Oxidation of cyanobenzocycloheptatrienes: Synthesis, photooxygenation reaction and carbonic anhydrase isoenzymes inhibition properties of some new benzotropone derivatives

• Published in: Bioorganic & medicinal chemistry 2014-07, Vol.22 (13), p.3537-3543
• Main Authors: Güney, Murat, Coşkun, Ahmet, Topal, Fevzi, Daştan, Arif, Gülçin, İlhami, Supuran, Claudiu T.
• Format: Article
• Language: English
• Subjects: Benzocycloheptatriene; Benzotropone; Carbonic Anhydrase I - antagonists & inhibitors; Carbonic Anhydrase I - metabolism; Carbonic Anhydrase II - antagonists & inhibitors; Carbonic Anhydrase II - metabolism; Carbonic anhydrase inhibition; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Dose-Response Relationship, Drug; Humans; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Models, Molecular; Molecular Structure; Nitrile-substituted drugs; Oxidation; Oxidation-Reduction; Photochemical Processes; Rearrangement; Structure-Activity Relationship; Tropolone - analogs & derivatives; Tropolone - chemical synthesis; Tropolone - chemistry; Tropolone - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.04.007

The oxidation of some cyanocycloheptatrienes with CrO3 and pyridine was investigated and a few new nitrile functionalised benzotropone derivatives were obtained. Photooxygenation reaction of these products was also studied. The structures of the formed products were determined on the basis of NMR spectroscopy and the formation mechanism of unusual products was discussed. Human carbonic anhydrase isoenzymes I, and II (hCA I and hCA II) inhibition properties of nitrile functionalized new benzotropone derivatives were also studied. Both CA isozymes were inhibited in the low micromolar range by these nitrile functionalized benzotropone analogues. The newly synthesized benzotropone derivatives showed inhibition constants in the sub-micromolar range (2.51–4.06μM). The best hCA I inhibition was observed in 5H-benzocycloheptene-7-carbonitrile (Ki: 2.88±0.86μM). On the other hand, 5-oxo-5H-benzocycloheptatriene-7-carbonitrile showed the powerful inhibitory effect against hCA II (Ki: 2.51±0.34μM).