Optimizing the aryl-triazole of cjoc42 for enhanced gankyrin binding and anti-cancer activity

Kanabar, Dipti; Farrales, Pamela; Kabir, Abbas; Juang, Daniel; Gnanmony, Manu; Almasri, Joseph; Torrents, Nicolas; Shukla, Snehal K.; Gupta, Vivek; Dukhande, Vikas V.; D’Souza, Amber M.; Muth, Aaron

doi:10.1016/j.bmcl.2020.127372

Cited by 7 publications

(6 citation statements)

References 28 publications

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“…Additionally, the activity of 1,2,3-triazole-containing dibenzo [b, e][1,4]diazepin-11-one hybrid 83 (IC 50 : 0.71 μm, MTT assay) against A549 cells is much higher than that of 5fluorouracil (IC 50 : 3.47 μm), and this hybrid could induce the G2/M phase of cell cycle arrest and apoptosis, indicating that hybrid 83 could be used for further studies as anti-lung cancer candidates (Praveen Kumar et al, 2016). Some other compounds which are combined by 1,2,3-triazole and benzodiazepine/benzoxepine/dithiocarbamate/ deoxysalinomycin/myrrhanone B /phenanthrene/pyrano(2,3-c) phenazine/paeonol/naphthalimide/sesquiterpene/sulfonate ester/sapinofuranone/triterpene/thiourea/benzothiazinone/ benzoxazinone/furan/nimesulide (Kuntala et al, 2015;Poornima et al, 2015;Sudhapriya et al, 2015;Chandrashekhar et al, 2016;Reddy et al, 2016;Shaikh et al, 2016;Abdallah et al, 2017;Battula et al, 2017;Kumar et al, 2017;Lu et al, 2017;Mareddy et al, 2017;Mo et al, 2017;Nguyen et al, 2017;Narsimha et al, 2018;Ou et al, 2019;Yang et al, 2019;Jiang et al, 2020;Kanabar et al, 2020;Madasu et al, 2020;Qi et al, 2020;) also possess certain activity against lung cancer cell lines, but their activities are generally far inferior to those of the references. Hence, these derivatives still need further structural modifications.…”

Section: Miscellaneous 123-triazole-containing Compoundsmentioning

confidence: 99%

1,2,3-Triazole-Containing Compounds as Anti–Lung Cancer Agents: Current Developments, Mechanisms of Action, and Structure–Activity Relationship

Liang

Sun

et al. 2021

Front. Pharmacol.

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Lung cancer is the most common malignancy and leads to around one-quarter of all cancer deaths. Great advances have been achieved in the treatment of lung cancer with novel anticancer agents and improved technology. However, morbidity and mortality rates remain extremely high, calling for an urgent need to develop novel anti–lung cancer agents. 1,2,3-Triazole could be readily interact with diverse enzymes and receptors in organisms through weak interaction. 1,2,3-Triazole can not only be acted as a linker to tether different pharmacophores but also serve as a pharmacophore. This review aims to summarize the recent advances in 1,2,3-triazole–containing compounds with anti–lung cancer potential, and their structure–activity relationship (SAR) together with mechanisms of action is also discussed to pave the way for the further rational development of novel anti–lung cancer candidates.

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Section: Miscellaneous 123-triazole-containing Compoundsmentioning

confidence: 99%

1,2,3-Triazole-Containing Compounds as Anti–Lung Cancer Agents: Current Developments, Mechanisms of Action, and Structure–Activity Relationship

Liang

Sun

et al. 2021

Front. Pharmacol.

