New β-arylchalcogeno amines with procognitive properties targeting Carbonic Anhydrases and Monoamine Oxidases

Provensi, Gustavo; Costa, Alessia; Rani, Barbara; Becagli, Maria Vittoria; Vaiano, Fabio; Passani, Maria Beatrice; Tanini, Damiano; Capperucci, Antonella; Carradori, Simone; Petzer, Jacobus P.; Petzer, Anél; Vullo, Daniela; Costantino, Gabriele; Blandina, Patrizio; Angeli, Andrea; Supuran, Claudiu T.

doi:10.1016/j.ejmech.2022.114828

Cited by 10 publications

(2 citation statements)

References 40 publications

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“…The potential of linking the coumarin nucleus to a distinctive (pseudo)-peptide portion to target tumor-associated hCAs (IX/XII) and the hMAOs have been demonstrated in this study exploring an emerging field of interest of dual modulators [44]. The novel molecules have proven to potently inhibit hCAs IX/XII in vitro, without affecting the I and II cytosolic human isoforms.…”

Section: Discussionmentioning

confidence: 89%

Coumarin-Based Dual Inhibitors of Human Carbonic Anhydrases and Monoamine Oxidases Featuring Amino Acyl and (Pseudo)-Dipeptidyl Appendages: In Vitro and Computational Studies

et al. 2022

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The involvement of human carbonic anhydrase (hCA) IX/XII in the pathogenesis and progression of many types of cancer is well acknowledged, and more recently human monoamine oxidases (hMAOs) A and B have been found important contributors to tumor development and aggressiveness. With a view of an enzymatic dual-blockade approach, in this investigation, new coumarin-based amino acyl and (pseudo)-dipeptidyl derivatives were synthesized and firstly evaluated in vitro for inhibitory activity and selectivity against membrane-bound and cytosolic hCAs (hCA IX/XII over hCA I/II), as well as the hMAOs, to estimate their potential as anticancer agents. De novo design of peptide-coumarin conjugates was subsequently carried out and involved the combination of the widely explored coumarin nucleus with the unique biophysical and structural properties of native or modified peptides. All compounds displayed nanomolar inhibitory activities towards membrane-anchored hCAs, whilst they were unable to block the ubiquitous CA I and II isoforms. Structural features pertinent to potent and selective CA inhibitory activity are discussed, and modeling studies were found to support the biological data. Lower potency inhibition of the hMAOs was observed, with most compounds showing preferential inhibition of hMAO-A. The binding of the most potent ligands (6 and 16) to the hydrophobic active site of hMAO-A was investigated in an attempt to explain selectivity on the molecular level. Calculated Ligand Efficiency values indicate that compound 6 has the potential to serve as a lead compound for developing innovative anticancer agents based on the dual inhibition strategy. This information may help design new coumarin-based peptide molecules with diverse bioactivities.

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Section: Discussionmentioning

confidence: 89%

Coumarin-Based Dual Inhibitors of Human Carbonic Anhydrases and Monoamine Oxidases Featuring Amino Acyl and (Pseudo)-Dipeptidyl Appendages: In Vitro and Computational Studies

et al. 2022

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“…The antiinfectives based on CAIs started to be seriously considered only in the last decade 90 , and several highly interesting studies for the design of antibacterials 91–93 and antifungals 94–96 which target CAs present in pathogenic organism have emerged. However, in these cases the use of click chemistry has not yet been contemplated, as it is also the situation for CA activators 97 , which might be useful for the management of emotional/fear memory therapy and several cognitive disorders 98 , 99 . As outlined here, there are many other hot topics in the CA research field in which click chemistry reactions may contribute to the development of highly interesting inhibitors and activators, and hopefully such studies will be stimulated to be performed by this review.…”

Section: Conclusion and Future Prospectsmentioning

confidence: 99%

Click chemistry approaches for developing carbonic anhydrase inhibitors and their applications

Angeli

Supuran

2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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Click chemistry reactions constitute an important and relatively new approach in the medicinal chemistry toolbox and offer substantial advantages to medicinal chemists in terms of overcoming the limitations of facile chemical synthesis, increased throughput, yields and improved quality of compound libraries. Over the last two decades, click chemistry has been widely used in different aspects of carbonic anhydrase (CA, EC 4.2.1.1) modulators drug design. This review provides an overview of the general principles and applications of click chemistry in CA-related research, including the design of selective CA inhibitors (CAIs), their applications against several diseases such as innovative anticancer and anti-infective agents, fluorescent and radiopharmaceutical probes as new theranostic agents, as well as their application in protein labelling.

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Carbonic anhydrases

Supuran

2024

Metalloenzymes

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New β-arylchalcogeno amines with procognitive properties targeting Carbonic Anhydrases and Monoamine Oxidases

Cited by 10 publications

References 40 publications

Coumarin-Based Dual Inhibitors of Human Carbonic Anhydrases and Monoamine Oxidases Featuring Amino Acyl and (Pseudo)-Dipeptidyl Appendages: In Vitro and Computational Studies

Coumarin-Based Dual Inhibitors of Human Carbonic Anhydrases and Monoamine Oxidases Featuring Amino Acyl and (Pseudo)-Dipeptidyl Appendages: In Vitro and Computational Studies

Click chemistry approaches for developing carbonic anhydrase inhibitors and their applications

Carbonic anhydrases

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