Detlef Geffken

Synthesis, antiproliferative and apoptotic activities of N-(6(4)-indazolyl)-benzenesulfonamide derivatives as potential anticancer agents.

Recently, it has been reported that compounds bearing a sulfonamide moiety possess many types of biological activities, including anticancer activity. The present work reports the synthesis and antiproliferative evaluation of some N-(6(4)-indazolyl)benzenesulfonamides and 7-ethoxy-N-(6(4)-indazolyl)benzenesulfonamides. All compounds were evaluated for their in vitro antiproliferative activity against three tumor cell lines: A2780 (human ovarian carcinoma) A549 (human lung adenocarcinoma) and P388 (murine leukemia). The results indicated that sulfonamides 2c, 3c, 6d, 8, 13, 3b and 16 were endowed with a pharmacologically interesting antiproliferative activity with compounds 2c and 3c showing the lower IC(50) (from 0.50 ± 0.09 to 1.83 ± 0.52 μM and from 0.58 ± 0.17 to 5.83 ± 1.83 μM, respectively). Moreover, these indazoles were able to trigger apoptosis through the upregulation of the typical apoptosis markers p53 and bax. As regard to the hypothetic targets of these compounds, a preliminary docking analysis showed that all compounds seemed to interact with β-tubulin, in particular compound 3b that showed the lower Ki. The cytofluorimetric analysis of the cell cycle phases indicates that all compounds, when administered at their IC(75), caused a block in the G2/M phase of the cell cycle with the generation of subpopulations of cells with a number of chromosome >4n. When the IC(50)s were applied we observed a prevalent block in the G0/G1 phase except for compounds 16 and 8 where a partial G2/M block was present with a concomitant decrease of cells in the G0/G1 and S phases of the cell cycle. Altogether these results suggest a possible, but not exclusive, interaction with microtubules.

Famoxadone: the discovery and optimisation of a new agricultural fungicide

Famoxadone (3-anilino-5-methyl-5-(4-phenoxyphenyl)-1,3-oxazolidine-2,4-dione), is a new agricultural fungicide recently commercialized by DuPont under the trade name Famoxate. Famoxadone is a member of a new class of oxazolidinone fungicides that demonstrate excellent control of plant pathogens in the Ascomycete, Basidiomycete, and Oomycete classes that infect grapes, cereals, tomatoes, potatoes and other crops. DuPonts entry into the oxazolidinone area resulted from the procurement of 5-methyl-5-phenyl-3-phenylamino-2-thioxo-4-oxazolidinone (1) from Professor Detlef Geffken, then at the University of Bonn. An extensive analog program was initiated immediately after the fungicidal activity of 1 was discovered through routine greenhouse testing. The discovery program in the oxazolidinone area eventually culminated in the advancement of famoxadone to commercial development in the early 1990s. The synthesis of various oxazolidinone ring systems and the development of the structure-activity relationships that led to the discovery of famoxadone are described.

Synthesis of new series of pyrazolo[4,3-d]pyrimidin-7-ones and pyrido[2,3-d]pyrimidin-4-ones for their bacterial and cyclin-dependent kinases (CDKs) inhibitory activities

Two series of pyrazolo[4,3-d]pyrimidin-7-ones and pyrido[2,3-d]pyrimidin-4-ones were designed, synthesised, and evaluated for their antibacterial activities and CDKs inhibitory activities. The pyridazine derivative: 6-phenyl-5-phenylhydrazono-2,3,4,5-tetrahydropyridazine-3,4-dione (3a) revealed activity against Staphylococcus aureus as Gram-positive bacteria while compound 2-(2-Ethoxyphenyl-5-Phenylpiperazinosulfonamido)-3H-pyrido[2,3-d]pyrimidin-4-one (13c) was showing moderate antifungal activity against Candida albicans.

Synthesis of Novel 2-Methylsulfanyl-4H-[1,2,4]triazolo[1,5-a]quinazolin-5-one and Derivatives

Abstract A novel 2-methylsulfanyl-4H-[1,2,4]triazolo[1,5-a]quinazolin-5-one was synthesized using dimethyl-n-cyanoimidodithiocarbonate and 2-hydrazinobenzoic acid as building blocks. Chemical transformation of the inherent lactam moiety in the targeted 2-methylsulfanyl-[1,2,4]triazolo[1,5-a]quinazolin-5-one offered access to a variety of derivatives.

