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Coumarins incorporating hydroxy- and chloro-moieties selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic ones I and II.
Bioorg Med Chem Lett. 2010 Aug 01; 20(15):4511-4.BM

Abstract

A series of coumarins incorporating hydroxy-, chloro- and/or chloromethyl-moieties in positions 3-, 4-, 6- and 7- of the heterocyclic ring were investigated for the inhibition of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). These coumarins were very weak or ineffective as inhibitors of the house-keeping, offtarget isoforms CA I and II, but showed effective, submicromolar inhibition of the transmembrane, tumor-associated isoforms CA IX and XII. The nature and position of the groups substituting the coumarin ring greatly influenced CA inhibitory properties. 6-Hydroxycoumarin showed K(I)s >100 microM against CA I and II, of 0.198 microM against CA IX and of 0.683 microM against CA XII, being thus a selective, efficient inhibitor for the tumor-associated over cytosolic isoforms. These compounds are also excellent leads for designing isoform-selective enzyme inhibitors.

Authors+Show Affiliations

Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Sesto Fiorentino (Firenze), Italy.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20580555

Citation

Maresca, Alfonso, and Claudiu T. Supuran. "Coumarins Incorporating Hydroxy- and Chloro-moieties Selectively Inhibit the Transmembrane, Tumor-associated Carbonic Anhydrase Isoforms IX and XII Over the Cytosolic Ones I and II." Bioorganic & Medicinal Chemistry Letters, vol. 20, no. 15, 2010, pp. 4511-4.
Maresca A, Supuran CT. Coumarins incorporating hydroxy- and chloro-moieties selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic ones I and II. Bioorg Med Chem Lett. 2010;20(15):4511-4.
Maresca, A., & Supuran, C. T. (2010). Coumarins incorporating hydroxy- and chloro-moieties selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic ones I and II. Bioorganic & Medicinal Chemistry Letters, 20(15), 4511-4. https://doi.org/10.1016/j.bmcl.2010.06.040
Maresca A, Supuran CT. Coumarins Incorporating Hydroxy- and Chloro-moieties Selectively Inhibit the Transmembrane, Tumor-associated Carbonic Anhydrase Isoforms IX and XII Over the Cytosolic Ones I and II. Bioorg Med Chem Lett. 2010 Aug 1;20(15):4511-4. PubMed PMID: 20580555.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Coumarins incorporating hydroxy- and chloro-moieties selectively inhibit the transmembrane, tumor-associated carbonic anhydrase isoforms IX and XII over the cytosolic ones I and II. AU - Maresca,Alfonso, AU - Supuran,Claudiu T, Y1 - 2010/06/10/ PY - 2010/05/10/received PY - 2010/06/04/revised PY - 2010/06/05/accepted PY - 2010/6/29/entrez PY - 2010/6/29/pubmed PY - 2010/12/14/medline SP - 4511 EP - 4 JF - Bioorganic & medicinal chemistry letters JO - Bioorg Med Chem Lett VL - 20 IS - 15 N2 - A series of coumarins incorporating hydroxy-, chloro- and/or chloromethyl-moieties in positions 3-, 4-, 6- and 7- of the heterocyclic ring were investigated for the inhibition of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). These coumarins were very weak or ineffective as inhibitors of the house-keeping, offtarget isoforms CA I and II, but showed effective, submicromolar inhibition of the transmembrane, tumor-associated isoforms CA IX and XII. The nature and position of the groups substituting the coumarin ring greatly influenced CA inhibitory properties. 6-Hydroxycoumarin showed K(I)s >100 microM against CA I and II, of 0.198 microM against CA IX and of 0.683 microM against CA XII, being thus a selective, efficient inhibitor for the tumor-associated over cytosolic isoforms. These compounds are also excellent leads for designing isoform-selective enzyme inhibitors. SN - 1464-3405 UR - https://www.unboundmedicine.com/medline/citation/20580555/Coumarins_incorporating_hydroxy__and_chloro_moieties_selectively_inhibit_the_transmembrane_tumor_associated_carbonic_anhydrase_isoforms_IX_and_XII_over_the_cytosolic_ones_I_and_II_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0960-894X(10)00814-0 DB - PRIME DP - Unbound Medicine ER -