Dual-tail approach to discovery of novel carbonic anhydrase IX inhibitors by simultaneously matching the hydrophobic and hydrophilic halves of the active site

Hou, Zhuang; Lin, Bin; Bao, Yu; Yan, Haining; Zhang, Miao; Chang, Xiao; Zhang, Xinxin; Wang, Zi-jie; Wei, Gaofei; Cheng, Maosheng; Yang, Liu; Guo, Chun

doi:10.1016/j.ejmech.2017.03.023

Cited by 32 publications

(21 citation statements)

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“…[28][29][30][31] Previous studies have shown that certain artificial sweeteners bind selectively to CA IX, some with nanomolar affinities. [32][33][34][35] The artificial sweetener saccharin has been used as a ZBG in drug development using the "tail-approach" [36][37] along with a methylene triazole linker and glucose tail moiety (compound 1a, Figure 1). [38] The saccharin-based compound (SBC) displayed over 1000-fold selectivity for CA IX over off-target CA isoforms CA I and CA II.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of saccharin-glycoconjugates targeting carbonic anhydrase using a one-pot cyclization/deprotection strategy

Murray

Quadri

et al. 2019

Carbohydrate Research

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Carbonic anhydrase IX (CA IX) has been identified as a biomarker and drug target for several malignant tumors due to its role in cancer cell growth and proliferation. Simple cyclic sulfonamides, like saccharin (SAC), have shown up to a 60-fold selectivity towards CA IX over other ubiquitous CA isoforms, with greater selectivity obtained applying the "tail-approach" to derivatize SAC with a methylene triazole linker that connected to a "tail" beta glucoside. These modifications of SAC led to an increased selectivity of more than 1000-fold towards CA IX, whereas clinically available CA inhibitors show little to no isoform selectivity. As part of our interest in the development of new CA inhibitors, we found the existing synthetic protocol, which relies on a N-tert-butyl saccharin intermediate, to be problematic in the final deprotection steps. We therefore describe an alternative approach to the synthesis of these compounds featuring a gentle "one pot" deprotection/cyclization as the final synthetic step, and report new galactosyl and glucosyl conjugates with low to mid nM inhibition of CA IX.

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Section: Introductionmentioning

confidence: 99%

Synthesis of saccharin-glycoconjugates targeting carbonic anhydrase using a one-pot cyclization/deprotection strategy

Murray

Quadri

et al. 2019

Carbohydrate Research

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“…Sulfonamide derivatives were extensively studied due to a variety of biological activities such as antimicrobial, anticancer and antiviral properties [1][2][3] . Benzenesulfonamide derivative 1 (Figure 1) induced nuclear condensation, cell shrinkage, and nuclear fragmentation to apoptosis against COLO-205 cell line 4 .…”

Section: Introductionmentioning

confidence: 99%

Anticancer sulfonamide hybrids that inhibit bladder cancer cells growth and migration as tubulin polymerisation inhibitors

Liu

Zhang

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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Novel sulfonamide-dithiocarbamate hybrids were designed and synthesised via the molecular hybridisation strategy. Among them, compound 13d displayed a potent activity with IC 50 values of 0.9, 0.7, 1.9 and 2.6 µM against UM-UC-3, RT-112, RT4 and T24. Compound 13d inhibited the migration and regulated the migration-related markers (E-cadherin, N-cadherin, Vimentin, Snail and Slung) against RT-112 cells in a concentration dependent manner. By the tubulin polymerisation assay in vitro and immunostaining assay, compound 13d was identified as a novel tubulin polymerisation inhibitor. Intragastric administration of compound 13d could inhibit the growth of RT-112 cells in vivo in a xenograft mouse model with the low toxicity, indicating that it may be a leading candidate with antitumor properties to treat bladder cancer.

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“…As a class of polyhydroxy products, carbohydrates are widespread and ubiquitous in nature and have excellent water solubility and various bioactivities, which have made them a reliable and valuable source for drug design [16]. In addition, the “click reaction”, namely the Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition, has been widely used to construct the 1,2,3-triazoles fragment, which can play an important role in drug design [17].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Molecular Docking Analysis of Flavonoid Derivatives as Potential Telomerase Inhibitors

Fan

Wen

et al. 2019

Molecules

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Based on the structural scaffolds of natural products, two series of flavonoid derivatives, for a total of twelve compounds, were designed and synthesized as potential human telomerase inhibitors. Using a modified TRAP-PCR assay, compound 5c exhibited the most potent inhibitory activity against human telomerase with an IC50 value of less than 50 μM. In vitro, the results demonstrated that compound 5c had potent anticancer activity against five classes of tumor cell lines. The molecular docking and molecular dynamics analyses binding to the human telomerase holoenzyme were performed to elucidate the binding mode of active compound 5c. This finding helps the rational design of more potent telomerase inhibitors based on the structural scaffolds of natural products.

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Dual-tail approach to discovery of novel carbonic anhydrase IX inhibitors by simultaneously matching the hydrophobic and hydrophilic halves of the active site

Cited by 32 publications

References 50 publications

Synthesis of saccharin-glycoconjugates targeting carbonic anhydrase using a one-pot cyclization/deprotection strategy

Synthesis of saccharin-glycoconjugates targeting carbonic anhydrase using a one-pot cyclization/deprotection strategy

Anticancer sulfonamide hybrids that inhibit bladder cancer cells growth and migration as tubulin polymerisation inhibitors

Design, Synthesis and Molecular Docking Analysis of Flavonoid Derivatives as Potential Telomerase Inhibitors

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