Synthesis of novel isoindoline-1,3-dione-based oximes and benzenesulfonamide hydrazones as selective inhibitors of the tumor-associated carbonic anhydrase IX

• Published in: Bioorganic chemistry 2018-10, Vol.80, p.706-713
• Main Authors: Abdel-Aziz, Alaa A.-M., El-Azab, Adel S., Abu El-Enin, Mohamed A., Almehizia, Abdulrahman A., Supuran, Claudiu T., Nocentini, Alessio
• Format: Article
• Language: English
• Subjects: Anti-tumor; Antigens, Neoplasm - metabolism; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Benzenesulfonamide; Benzenesulfonamides; Carbonic anhydrase inhibition; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Carbonic anhydrase IX; Carbonic Anhydrase IX - antagonists & inhibitors; Carbonic Anhydrase IX - metabolism; Humans; Hydrazone; Hydrazones - chemical synthesis; Hydrazones - chemistry; Hydrazones - pharmacology; Isoindoles - chemical synthesis; Isoindoles - chemistry; Isoindoles - pharmacology; Isoindoline-1,3-dione; Neoplasms - drug therapy; Neoplasms - enzymology; Oxime; Oximes - chemical synthesis; Oximes - chemistry; Oximes - pharmacology; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2018.07.027

[Display omitted] •A new chemotype for CA inhibition was identified: isoindoline-1,3-dione-based oximes.•Isoindoline-1,3-dione benzenesulfonamides were also evaluated as CAIs.•Remarkable CA IX selectivity was found within both series.•Promising anti-cancer leads/tools were reported. The synthesis, characterization and biological evaluation of a library of isoindoline-1,3-dione-based oximes and benzenesulfonamide hydrazones is disclosed. The set of hydroxyiminoethyl aromatic derivatives 10–18 was designed to assess the potentiality as zinc-binder for a feebly studied functional group in the field of carbonic anhydrase (CA, EC 4.2.1.1) inhibition. Analogue phenylphthalimmides were linked to benzenesulfonamide scaffold by hydrazone spacers in the second subset of derivatives 20–28 to further investigate the application of the “tail approach” as tool to afford CA selective inhibition profiles. The compounds were assayed for the inhibition of physiologically relevant isoforms of human carbonic anhydrases (hCA, EC 4.2.1.1), the cytosolic CA I and II, and the membrane-bound CA IV and tumor-associated CA IX. The new zinc-binders, both of the oxime and sulfonamide types, showed a striking selective activity against the target hCA IX over ubiquitous hCA I and II, with diverse inhibitory ranges and ratio differing the two subsets. With CA IX being a strongly current antitumor/antimetastatic drug target, these series of compounds may be of interest for the development of new, both conventional and unconventional anticancer drugs targeting hypoxia-induced CA isoforms such as CA IX with minimum ubiquitous CAs-related side effects.