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  • Additional derivatives were synthesised using a


    Additional derivatives were synthesised using a modified approach (). Commercially available 4-bromo-2-methoxyaniline () was converted into the boronic ester , followed by a Suzuki–Miyaura cross-coupling with chromenone triflate to afford the corresponding arylamine . Acylation of with chloroacetyl chloride, followed by reaction with morpholine, provided the methoxy-variant and subsequent deprotection gave the phenol . The key intermediate was also accessed using an alternative synthetic route (). Commercially available 1-bromo-4-nitrobenzene () was converted into 5-bromo-2-nitrophenol () in 79% yield, using cumene hydroperoxide and -BuOK in the presence of ammonia. Again, Suzuki–Miyaura cross-coupling with followed by reduction of the nitrophenol intermediate gave aniline . Finally, phenol was obtained in 78% yield by chloroacetylation followed by reaction with morpholine. The effect upon biological activity of alkylation of hydroxyphenylchromen-4-one was investigated through the preparation of a small series of -alkoxyphenyl derivatives – ( and )., To enable further SAR studies, the 2-hydroxyethoxy () and aminoethoxy () derivatives were also synthesised (). Alkylation of phenol intermediate with 2-(butyldimethylsilyloxy)ethyl bromide, proceeded in 92% yield, followed by TBDMS removal giving the desired alcohol in quantitative yield. Tosylation of and treatment with NaN in DMF at 60°C gave azide , which was reduced with triphenylphosphine in the presence of water to afford the desired amine in 34% yield. Our previous SAR studies have highlighted the importance of an appropriate 8-aryl substituent for chromenone-based inhibitors (e.g., dibenzothiophen-4-yl in or a 3-arylphenyl moiety in ). The overall objective of this study was to investigate the effect upon DNA-PK inhibitory activity of replacing the planar dibenzothiophenyl group by a conformationally flexible and less lipophilic -alkoxyphenyl system, to probe the Tolvaptan pocket of the ATP-binding site. In addition, the analogues were chosen to investigate whether alkyl substituents were tolerated at this position, given that all other known derivatives are substituted with an aryl or heteroaryl group at C-8. The chemical structures and inhibitory activities of the library compounds are summarised in . With a view to delineating SARs and designing a selective DNA-PK inhibitor, all compounds were also tested against the related enzyme PI3-kinase α. For the series of arylchromenone-4-ones bearing small -alkoxy substituents at the phenyl 3-position (, –), it is evident that substitution improved neither activity nor selectivity compared with the dibenzothiophenyl analogue . Overall, a 6- to 12-fold reduction in potency was observed, and with the exception of the ethoxy derivative , which showed approximately a twofold selectivity for DNA-PK, all compounds proved to be equipotent for DNA-PK and PI3Kα. Increasing the length and steric bulk of the side chain (e.g., –) proved detrimental to inhibitory activity for both DNA-PK and PI3Kα. For example, with the cyclopropylethoxy derivative , a noticeable reduction in potency towards DNA-PK and PI3Kα was observed. This is consistent with homology modelling studies and previous SARs around this position, that indicate a limited steric tolerance in this region of the ATP-binding domain. Disappointingly, the incorporation of hydrogen bond donor and acceptor groups onto the alkoxy side chain (e.g., , and ) was not beneficial for DNA-PK inhibitory activity, and resulted in up to 117-fold reduction in potency compared with the parent 8-dibenzothiophenyl chromen-4-one . These compounds also proved to be non-selective being equipotent for DNA-PK and PI3Kα. Replacement of the methoxy group of by a hydroxyl function () resulted in a modest improvement in activity, but both compounds were non-selective for DNA-PK versus PI3Kα. Interestingly, removal of the alkoxy side chain conferred good DNA-PK inhibitory activity, with phenol exhibiting a fivefold selectivity profile for DNA-PK (IC=0.08μM) versus PI3Kα (IC=0.43μM).