Abstract
After hydrofluorination of ynesulphonamides in superacid or in the presence of hydrofluoric acid/base reagents, a series of α-fluoroenamides has been synthesised and tested for the inhibition of carbonic anhydrase (CA, EC 4.2.1.1) isoforms. This study reveals a new, highly selective family of cancer-related transmembrane human (h) CA IX/XII inhibitors. These original fluorinated ureido isosters do not inhibit the widespread cytosolic isoforms hCA I and II and selectively inhibit the transmembrane cancer-related hCA IX and XII, offering interesting new leads for future studies.
Highlights
The elevated metabolic rate of solid cancer tumors leads frequently to acidosis and hypoxia[1], which can be directly related to spatial disorganisation and flow-based disruption of an abnormal microvascularisation initiated by the growing tumor[2]
Tumor cells respond by transcription hypoxia inducible factor-1 (HIF-1a-activates), reprogramming their metabolism to overcome the reduced supply of oxygen[3,4]
Exploiting a strategy commonly used in medicinal chemistry, the use of isosters of bioactive compounds[23,24], we recently developed a method to design new fluoroenesulphonamides as N-sulphonylureas isosters[25] and demonstrated their similarities[26]: these compounds, stable in solution, can be considered as good
Summary
The elevated metabolic rate of solid cancer tumors leads frequently to acidosis and hypoxia[1], which can be directly related to spatial disorganisation and flow-based disruption of an abnormal microvascularisation initiated by the growing tumor[2]. CA IX and CA XII are recognised as especially relevant targets for cancer therapy Sulphonamides and their bioisosteres (sulphamates, sulphamides, etc.) constitute the most investigated inhibitors of these enzymes[7], with useful therapeutic applications[8]. They act on their deprotonated forms and bind the Zn2þ ion of the active site, disrupting the catalytic process[9]. Numerous efforts were dedicated over the last years to the evaluation of non-zinc binding inhibitors This resulted for example in the discovery that coumarins, thiocoumarines[11] and, more recently, sulphocoumarins[12], located at the entrance of the enzyme active site, were selective inhibitors of hCA IX isozyme. Following our seminal contribution on the use of tertiary benzene sulphonamides as selective cancer-related hCAs inhibitors, we considered that fluoroenesulphonamide group could represent an interesting novel selective chemotype and evaluated the activity of this new series against hCA I, hCA II, hCA IX and hCA XII
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