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Bioorg Med Chem. 2017 May 1;25(9):2569-2576. doi: 10.1016/j.bmc.2017.03.027. Epub 2017 Mar 18.

Synthesis and carbonic anhydrase inhibition of a series of SLC-0111 analogs.

Author information

1
Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
2
Università degli Studi di Firenze, Dipartimento di Chimica Ugo Schiff, Laboratorio di Chimica Bioinorganica, Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence, Italy.
3
Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.
4
Università degli Studi di Firenze, Dipartimento Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via U. Schiff 6, 50019 Sesto Fiorentino, Florence, Italy; Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia. Electronic address: claudiu.supuran@unifi.it.

Abstract

SLC-0111 is a sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor (CAI) in Phase I/II clinical trials for the treatment of advanced hypoxic tumors complicated with metastases. Its antitumor effects are due to inhibition of the enzymatic activity of CA IX, an isoform predominantly found in tumors/metastases, but it also reduces the cancer stem cells population. Here we report the synthesis of analogs of SLC-0111, both of the sulfanilamide and metanilamide series, which possess diverse substitution patterns at the terminal ureido-phenyl moiety, thus including one or more halogens, trifluoromethyl, perchloro-/perfluorophenyl groups instead of the 4-fluorophenyl present in SLC-0111. Most of the sulfanilamide ureido derivatives were highly effective inhibitors of the tumor associated isoform and some showed selective CA IX/XII inhibitory profiles. Most of the sulfanilamide ureido derivatives were highly effective and in some cases selective CA IX/XII inhibitors, whereas the metanilamide ureido derivatives were less effective as transmembrane CA isoforms inhibitors. Structure activity relationship for this class of sulfonamides is discussed in detail.

KEYWORDS:

Carbonic anhydrase; Inhibitor; SLC-0111; Sulfonamide; Tumor; Urea derivative

PMID:
28347633
DOI:
10.1016/j.bmc.2017.03.027
[Indexed for MEDLINE]

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