Abstract
In this study, phthalocyanine precursors (5 and 9) and 1,2,3-triazole-substituted metal-free and metallo phthalocyanines (9a-c) were designed and synthesized for the first time and evaluated in vitro for key molecular targets. The structures of the novel compounds were characterized via FT-IR, 1H/13C NMR, UV-Vis, and mass spectroscopy. The inhibitory activities of the compounds were tested against human carbonic anhydrase isoforms hCA I, II (cytosolic, ubiquitous isozymes), and IX (transmembrane, cancer-associated isozyme) and cholinesterases (AChE and BChE, which are associated with Alzheimer's disease). Among the three phthalocyanines and starting compounds, 9b showed the most interesting profile as a nanomolar selective inhibitor of hCA I (Ki = 37.2 nM) and 9c showed the most effective inhibitory effect on hCA II, IX, AChE and BChE (Ki = 41.9, 27.4, 5.8 and 45.8 nM, respectively). This study is also the first example of cancer-associated isozyme hCA IX inhibition by phthalocyanines.
MeSH terms
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Acetylcholinesterase / chemistry
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Acetylcholinesterase / metabolism
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Antigens, Neoplasm / metabolism
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Butyrylcholinesterase / chemistry
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Butyrylcholinesterase / metabolism
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Carbonic Anhydrase I / antagonists & inhibitors
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Carbonic Anhydrase I / metabolism
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Carbonic Anhydrase II / antagonists & inhibitors
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Carbonic Anhydrase II / metabolism
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Carbonic Anhydrase IX / antagonists & inhibitors
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Carbonic Anhydrase IX / metabolism
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Carbonic Anhydrase Inhibitors / chemical synthesis*
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Carbonic Anhydrase Inhibitors / chemistry
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Carbonic Anhydrase Inhibitors / metabolism
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Cholinesterase Inhibitors / chemical synthesis*
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Cholinesterase Inhibitors / chemistry
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Cholinesterase Inhibitors / metabolism
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Drug Design*
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Humans
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Indoles / chemistry*
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Inhibitory Concentration 50
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Isoindoles
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Pyridines / chemistry*
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Triazoles / chemistry*
Substances
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Antigens, Neoplasm
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Carbonic Anhydrase Inhibitors
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Cholinesterase Inhibitors
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Indoles
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Isoindoles
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Pyridines
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Triazoles
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Acetylcholinesterase
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Butyrylcholinesterase
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Carbonic Anhydrase I
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Carbonic Anhydrase II
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CA9 protein, human
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Carbonic Anhydrase IX
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pyridine
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phthalocyanine