Search

A new series of quinoline-based benzenesulfonamides ( QBS ) were developed as potential carbonic anhydrase inhibitors (CAIs). The target QBS CAIs is based on the 4-anilinoquinoline scaffold where the primary sulphonamide functionality was grafted at C4 of the anilino moiety as a zinc anchoring group ( QBS   13a - c ); thereafter, the sulphonamide group was switched to ortho - and meta -positions to afford regioisomers 9a - d and 11a - g . Moreover, a linker elongation approach was adopted where the amino linker was replaced by a hydrazide one to afford QBS   16 . All the described QBS have been synthesized and investigated for their CA inhibitory action against h CA I, II, IX and XII. In general, para -sulphonamide derivatives 13a - c displayed the best inhibitory activity against both cancer-related isoforms h CA IX ( K I s = 25.8, 5.5 and 18.6 nM, respectively) and h CA XII ( K I s = 9.8, 13.2 and 8.7 nM, respectively), beside the excellent h CA IX inhibitory activity exerted by meta -sulphonamide derivative 11c ( K I = 8.4 nM). The most promising QBS were further evaluated for their anticancer and pro-apoptotic activities on two cancer cell lines (MDA-MB-231 and MCF-7). In addition, molecular docking simulation studies were applied to justify the acquired CA inhibitory action of the target QBS.

In the present study, we describe the design of different series of benzofuran-based derivatives as potential carbonic anhydrase inhibitors (CAIs). The adopted design is based on bioisosteric replacement for the p-fluorophenyl SLC-0111 tail with the lipophilic 2-methylbenzofuran or 5-bromobenzofuran tails to furnish the 2-methylbenzofuran (MBF) sulfonamides (MBFS; 9, 11 and 13) and 5-bromobenzofuran (BBF) sulfonamides (BBFS; 27a-b, 28a-b and 29a-c), respectively. Thereafter, the urea spacer was either elongated to furnish MBFS (17 and 19), and BBFS (30) series, or replaced by a carbamate one to afford MBFS (15). All the designed compounds were synthesized and evaluated for their inhibitory activities against four human (h) CA isoforms: hCA I, II, IX and XII. MBFS (11b and 17) and BBFS (28b, 29a and 30) efficiently inhibited the tumor-related CA IX isoform in the single-digit nanomolar range (K I s = 8.4, 7.6, 5.5, 7.1 and 1.8 nM, respectively). In particular, MBFS 11b and BBFS 28b exhibited good selectivity toward hCA IX isoform over the main off-target hCA II isoform (S.I. = 26.4 and 58.9, respectively). As a consequence, 11b and 28b were examined for their anticancer and pro-apoptotic activities toward MDA-MB-231 and MCF-7 cancer cell lines., Competing Interests: Declaration of competing interest The authors have declared no conflict of interest., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

In the current medical era, the utilization of a single small molecule to simultaneously target two distinct molecular targets is emerging as a highly effective strategy in the battle against cancer. Carbonic Anhydrase (CA) and Vascular-Endothelial Growth Factor (VEGF) are genes that are activated in response to low oxygen levels (hypoxia) and play a role in the development and progression of tumors in hypoxic conditions. Herein we report the design, synthesis, and biological assessment of a series of novel indolinone-based benzenesulfonamides (8a-k , 11a-d , 15a-d , and 16) as potential dual inhibitors for cancer-associated h CA IX/XII and VEGFR-2. All the synthesized sulfonamides were assessed for their inhibitory effect against four CA isoforms I, II, IX, and XII where they displayed varying degrees of h CA inhibition. The most effective and selective h CA IX and XII inhibitors 8g , 8j and 15b were chosen to be tested for their in vitro inhibitory impact against VEGFR-2 as well as their antiproliferative impact against VEGFR-2 overexpressing MDA-MB-231 and MCF-7 breast cancer cells. Furthermore, molecular docking studies were conducted within the h CA IX, XII, and VEGFR-2 active sites to explain the observed inhibitory results. [Display omitted] • Novel series of isatin-based benzenesulfonamides (8a-k , 11a-d , 15a-d , 16) were synthesized. • Inhibitory activities of all molecules were evaluated towards hCA I, II, IX and XII isoforms. • All isatins efficiently inhibited the cancer-related h CA IX and XII in the low nanomolar ranges. • Isatins 8g , 8j and 15b effectively inhibited VEGFR-2 with good IC 50 values. • 8g , 8j, 15b exerted potent antiproliferative impact against MDA-MB-231 and MCF-7 cell lines. [ABSTRACT FROM AUTHOR]

Hypoxia, a characteristic feature of solid tumors, develops as a result of excessive cell proliferation and rapid tumor growth exceeding the oxygen supply, and can result in angiogenesis activation, increased invasiveness, aggressiveness, and metastasis, leading to improved tumor survival and suppression of anticancer drug therapeutic impact. SLC-0111, a ureido benzenesulfonamide, is a selective human carbonic anhydrase (hCA) IX inhibitor in clinical trials for the treatment of hypoxic malignancies. Herein, we describe the design and synthesis of novel 6-arylpyridines 8a-l and 9a-d as structural analogues of SLC-0111, in the aim of exploring new selective inhibitors for the cancer-associated hCA IX isoform. The para -fluorophenyl tail in SLC-0111 was replaced by the privileged 6-arylpyridine motif. Moreover, both ortho- and meta- sulfonamide regioisomers, as well as an ethylene extended analogous were developed. All 6-arylpyridine-based SLC-0111 analogues were screened in vitro for their inhibitory potential against a panel of hCAs (hCA I, II, IV and IX isoforms) using stopped-flow CO 2 hydrase assay. In addition, the anticancer activity was firstly explored against a panel of 57 cancer cell lines at the USA NCI-Developmental Therapeutic Program. Compound 8g emerged as the best anti-proliferative candidate with mean GI% value equals 44. Accordingly, a cell viability assay (MTS) for 8g was applied on colorectal HCT-116 and HT-29 cancer cell lines as well as on the healthy HUVEC cells. Thereafter, Annexin V-FITC apoptosis detection, cell cycle, TUNEL, and qRT-PCR, colony formation, and wound healing assays were applied to gain mechanistic insights and to understand the behavior of colorectal cancer cells upon the treatment of compound 8g. Also, a molecular docking analysis was conducted to provide in silico insights into the reported hCA IX inhibitory activity and selectivity. [Display omitted] • New series of sulfonamide-tethered 6-arylpyridines 8a-l and 9a-d was designed and synthesized. • Inhibitory activities of all derivatives were evaluated toward hCA I, II, IV and IX isoforms. • The anticancer activity was explored against a panel of 57 cancer cell lines at the NCI-USA. • Compound 8g showed promising CA inhibitory and anti-proliferative activities. • A thorough investigation was done into the anticancer efficacy of 8g against colorectal cell lines. [ABSTRACT FROM AUTHOR]