6-Substituted sulfocoumarins are selective carbonic anhdydrase IX and XII inhibitors with significant cytotoxicity against colorectal cancer cells

Aiga Grandane; Muhammet Tanc; Lorenzo Di Cesare Mannelli; Fabrizio Carta; Carla Ghelardini; Raivis Žalubovskis; Claudiu T Supuran

doi:10.1021/acs.jmedchem.5b00523

6-Substituted sulfocoumarins are selective carbonic anhdydrase IX and XII inhibitors with significant cytotoxicity against colorectal cancer cells

J Med Chem. 2015 May 14;58(9):3975-83. doi: 10.1021/acs.jmedchem.5b00523. Epub 2015 Apr 23.

Authors

Aiga Grandane¹, Muhammet Tanc^{2

3}, Lorenzo Di Cesare Mannelli⁴, Fabrizio Carta³, Carla Ghelardini⁴, Raivis Žalubovskis¹, Claudiu T Supuran^{2

3}

Affiliations

¹ †Latvian Institute of Organic Synthesis, Aizkraukles 21, LV-1006 Riga, Latvia.
² ‡NEUROFARBA Department, Section of Pharmaceutical Chemistry, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
³ §Laboratorio di Chimica Bioinorganica, Polo Scientifico, Università degli Studi di Firenze, Rm. 188, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
⁴ ∥NEUROFARBA Department, Section of Pharmacology and Toxicology, Università degli Studi di Firenze, Viale Pieraccini 6, 50139 Florence, Italy.

PMID: 25875209
DOI: 10.1021/acs.jmedchem.5b00523

Abstract

6-Substituted sulfocoumarins bearing the carboxamido, trimethylammonium as well as the cyano and methoxy moieties with interesting inhibitory activity/selectivity against the tumor associated carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA IX and XII are reported. Moieties leading to the best inhibition were tert-butylcarboxamido, phenylcarboxamido, and 4-pyridylcarboxamido, with K(I) values of 2.1-8.1 nM. No inhibition of the off-target hCA II and I was observed. A number of these compounds were evaluated against HT-29 colon cancer cell lines ex vivo. Compounds 9c and 9e revealed effective cytotoxic effects after 72 h of incubation in both normoxic and hypoxic conditions, unlike sulfonamide CA inhibitors that show such effects only in hypoxia. These results may be of particular importance for the choice of future drug candidates targeting hypoxic tumors and metastases, considering the fact that a sulfonamide CA IX inhibitor (SLC-0111) is presently in phase I clinical trials.

Publication types

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

MeSH terms

Antigens, Neoplasm / metabolism*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology
Benzamides / chemical synthesis
Benzamides / chemistry*
Benzamides / pharmacology
Carbonic Anhydrase IX
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry*
Carbonic Anhydrase Inhibitors / pharmacology
Carbonic Anhydrases / metabolism*
Cell Hypoxia
Cell Line, Tumor / drug effects
Colorectal Neoplasms / drug therapy*
Cyclic S-Oxides / chemical synthesis
Cyclic S-Oxides / chemistry*
Cyclic S-Oxides / pharmacology
Drug Screening Assays, Antitumor
Humans
Isoenzymes / antagonists & inhibitors
Isoenzymes / metabolism
Structure-Activity Relationship

Substances

2-bromo-N-(2,2-dioxido-1,2-benzoxathiin-6-yl)benzamide
Antigens, Neoplasm
Antineoplastic Agents
Benzamides
Carbonic Anhydrase Inhibitors
Cyclic S-Oxides
Isoenzymes
N-(2,2-dioxido-1,2-benzoxathiin-6-yl)benzamide
CA9 protein, human
Carbonic Anhydrase IX
Carbonic Anhydrases
carbonic anhydrase XII