Development of Novel Quinoline-Based Sulfonamides as Selective Cancer-Associated Carbonic Anhydrase Isoform IX Inhibitors

Abstract

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 hCA I, II, IX and XII. In general, para-sulphonamide derivatives 13a–c displayed the best inhibitory activity against both cancer-related isoforms hCA IX (KIs = 25.8, 5.5 and 18.6 nM, respectively) and hCA XII (KIs = 9.8, 13.2 and 8.7 nM, respectively), beside the excellent hCA IX inhibitory activity exerted by meta-sulphonamide derivative 11c (KI = 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.

An Overview of Quinoline Derivatives as Anti-Cancer Agents

“…Moreover, the described have been synthesized and investigated for their CA inhibitory action against hCA I, II, IX and XII. In general, parasulphonamide derivatives 52a-c demonstrated the best inhibitory activity against both cancer-related isoforms hCA IX (KIs = 25.8, 5.5 and 18.6 nM, respectively) and hCA XII (KIs = 9.8, 13.2 and 8.7 nM, respectively), beside the excellent hCA IX inhibitory activity exerted by meta-sulphonamide derivative 53 (KI = 8.4 nM) (Shaldam et al, 2021).…”

Synthesis, characterization and anti-breast cancer potential of an incensole acetate nanoemulsion from Catharanthus roseus essential oil; in silico, in vitro, and in vivo study

“… 30 MD simulations may be used to analyze the interactions between drugs and their intended protein targets, determine potential binding sites, and calculate the binding affinities of medications. 31 With the ability to predict conformational changes, protein–ligand interactions, the stability of a protein and provide atomic level details of the structural changes occurring within a system, MD simulations can be a useful tool to supplement experimental data. The Desmond module (Schrödinger Release 2020-4) package was used to run an all-atom NTP simulation of the incensole acetate docked complex that was energy-minimized, with a TIP3P water model being used to fill in the empty space.…”

Novel 3-(6-methylpyridin-2-yl)coumarin-based chalcones as selective inhibitors of cancer-related carbonic anhydrases IX and XII endowed with anti-proliferative activity

“…The CA inhibition activity for the herein reported MPC derivatives was evaluated against the h CA isoforms I, II, IX, and XII using stopped-flow CO 2 hydrase test 7 , 33–36 (see the Supplementary Material ).…”

“…Among the sixteen human carbonic anhydrases ( h CAs) isozymes found, the h CA IX and XII play a crucial role in the cancer cell persistence by controlling the intracellular pH; thus, their inhibitors are deemed to be an efficient antitumor approach 4 , 6 . h CA IX expression is associated with a bad prognosis in cancer, whereas h CA XII isozyme is expressed in normal tissues and overexpressed in a variety of malignancies 7–10 . Furthermore, non-selective inhibition of h CAs leads to some side effects while treating cancer 11 .…”