Novel 2,4-Dichloro-5-sulfamoylbenzoic Acid Oxime Esters: First Studies as Potential Human Carbonic Anhydrase Inhibitors

Abstract

In this study, a focused library of oxime ester derivatives of 2,4-dichloro-5-sulfamoylbenzoic acid (lasamide) containing Schiff bases was synthesized and tested in vitro for their ability to inhibit the cytosolic human carbonic anhydrases (hCAs) I and II, as well as the transmembrane and tumor-associated IX and XII isoforms. As a result, we obtained a first line of knowledge on lasamide derivatives potentially useful for development as CA inhibitors (CAIs). In particular, we focused our attention on the derivative 11, which was selective toward hCAs IX and XII over the cytosolic isoenzymes. An in silico study was conducted to assess the binding mode of 11 within hCAs IX and XII. Also, antiproliferative assays highlighted promising derivatives. The data obtained in this study are currently in use for the development of better-performing compounds on the tumor-associated isoforms.

Scheme 1. Synthetic Approach for Oxime Ester Series (4–16) of Lasamide 1 Reported in This Work

Reagents and conditions: (i) SOCl₂, toluene, 45 °C, 6 h; (ii) N-Boc-hydroxylamine, TEA, THF, 5 °C to rt, 10 h; (iii) TFA, DCM, 5 °C, 5 h; (iv) aldehyde or ketone, AcONa, EtOH, 75 °C, 5 h.

Figure 1

Chemical structures of O-benzoyl oximes 4–16.

Figure 2

Predicted binding mode of compound 11 against the crystallographic structure of (A) hCA IX (orange cartoons and lines) and (C) hCA XII (gold cartoons and lines). Compound 11 is shown as cyan sticks, and the catalytic Zn (II) ion is shown as a gray sphere. Polar interactions in panels (A) and (C) are highlighted by black dashed lines, and residues contacted by the ligand are shown as sticks. In panels (B) and (D), the overlay between the docking pose of compound 11 and the cocrystallized AAZ (colored gray) is shown.

Figure 3

Cells proliferation of triple-negative breast cancer MDA-MB-231 cells treated for 72 h with 4, 11, 12, and SLC-0111. Cell count refers to the untreated/control as 100%.