10-α-Aminoacyl-9(10H)-anthracenones: Inhibition of 12(S)-HETE Biosynthesis and HaCaT Cell Growth

Abstract

1,8‐Dihydroxy‐9(10H)‐anthracenones with a 10‐α‐aminoacyl group were synthesized using either a mixed‐anhydride coupling method or Boc‐protected oxazolidinediones. The novel anthracenones were evaluated as inhibitors of the biosynthesis of 12(S)‐hydroxyeicosatetraenoic acid (12(S)‐HETE) in epidermal homogenate of mice and for inhibition of the growth of HaCaT keratinocytes. These cells were also tested for their susceptibility for the action of the most potent members of this series on plasma membrane integrity, in order to confirm that inhibition of cell growth is not a result of membrane damage induced by prooxidants released from anthracenones. Hydroxyl‐radical generation as measure of the prooxidant potential of the compounds was determined by deoxyribose degradation. The most potent analogues of this series were equally potent as anthralin against 12(S)‐HETE biosynthesis and keratinocyte proliferation, while oxygen‐radical generation and the resulting damage to cell membrane was strongly reduced as compared to the antipsoriatic drug.

Antipsoriatic Anthrones with Modulated Redox Properties. 5. Potent Inhibition of Human Keratinocyte Growth, Induction of Keratinocyte Differentiation, and Reduced Membrane Damage by Novel 10-Arylacetyl-1,8-dihydroxy-9(10H)-anthracenones

“…The novel 10-phenylacetyl analogues were prepared by reaction of 1 with appropriate phenylacetyl chlorides in the presence of pyridine (Scheme , method A, X = Cl), where acylation takes place at the C-10 position via the carbanion . The required phenylacetyl chlorides were prepared from the corresponding phenylacetic acids 2 according to literature procedures. , In an alternative method (method B, X = OH), phenylacetic acids 2 were directly introduced onto the 10-position of 1 via the coupling agent dicyclohexylcarbodiimide (DCC) . For easier workup in the preparation of 3n , ethyl N , N -dimethylaminopropylcarbodiimide (EDC) was used in place of DCC.…”

“…14,15 In an alternative method (method B, X ) OH), phenylacetic acids 2 were directly introduced onto the 10-position of 1 via the coupling agent dicyclohexylcarbodiimide (DCC). 16 For easier workup in the preparation of 3n, ethyl N,N-dimethylaminopropylcarbodiimide (EDC) was used in place of DCC. EDC was also used to obtain the hydroxamate 3o from 3n and N-methylhydroxylamine hydrochloride.…”