Terminators or Guardians? Design, Synthesis, and Cytotoxicity Profiling of Chalcone-Sulfonamide Hybrids

Abstract

With a "less is more" philosophy, a series of 15 chalcone-sulfonamide hybrids were designed anticipating synergistic anticancer activity. The aromatic sulfonamide moiety was included as a known direct inhibitor of carbonic anhydrase IX activity through its zinc chelating property. The chalcone moiety was incorporated as an electrophilic stressor to indirectly inhibit carbonic anhydrase IX cellular activity. Screening by the Developmental Therapeutics Program of the National Cancer Institute, NCI-60, revealed that 12 derivatives were potent inhibitors of cancer cell growth in multiple cell lines and were promoted to the five-dose screen. The cancer cell growth inhibition profile indicated sub-to two-digit micromolar potency (GI 50 down to 0.3 μM and LC 50 as low as 4 μM) against colorectal carcinoma cells, in particular. Unexpectedly, most compounds demonstrated low to moderate potency as direct inhibitors of carbonic anhydrase catalytic activity in vitro, with 4d being the most potent, having an average Ki value of 4 μM. Compound 4j showed ca. six-fold selectivity to carbonic anhydrase IX over the other tested isoforms in vitro. Cytotoxicity of both 4d and 4j in live HCT116, U251, and LOX IMVI cells under hypoxic conditions confirmed their targeting of carbonic anhydrase activity. Elevation of oxidative cellular stress was stipulated from the increase in Nrf2 and ROS levels in 4j-treated colorectal carcinoma, HCT116, cells compared to the control. Compound 4j arrested the cell cycle of HCT116 cells at the G1/S phase. In addition, both 4d and 4j showed up to 50-fold cancer cell selectivity compared to the non-cancerous HEK293T cells. Accordingly, this study presents 4d and 4j being new, synthetically accessible, simplistically designed derivatives as potential candidates to be further developed as anticancer therapeutics. ■ HIGHLIGHTS• Hybrid chalcone-sulfonamides were designed as potential carbonic anhydrase inhibitors. • The derivatives inhibited cancer cell growth in the NCI-60 screen with high potency. • Up to 50-fold selectivity on cancer cells compared to normal cells was demonstrated. • Cell cycle arrest was observed at the G1/S phase in HCT116 colorectal carcinoma cells. • Nrf2 and ROS levels were elevated in response to one of the compounds in HCT116 cells.

Discovery of sulfonamide-tethered isatin derivatives as novel anticancer agents and VEGFR-2 inhibitors

“…On the other hand, all the evaluated isatin derivatives failed to inhibit the CA isoforms ( K I > 100 µM), contrary to predictions, that could be attributable to the steric hindrance by the neighbouring methoxy group 37 .…”

“…After that, 4-methoxyacetophenone 1 (15 mmol) was added to the mixture dropwise, followed by stirring the reaction mixture for 26 h at room temperature. Subsequently, ice water was added, and the resulting pale orange precipitate 2 was taken after being filtered and washed using H 2 O (3.35 g, 90%), Mp: 102–103 °C 22 , 37 .…”

Identification of 3‐(5‐cyano‐6‐oxo‐pyridin‐2‐yl)benzenesulfonamides as novel anticancer agents endowed with EGFR inhibitory activity

“…Briefly, sulfonamide 3 was prepared in a two-step reaction starting with 4-methoxyacetophenone 1 and a mixture of chlorosulfonic acid and thionyl chloride yielded benzenesulfonyl chloride 2. [39] By the action of ammonia, benzene sulfonyl chloride 2 was converted into sulfonamide 3. [40,41] The targeted 3cyanopyridin-2-one derivatives (6a-m and 8a-d) were obtained by a four-component one-pot condensation reaction [28] of sulfonamide 3, different aromatic aldehyde derivatives (5a-m and 7a-d), ethyl cyanoacetate 4 and anhydrous ammonium acetate in absolute ethanol.…”

“…The product (1.68 g, 90%, Mp: 102-103°C) did not require additional purification. [39] 4.1.3 | General procedure for synthesis of 5-acetyl-2-methoxybenzenesulfonamide 3…”

“…The finished product was filtered and washed with EtOH and H 2 O (0.91 g, 79%), Mp: 202-203°C. [39] 4.1.4 | General procedure for synthesis of 3-cyanopyridin-2-one derivatives (6a-m and 8a-d)…”