research and to the University of Setif for sponsoring the trainings carried out at EA 4446 “Biomolécules Cancer et Chimiorésistances”.

We acknowledge financial support given to Samar Issa by the “Agence Universitaire de la Francophonie” (AUF) and the Région Rhône-Alpes (MIRA).