NOVEL SYNTHESIS OF 2-ALKOXY(ARALKOXY)-5-CHLORO[1,2,4]TRIAZOLO[1,5-a]QUINAZOLINES AND THEIR DERIVATIVES

2-Alkoxy(aralkoxy)-5-chloro[1,2,4]triazolo[1,5-a]quinazolines have been synthesized. The corresponding 2-alkoxy(aralkoxy)[1,2,4]triazolo[1,5-a]quinazolin-5-ones were chlorinated with either oxalyl chloride or phosphorus oxychloride. The chlorine atom at 5-position of the targeted [1,2,4]triazolo[1,5-a]quinazolines was replaced with multifunctional N-nucleophiles. This provided the preparation of the heterocyclic system bearing a variety of substituents at 5-position.

Efficient synthesis and 5-LOX/COX-inhibitory activity of some 3-hydroxybenzo[b]thiophene-2-carboxylic acid derivatives.

A series of 3-hydroxybenzo[b]thiophene-2-carboxylic acid derivatives has been prepared and subsequently evaluated with regards to the inhibition of 5-LOX/COX. Structure optimization furnished derivatives with promising in vitro activity as dual 5-LOX/COX inhibitors with submicromolar IC(50) values for inhibition of 5-LOX and COX-1, respectively.

Fluorierte Elementorganika. XX: Synthese von Fluormethyltrimethylsilanen

Abstract The synthesis of the fluoromethyltrimethylsilanes 4 [(H 3 C) 3 SiCF 2 X, 4a : X = Cl; 4b : X = Br; 4c : X = H; (H 3 C) 3 SiCFXY, 4d : X = Cl; Y = H; 4e : X, Y = H] is described. The reaction of the tris-(diethylamino)-phosphane ( 1 )/trimethylsilyl-halogenide 3 system with the difluorodihalogenomethanes 2 gives the hitherto unknown 4a,b . The reduction of 4a,b and dichloroflouromethyltrimethylsilane ( 13 ) [(H 3 C) 3 SiCFCl 2 ] with tris-(n-butyl)-stannane ( 14 ) produces 4c-e in fair yields.

Zur Reaktion 2,2-disubstituierter 3-Hydroxypropionsäuren mit aliphatischen Carbodiimiden

Die Reaktion 2,2-disubstituierter 3-Hydroxypropionsauren mit aliphatischen Carbodiimiden in Tetrahydrofuran fuhrt zu Verbindungen vom Typ 3, 4 und 7 sowie zu den bekannten β-Lactonen 6a–c. In Gegenwart katalytischer Mengen Natriumhydroxid last sich 3a in das Strukturisomere 4a uberfuhren, das auch bei der alkalischen Hydrolyse von 7a entsteht. The Reaction of 2,2-Disubstituted 3-Hydroxypropionic Acids with Aliphatic Carbodiimides The reaction of 2,2-disubstitued 3-hydroxypropionic acids with aliphatic carbodiimides in tetrahydrofuran yields products like 3, 4, and 7 besides the already known β-lactones 6a–c. In the presence of catalytic amounts of sodium hydroxide 3a rearranges to the isomeric product 4a which is also formed by alkaline hydrolysis of 7a.

An Improved Synthesis of N-Alkoxy-α-Oxo-Arylacetamides

Abstract The title compounds can be prepared in good yields in a one-pot procedure from arylglyoxylic acid chlorides, 2-pyridone and O-alkylhydroxylamines.

Synthese von 6-Thioxo-1,2,5-oxadiazinan-3-onen und Umwandlung in 3-Amino-2-thiohydantoine und 3-Hydroxy-2-thiohydantoine / Synthesis of 6-Thioxo-1,2,5-oxadiazinan-3-ones and Transformation into 3-Amino-2-thiohydantoins and 3-Hydroxy-2-thiohydantoins

6-Thioxo-1,2,5-oxadiazinan-3-ones 5, easily available by cyclic thiocarbonylation of Nα ,Ndisubstituted α-aminocarbohydroxamic acids 4 with 1,1′-thiocarbonyldiimidazole, are transformed by hydrazine or hydroxylamine into 3-amino-2-thiohydantoins 6 and 3-hydroxy-2-thiohydantoins 7.