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“…The crude products of phenyl azides 7f’ and 7i’ were further purified by column chromatography (silica gel, hexane). All phenyl azides are known [ 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 ]. The characteristics and spectroscopic data are given in the supporting information .…”

Section: Methodsmentioning

confidence: 99%

The Design and Synthesis of a New Series of 1,2,3-Triazole-Cored Structures Tethering Aryl Urea and Their Highly Selective Cytotoxicity toward HepG2

et al. 2022

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Target cancer drug therapy is an alternative treatment for advanced hepatocellular carcinoma (HCC) patients. However, the treatment using approved targeted drugs has encountered a number of limitations, including the poor pharmacological properties of drugs, therapy efficiency, adverse effects, and drug resistance. As a consequence, the discovery and development of anti-HCC drug structures are therefore still in high demand. Herein, we designed and synthesized a new series of 1,2,3-triazole-cored structures incorporating aryl urea as anti-HepG2 agents. Forty-nine analogs were prepared via nucleophilic addition and copper-catalyzed azide-alkyne cycloaddition (CuAAC) with excellent yields. Significantly, almost all triazole-cored analogs exhibited less cytotoxicity toward normal cells, human embryonal lung fibroblast cell MRC-5, compared to Sorafenib and Doxorubicin. Among them, 2m’ and 2e exhibited the highest selectivity indexes (SI = 14.7 and 12.2), which were ca. 4.4- and 3.7-fold superior to that of Sorafenib (SI = 3.30) and ca. 3.8- and 3.2-fold superior to that of Doxorubicin (SI = 3.83), respectively. Additionally, excellent inhibitory activity against hepatocellular carcinoma HepG2, comparable to Sorafenib, was still maintained. A cell-cycle analysis and apoptosis induction study suggested that 2m’ and 2e likely share a similar mechanism of action to Sorafenib. Furthermore, compounds 2m’ and 2e exhibit appropriate drug-likeness, analyzed by SwissADME. With their excellent anti-HepG2 activity, improved selectivity indexes, and appropriate druggability, the triazole-cored analogs 2m’ and 2e are suggested to be promising candidates for development as targeted cancer agents and drugs used in combination therapy for the treatment of HCC.

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“…Therefore, we hypothesized that bioisosteric replacement of the sulfonate ester and triazole ring would optimize known interactions with gankyrin, as well as probe for potentially new interactions (Figure D). Additionally, cjoc42 ( 1 ) and its early derivatives (Figure D), AFM-1–2 ( 2 ) and DK-1–67 ( 3 ), , have found limited use against breast cancer and lung cancer, where small-molecule inhibition of gankyrin and its role in TSP degradation have not been shown. Therefore, we sought to develop gankyrin inhibitors based on the cjoc42 ( 1 ) scaffold with enhanced gankyrin binding and anti-proliferative activity against lung and breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Small-Molecule Gankyrin Inhibition as a Therapeutic Strategy for Breast and Lung Cancer

et al. 2022

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Gankyrin is an oncoprotein responsible for the development of numerous cancer types. It regulates the expression levels of multiple tumor suppressor proteins (TSPs) in liver cancer; however, gankyrin’s regulation of these TSPs in breast and lung cancers has not been thoroughly investigated. Additionally, no small-molecule gankyrin inhibitor has been developed which demonstrates potent anti-proliferative activity against gankyrin overexpressing breast and lung cancers. Herein, we are reporting the structure-based design of gankyrin-binding small molecules which potently inhibited the proliferation of gankyrin overexpressing A549 and MDA-MB-231 cancer cells, reduced colony formation, and inhibited the growth of 3D spheroids in an in vitro tumor simulation model. Investigations demonstrated that gankyrin inhibition occurs through either stabilization or destabilization of its 3D structure. These studies shed light on the mechanism of small-molecule inhibition of gankyrin and demonstrate that gankyrin is a viable therapeutic target for the treatment of breast and lung cancer.

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Optimizing the aryl-triazole of cjoc42 for enhanced gankyrin binding and anti-cancer activity

Cited by 7 publications

References 28 publications

1,2,3-Triazole-Containing Compounds as Anti–Lung Cancer Agents: Current Developments, Mechanisms of Action, and Structure–Activity Relationship

1,2,3-Triazole-Containing Compounds as Anti–Lung Cancer Agents: Current Developments, Mechanisms of Action, and Structure–Activity Relationship

The Design and Synthesis of a New Series of 1,2,3-Triazole-Cored Structures Tethering Aryl Urea and Their Highly Selective Cytotoxicity toward HepG2

Small-Molecule Gankyrin Inhibition as a Therapeutic Strategy for Breast and Lung Cancer

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