The novel 1-acyl-4-cycloalkyl/arylsemicarbazides (5a-y) and 1-acyl-5-benzyloxy/hydroxycarbamoylcarbazides (8a-f) derived from the nonsteroidal anti-inflammatory drugs ibuprofen, fenoprofen and reduced ketoprofen were prepared, fully chemically characterized and evaluated for their cytostatic, antiviral and antioxidant activities. Compounds 5 and 8 consist of a region rich in electronegative atoms (five to nine nitrogen and oxygen atoms) framed by aryl or cycloalkyl residues on one or both terminal ends. The synthetic pathways applied for the preparation of the title compounds involved a benzotriazole as a synthetic auxiliary in several steps. Three of the tested compounds, namely 4-benzhydryl-1-[2-(3-phenoxyphenyl)propanoyl]semicarbazide (5l), 4-benzhydryl-1-[2-(3-benzylphenyl)propanoyl]semicarbazide (5s), and 4-benzhydryl-1-[2-(4-isobutylphenyl)propanoyl]semicarbazide (5f) showed pronounced antiproliferative activity in vitro against six cancer cell lines (IC(50)=3-23 μM). The same compounds highly inhibited soybean lipoxygenase (IC(50)=60 and 51.5 μM) and lipid peroxidation as well (99, 88 and 74%, respectively). 4-Benzyloxy-1-[2-(4-isobutylphenyl)propanoyl]semicarbazide (5t) and 5-benzyloxycarbamoyl-1-[2-(3-benzylphenyl)propanoyl]carbazide (8c) exerted complete lipid peroxidation inhibition. Semicarbazides 5w-y and carbazides 8d-f bearing a hydroxamic acid/hydroxyurea moiety showed a modest antiradical activity in DPPH test, while the best radical scavenger was 1-(1-benzotriazolecarbonyl)-4-benzyloxysemicarbazide (7). None of the compounds were inhibitory to a broad panel of DNA and RNA viruses in the cell culture at subtoxic concentrations.
The novel hydroxyurea derivatives of l- and d-amino acid amides 5a-l were prepared by aminolysis of N-(1-benzotriazolecarbonyl)-amino acid amides 4a-f with O-benzylhydroxylamine and N-methylhydroxylamine and evaluated for their antiviral and cytostatic activity against malignant tumor cell lines and normal human fibroblasts. Compounds 5a, 5c, 5e and 5k showed the highest antiproliferative effects against all tumor cell lines tested. The strongest non-specific cytostatic activities against HeLa cells were affected by compounds 5a, 5c, 5e and 5k on MCF-7 cells by 5c, 5e and 5k and MIA PACa-2 cells by 5c and 5k. Differential effects at micromolar concentrations were observed for compounds 5a, 5c, 5e, 5k and 5l in Hep G2 cells, for compounds 5c, 5e, 5k and 5l in PC-3 cells and for compounds 5e, 5k and 5l in SW 620 cells.
Die verbruckten Oxazoline 1 wurden mit Lithiumaluminiumhydrid zu den entsprechenden 2,2'-(~thylendiimino)dialkoholen 2 reduziert. 2c wurde auch durch Reduktion von 4,4'-Diathyl-2,2'-bioxazolidin (3) mit LiAlH4 oder NaBH4 gewonnen. Die 2,2'-Bioxazoline konnen auch katalytisch an Platin oder Rhodium/Platin zu entsprechenden 2,2'-(Athylendiirnino)dialkoholen hydrogenolysiert werden.Catalytic Hydrogenation of Nitrogen Containing Heterocycles, IV. -Hydrogenolysis of Bridged
Oxazlines and OxazolidinesThe bridged oxazolines 1 were reduced to the 2,2'-(ethylenediimino)dialcohols 2 by lithium aluminium hydride. 2c was also prepared by reduction of 4,4'-diethyl-2,2'-bioxazolidine (3) either with LiAIH4 or with NaBH4. 2,2'-Bioxazolines can be hydrogenolysed over platinum or rhodiurn/platinium to 2,2'-(ethylenediimino)dialcohols.Die Reduktion von Oxazolen und Oxazolidinen wurde mehrfach untersucht, die der Oxazoline dagegen nur in Einzelfallen.Fischer 2) reduzierte 2,5-Diphenyloxazol mit Natrium und #than01 zurn 2-Amino-l,3-diphenylpropanol und Robertson und Young3) hydrierten ein ahnlich substituiertes Oxazol katalytisch zum entsprechend substituierten Acetamid. Dornow und Eicholtz4) haben diese reduktive Spaltung an einer Reihe von 2-Alkyl-und 2-Aryloxazolen untersucht und dabei folgende Regel aufgestellt: Bei der Reduktion niit Natrium und Alkohol wird bei 2-Alkyloxazolen die 1 ~ 5-Bindung des Heterorings aufgespalten, wobei die entsprechenden Amide gebildet werden. Bei 2-Arylderivaten entstehen dagegen durch Offnen der 1 -2-Bindung die entsprechenden Amine. Katalytische Hydrierung von Alkyl-und Arylderivaten an Platinkatalysatoren in Eisessig oder Athanol fiihrt immer unter primare Absattigung von aromatischen Doppelbindungen zu entsprechenden Amiden. *) Korrespondenz bitte an diesen Autor richten; neue Anschrift : Pharmazeutisch-biochemische Fakultat der Universitat 41000 Zagreb, Jugoslawien.
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