Potent enantioselective inhibition of DNA-dependent protein kinase (DNA-PK) by atropisomeric chromenone derivatives

Kate M. Clapham; Tommy Rennison; Gavin Jones; Faye Craven; Julia Bardos; Bernard T. Golding; Roger J. Griffin; Karen Haggerty; Ian R. Hardcastle; Pia Thommes; Attilla Ting; Céline Cano

doi:10.1039/C2OB26035B

Potent enantioselective inhibition of DNA-dependent protein kinase (DNA-PK) by atropisomeric chromenone derivatives†

Kate M. Clapham,‡^a Tommy Rennison,‡^a Gavin Jones,^a Faye Craven,^a Julia Bardos,^b Bernard T. Golding,^a Roger J. Griffin,^a Karen Haggerty,^a Ian R. Hardcastle,^a Pia Thommes,^c Attilla Ting^c and Céline Cano*^a

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* Corresponding authors

^a Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne, UK
E-mail: celine.cano@ncl.ac.uk
Tel: +44 (0) 1912227060

^b KuDOS Pharmaceuticals, Ltd, 410 Cambridge Science Park, Milton Road, Cambridge CB4 0PE, UK

^c AstraZeneca Oncology iMed, Mereside, Alderley Park, Macclesfield SK10 4TG, UK

Abstract

Substitution at the 7-position of the chromen-4-one pharmacophore of 8-(dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one NU7441, a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor, with allyl, n-propyl or methyl enabled the resolution by chiral HPLC of atropisomers. Biological evaluation against DNA-PK of each pair of atropisomers showed a marked difference in potency, with biological activity residing exclusively in the laevorotatory enantiomer.

Organic & Biomolecular Chemistry

Potent enantioselective inhibition of DNA-dependent protein kinase (DNA-PK) by atropisomeric chromenone derivatives†

Abstract

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Potent enantioselective inhibition of DNA-dependent protein kinase (DNA-PK) by atropisomeric chromenone derivatives

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