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A facile convergent total synthesis of the selective, potent, and orally active V2 non- peptide antagonist, SR-121463, was developed by modification of the discovery route. One of the late intermediates, the sulfonyl chloride 1, was synthesized from 3-hydroxybenzoic acid (19) by regioselective sulfonation, O-methylation and amidation in four steps....
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... Several of them are pivotal intermediates in the preparation of biologically active compounds or exhibited various interesting biological activities ( Fig.). [10][11][12][13][14][15][16] Despite its importance in organic chemistry and medicinal chemistry, efficient synthetic methods for spirocyclohexadienones are still rare. [17][18][19][20][21][22][23] Owing to the significance of the pyrazolone spirocyclohexadienones framework, the scope of the reaction of substrates 7 were further probed. ...
Starting from easy accessible pyrazoletetrahydropyran acetals, a series of new pyrazolone spirocyclohexadienone derivatives were synthesized and assayed for antitumor activity. Compound 10s was identified to possess good antitumor activity. It could induce MDA-MB-231 cancer cell apoptosis in a concentration dependent manner and arrest the cell cycle progression mainly at the G1 phase.
Spirocyclic scaffolds are incorporated in variousapproved drugs and drug candidates. The increasing interest inless planar bioactive compounds has given rise to the developmentof synthetic methodologies for the preparation of spirocyclicscaffolds. In this Perspective, we summarize the diverse syntheticroutes to obtain spirocyclic systems. The impact of spirocycles onpotency and selectivity, including the aspect of stereochemistry, isdiscussed. Furthermore, we examine the changes in physicochemicalproperties as well as in in vitro and in vivo ADME using selectedstudies that compare spirocyclic compounds to their nonspirocycliccounterparts. In conclusion, the value of spirocyclic scaffolds in medicinal chemistry is discussed.
Six derivatives of 3-methylquinoline acids having latency biological activity were synthesized by addition of substituted anilines to ethyl ethoxalylpropionate and followed by high-temperature cyclization. Among them, three new compounds containing fluorine were identified through elemental analyses, 1H NMR, IR and MS spectra.
A new and convenient silver-catalyzed direct oxidative spirocyclization of alkynes with thiophenols is described. This methodology provides a simple and practical approach to various 3-thioazaspiro[4,5]trienones in moderate to good yields with high atom efficiency and excellent functional group tolerance.
A novel and direct oxidative spirocyclization of arylpropiolamides with sulfonylhydrazides leading to 3-sulfonated azaspiro[4,5]trienones has been developed under metal-free conditions. The reaction is performed in a tandem manner constituted by the sequential sulfonylation of alkynes, ipso-carbocyclization, dearomatization, hydration, and oxidation processes, providing a convenient and efficient approach to various sulfonated azaspiro[4,5] trienones of biological importance. (Chemical Equation Presented).
Nucleophilic substitution of an iron(II) dichloroclathrochelate with morpholine as a N-nucleophilic agent afforded a monomorpholine-containing cage complex, characterized by X-ray diffraction. This complex as a monochloroclathrochelate precursor easily undergoes further nucleophilic substitution with 2-ethanolamine as a N-nucleophile and with meta- and para-mercaptobenzoic acids as S-nucleophiles, giving the bifunctional N, N- and N, S-substituted macrobicyclic iron(II) complexes. In vitro testing in a transcription assay based on T7 RNA polymerase showed the efficient structure- and concentration-dependent inhibition of transcription by these heterofunctionalized cage compounds in low- and submicromolar concentration range. The proposed mode of inhibition includes a trapping of clathrochelate inhibitor molecule by the binding pocket formed by three interconnected macromolecules of the transcription complex.
The review analyzes methods of synthesis of 1,4-oxazines (morpholines) starting from vicinal amino alcohols and their derivatives, oxiranes, and aziridines. Examples of using morpholines in medicinal and organic chemistry as catalysts, auxiliaries, biologically active substances, and building blocks for their preparation are considered. The data published until February 2013 have been covered.
Heteropines received much attention, primarily because of continuous interest in the psychopharmacological activity of their bicyclic and tricyclic derivatives. Synthesis, structures, reactivity, and applications of tricyclic heteropines have been a part of the general indole and seven-membered rings discussions. It surveyed the synthesis of 1,5-benzodiazepines with three-, four- and five-membered rings fused to different positions of the 1,5-benzodiazepine skeleton. The synthesis of DNA-interactive pyrrole[ 2, l-c][1,4] benzodiazepines and medicinal chemistry aspects of the novel thieno benzodiazepine antipsychotic, Olanzapine, have been reviewed. This chapter focuses on the benzoheteropines with the fused pyrrole, thiophene, or furan rings that is ortho-fused 6+7+5 ring systems with carbons only on the six-membered ring, one heteroatom on the five-membered ring and one or more heteroatoms on the seven- membered ring. The variety of heteroatoms is limited to nitrogen, oxygen, and sulfur. Several examples of the related cyclic systems with the other heteroatom distribution or peri-fusion are briefly summarized in the chapter.
A new synthetic pathway to spiro[cyclohexane-1,3′-indoline]-2′,4-diones was found starting from 3-chloromethylene-2-indolones 1 and Danishefsky's diene 2. Their synthesis consists of several steps involving the formation of the cycloadducts, the 6-chloro-4-trimethylsilyloxy-2-methoxyspiro[cyclohex-3-en-1,3′-indolin]-2′-one derivatives, transformed into spiro[cyclohexa-2,5-dien-1,3′-indoline]-2′,4-diones via 6-chloro-spiro[cyclohex-2-en-1,3′-indoline]-2′,4-dione intermediates. The reduction of spiro[cyclohexa-2,5-dien-1,3′-indoline]-2′,4-diones gave spiro[cyclohexane-1,3′-indoline]-2′,4-diones 7. Using a ‘one pot reaction’, starting from 1 and 2, compounds 7 were obtained in satisfactory overall yield.
