459831-95-9Relevant academic research and scientific papers
Identification of 3,4-dihydroisoquinoline-2(1H)-sulfonamides as potent carbonic anhydrase inhibitors: Synthesis, biological evaluation, and enzyme-ligand X-ray studies
Gitto, Rosaria,Agnello, Stefano,Ferro, Stefania,De Luca, Laura,Vullo, Daniela,Brynda, Jiri,Mader, Pavel,Supuran, Claudiu T.,Chimirri, Alba
scheme or table, p. 2401 - 2408 (2010/09/11)
Following previous studies we herein report the exploration of the carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects and enzyme selectivity of a small class of l-(cyclo)alkylisoquinolines containing a sulfonamide function considered a key feature for inhibiting CA. The results of enzymatic assays against human (h) CA isoforms, hCA I and hCA II (cytosolic, ubiquitous enzymes), hCA IX (transmembrane, tumor-associated), and hCA XIV (transmembrane), suggested that the presence of C-I small substituents on isoquinoline scaffold controls both inhibitory potency and selectivity. Some derivatives showed potent hCA IX and hCA XIV inhibitory effects at nanomolar concentrations as well as low affinity for the ubiquitous hCA II. Moreover, we report the X-ray crystal structure of one of these derivatives in complex with dominant human isoform II, thus confirming the sulfonamide-zinc interactions. Finally, the results of docking experiments suggested the hypothetic interactions in the catalytic binding site for the most active and selective hCA IX and hCA XIV inhibitor.
Rapid and diverse route to natural product-like biaryl ether containing macrocycles
Cristau, Pierre,Vors, Jean-Pierre,Zhu, Jieping
, p. 7859 - 7870 (2007/10/03)
A two-step sequence involving an Ugi four-component reaction and an intramolecular nucleophilic aromatic substitution (SNAr) has been developed for the rapid access to biaryl-ether containing macrocycles. In the course of this study, we documented that ammonium chloride can promote the Ugi-4CR in non-polar aprotic solvent (toluene) without the interference of an alternative Passerini reaction. Solid phase synthesis of macrocycles by this two-step sequence was also developed using polymer (Wang resin) supported α-(4′-fluoro-3′-nitro)phenethyl isocyanoacetate as one of the inputs.
Tandem pummerer/mannich cyclization cascade of α-sulfinylamides as a method to prepare aza-heterocycles
Padwa, Albert,Heidelbaugh, Todd M.,Kuethe, Jeffrey T.,McClure, Michael S.,Wang, Qiu
, p. 5928 - 5937 (2007/10/03)
A series of α-sulfinylenamides was conveniently prepared by the condensation of a primary amine with a ketone, followed by reaction of the resulting imine with ethylsulfenylacetyl chloride and subsequent oxidation with sodium periodate. When treated with p-TsOH, cyclization occurred to produce fused isoquinoline lactams by a mechanism that involves an initial Pummerer reaction followed by a subsequent cyclization of the resulting N-acyliminium ion onto the tethered aromatic ring. The isolation of a single diastereomer was rationalized in terms of a Nazarov-type 4π-electrocyclic reaction followed by π-cyclization onto the least hindered side of the N-acyliminium ion. Another method that was used to generate the α-acylthionium ion intermediate involved the reaction of bis(ethylsulfenylacetyl)acetamides with dimethyl(methyl)thiosulfonium tetrafluoroborate (DMTSF). Treatment of several bis-ethylsulfenylenamides with DMTSF delivered novel spiroheterocycles as single diastereomers in good yield by a related process. The convergency and stereochemical control associated with this cascade sequence make it particularly suited for the assembly of natural product scaffolds. Some preliminary studies were directed toward both mesembrine and deethylibophyllidine. When the model Z-enamido sulfoxide 33 was heated with p-TsOH, a 80% yield of tosylate 34 was obtained as a single diastereomer. In this case, the carbocation intermediate derived from cyclization onto the terminal π-bond was trapped with p-TsOH from the least hindered face, opposite the angular carbomethoxy and methyl groups. Related cyclization cascades were also found to occur with systems containing tethered indole rings.
