Uwe Kuckländer

Reaction of N-Methyl-hydrazones as Azaenamines with Quinones

Abstract 1,4-Naphthoquinone derivatives reacted with N , N -disubstituted hydrazones to give C adducts, whereas N -monoalkylhydrazones yielded N adducts which underwent ring closure to benzindazole-4,9-diones. Michael addition with methoxycarbonylbenzoquinone led to open chain mono- and disubstituted N adducts or phthalazin-1-one derivatives, depending on the hydrazone. N Adducts obtained from dimethylbenzoquinone cyclized by hetero Diels–Alder reaction to benzoxadiazines.

Identification of novel CK2 inhibitors with a benzofuran scaffold by novel non-radiometric in vitro assays

Protein kinase CK2 is emerging as a target in neoplastic diseases. Inhibition of CK2 by small compounds could lead to new therapies by counteracting the elevated CK2 activities found in a variety of tumors. Currently, CK2 inhibitors are primarily evaluated by a radiometric in vitro assay tracing the amount of transferred γ-32P from ATP to a substrate peptide. Here, we present two alternative assays abandoning radioisotopes. The first assay is based on Förster resonance energy transfer between the fluorescence donor EDANS and the acceptor molecule DABCYL within the CK2 substrate peptide [DABCYL]-RRRDDDSDDD-[EDANS]. This peptide comprises a cleavage site for pancreatic elastase, which is located next to the phosphate acceptor serine. Only the non-phosphorylated peptide can be cleaved by elastase, disrupting the FRET effect. Thus fluorescence intensity is inversely correlated with CK2 activity. The second non-radiometric assay deploys the changing of charge that occurs within the peptide substrate RRRDDDSDDD upon phosphorylation by CK2. Substrate and product of a CK2 reaction consequently show a difference in electrophoretic mobility and thus can be separated by capillary electrophoresis. Absorption detection enabled quantification of both peptide species and allowed the determination of IC50 values. This method facilitated the testing of a small compound library by which benzofuran derivatives were identified as potent CK2 inhibitors with IC50 values in the submicromolar range.

Cyclisierung von β-[(1, 4-Chinon-2-yl)methyl]-enaminon-Derivaten

Starting from 2,5-bisbenzyloxy-4-methyl-benzaldehyd 2-(3-amino-2-acetyl-but-2-enyl)-5-methyl[1,4]benzoquinones 9a—e are synthesized as model compounds in order to study the ambident reactivity of enaminones and quinones. Spontaneus cyclization of 9b—e in ethanol or acetic acid to 1-aza-spiro[4,5]deca-2,7-dien-6,9-dion 20b—e in good yield is observed. 6-Hydroxy-3-acetyl-quinoline 21 is obtained from 9a. In one case (9c) 2-acetyl-3-benzylamino-7-hydroxy-naphthalene (17) was formed as by-product. 9d in alkoholic perchloric acid leads to quinolinium salt 18 in low yield.

Untersuchung zur 6-Hydroxyindol-Bildung bei der Nenitzescu-Reaktion, IV [1]. Cyclisierung von N-(Chinonylalkyl)enaminon-Derivaten, II [2] / Investigation on the Formation of 6-Hydroxyindole in the Nenitzescu Reaction, IV [1]. Cyclization of N-(Quinonylalkyl)enaminone Derivatives, II [2]

Quinonylmethylenaminones 5 and 6 are synthesized and cyclized to spiro compounds 7 and 8. Quinonylpropylenaminone 15 is made in the same way. Cyclization in acetic acid yields quinolines 11 and 12, in trifluoroacetic acid/trifluoroacetic anhydrid diacylenamine 16 is obtained. The product of 15 in perchloric acid is benzazocine 20. The structure of 20 is proven by X-ray analysis. The course of the reaction is discussed.