Design and biological evaluation of substituted 5,7-dihydro-6H-indolo[2,3-c]quinolin-6-one as novel selective Haspin inhibitors

Abstract

A library of substituted indolo[2,3-c]quinolone-6-ones was developed as simplified Lamellarin isosters. Synthesis was achieved from indole after a four-step pathway sequence involving iodination, a Suzuki-Miyaura cross-coupling reaction, and a reduction/lactamization sequence. The inhibitory activity of the 22 novel derivatives was assessed on Haspin kinase. Two of them possessed an IC₅₀ of 1 and 2 nM with selectivity towards a panel of 10 other kinases including the parent kinases DYRK1A and CLK1. The most selective compound exerted additionally a very interesting cell effect on the osteosarcoma U-2 OS cell line.

Keywords:

• Indoloquinoline
• Haspin kinase
• docking
• cell viability

Acknowledgements

The authors thank Gaëlle Al Feghali for technical assistance on FACS data analysis. The authors wish to thank the Cancéropôle Grand Ouest “Marine Molecules, Metabolism and Cancer network”, IBiSA (French Infrastructure en sciences du vivant: biologie, santé et agronomie), Biogenouest (Western France life science and environment core facility network supported by the Conseil Régional de Bretagne) for supporting KISSf facility.

Author contributions

Conceptualization, S.Ro, and C.N.; Methodology chemistry, S.A., S.Ro. and C.N.; Methodology biology, S.Br., S.Ba. and S.Ru.; Molecular modeling, S.Bo. and P.B.; Investigation, S.A., L.X., P. X., M.T., B.J., S.Bo., S.Ba., P.B., F.B., S.Ru., S.Ro. and C. N.; Writing –Original Draft, S.Ru., S.Ro., and C.N.; Writing–Review & Editing, S.Ru., S.Ro, S.Bo, S.A., P.B., F.B. and C.N.; Funding Acquisition & Resources & Supervision, S.Ru., S.Ro and C.N.

Disclosure statement

No potential conflict of interest was reported by the author(s). This work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Additional information

Funding

This work was funded by “La Ligue contre le Cancer du Grand Ouest” committee (districts 29, 22, 56, 35, 45 and 79) in Région Centre Val de Loire, by the RTR Motivhealth. This research was supported by the Drug Discovery Pipeline of Guangzhou Institute of Biomedicine and Health, GIBH.