Bioactive heterocycles containing a 3,4,5-trimethoxyphenyl fragment exerting potent antiproliferative activity through microtubule destabilization

Fu, Dong-Jun; Yang, Jiajia; Li, Ping; Hou, Yuhui; Huang, Shengnan; Tippin, Matthew; Pham, Victor; Song, Liankun; Zi, Xiaolin; Xue, Weili; Zhang, Lirong; Zhang, Sai‐Yang

doi:10.1016/j.ejmech.2018.07.060

Cited by 30 publications

(10 citation statements)

References 29 publications

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“…Based on these findings, benzothiazole was a promising scaffold to design anticancer agents. On the other hand, our group also reported three series of colchicine site tubulin inhibitors: (1) compound 4 could change the membrane potential of the mitochondria against MGC-803 cells 17 ; (2) b-lactam containing a 3,4,5trimethoxyphenyl unit 5 exhibited the well antiproliferative activity against MGC-803 cells in vitro and in vivo 18 ; (3) compound 6 could inhibit MGC803 cell growth and colony formation, induce G2/M phase arrest and promote apoptosis 19 .…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative benzothiazoles incorporating a trimethoxyphenyl scaffold as novel colchicine site tubulin polymerisation inhibitors

Liu

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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Tubulin polymerisation inhibitors exhibited an important role in the treatment of patients with prostate cancer. Herein, we reported the medicinal chemistry efforts leading to a new series of benzothiazoles by a bioisosterism approach. Biological testing revealed that compound 12a could significantly inhibit in vitro tubulin polymerisation of a concentration dependent manner, with an IC 50 value of 2.87 lM. Immunofluorescence and EBI competition assay investigated that compound 12a effectively inhibited tubulin polymerisation and directly bound to the colchicine-binding site of b-tubulin in PC3 cells. Docking analysis showed that 12a formed hydrogen bonds with residues Tyr357, Ala247 and Val353 of tubulin. Importantly, it displayed the promising antiproliferative ability against C42B, LNCAP, 22RV1 and PC3 cells with IC 50 values of 2.81 lM, 4.31 lM, 2.13 lM and 2.04 lM, respectively. In summary, compound 12a was a novel colchicine site tubulin polymerisation inhibitor with potential to treat prostate cancer. A novel colchicine site tubulin polymer ization inhibitor Time/minutesFluorescence intensity

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Section: Introductionmentioning

confidence: 99%

Antiproliferative benzothiazoles incorporating a trimethoxyphenyl scaffold as novel colchicine site tubulin polymerisation inhibitors

Liu

et al. 2020

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…The molecular hybridization (MH) is a powerful approach for rational design of new ligands or prototypes of active molecules 30,31 . The pharmacophoric sub-units in the molecular structure of two or more known bioactive molecules which are linked/fused together, lead to the design of new hybrid structures that maintain pre-selected characteristics of the original templates 32 .…”

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confidence: 99%

Design and efficient synthesis of pyrazoline and isoxazole bridged indole C-glycoside hybrids as potential anticancer agents

Kumari

Mishra

Narayana

et al. 2020

Sci Rep

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C-glycosides are important class of molecules exhibit diverse biological activities and present as structural motif in many natural products. Two series of new pyrazoline and isoxazole bridged indole C-glycoside molecular hybrids (n = 36) were efficiently synthesized starting from diverse indole 3-carboxaldehydes derived α, β-unsaturated ketone derivatives of β-D-glucosyl-propan-2-one, β-D-galactosyl-propan-2-one and β-D-mannosyl-propan-2-one, reacting with hydrazine hydrate and hydroxyl amine hydrochloride in shorter reaction time (15 min) under microwave assisted condition. Anticancer activity of these newly synthesized pyrazoline and isoxazole bridged indoles C-glycoside hybrids were determined in details through cellular assays against MCF-7, MDA-MB-453 and MDA-MB-231 cancer cell lines. The selected library members displayed low micromolar (IC 50 = 0.67-4.67 µM) and selective toxicity against breast cancer cell line (MCF-7). Whereas these compounds were nontoxic towards normal cell line (MCF-10A). Mechanistic studies showed that, active compounds inhibit COX-2 enzyme, which was also supported by molecular docking studies. These findings are expected to provide new leads towards anticancer drug discovery.C-Glycosides are stable surrogates of O-glycosides and are often used as investigative tool in chemical biology and medicinal chemistry, in particular C-glycoside analogues are often used as substrate mimics for different enzymes involved in the carbohydrate metabolism 1-10 . The use of glycomimetic in the design of inhibitors has proven to be a successful approach and now constitutes one of the most attractive ways to develop new generations of effective and selective inhibitors 11 . α, β-unsaturated ketone is a central core for many significant biological compounds 12,13 . According to literature α, β-unsaturated ketone derivatives from natural and synthetic analogues exhibit diverse pharmacological activities such as anti-tuberculosis, anti-inflammatory, anticancer, antineoplastic, antibacterial, antifungal, antimalarial, antiviral, antiallergic, estrogenic 12 and COX-2 inhibitor 13 .Pyrazoline derivatives are important biologically active heterocyclic compounds. These derivatives are the subject of many research studies due to their widespread potential biological activities such as anticancer, antioxidant, antibacterial activities 14 and COX-2 inhibitor 15 . The most prominent compounds containing pyrazoline nucleus are ampyrone, phenazone and propyphenzone. Isoxazole heterocycle is well known for its medicinal relevance 16,17 . There are isoxazole nucleus containing drug molecules currently available in market, such as acetylsulfisoxazole, cycloserine, sulfisoxazole, and zonisamide etc. These drugs possess antimicrobial 18 , antioxidant 19,20 tuberculostatic 21 neurotoxic 22 , antiepileptic activities 23,24 and COX-2 inhibitor 25 . The comparable activities are also observed in other isoxazole derivatives, captivates researcher to search for newer bioactive compounds of using this as pharmacophore. α, β-...

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“…In this study, we reported the identification of a novel Hippo activator, compound 9i ( Figure 1 ), based on unexpected findings from our previous work from an experimental screening and the SAR study of our reported compound 1 31 and compound 2 32 . Compound 1 was a tubulin inhibitor against MGC-803 cells with IC 50 value at the micromolar level and Compound 2 inhibited the AKT/mTOR and RAS/Raf/MEK/ERK pathways against MGC-803 cells with IC 50 value at the micromolar level.…”

Section: Introductionmentioning

confidence: 59%

Discovery of N-aryl sulphonamide-quinazoline derivatives as anti-gastric cancer agents in vitro and in vivo via activating the Hippo signalling pathway

Niu

Hua

Liu

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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Hippo signalling pathway plays a crucial role in tumorigenesis and cancer progression. In this work, we identified an N-aryl sulphonamide-quinazoline derivative , compound 9i as an anti-gastric cancer agent, which exhibited potent antiproliferative ability with IC 50 values of 0.36 μM (MGC-803 cells), 0.70 μM (HCT-116 cells), 1.04 μM (PC-3 cells), and 0.81 μM (MCF-7 cells), respectively and inhibited YAP activity by the activation of p-LATS. Compound 9i was effective in suppressing MGC-803 xenograft tumour growth in nude mice without obvious toxicity and significantly down-regulated the expression of YAP in vivo . Compound 9i arrested cells in the G2/M phase, induced intrinsic apoptosis, and inhibited cell colony formation in MGC-803 and SGC-7901 cells. Therefore, compound 9i is to be reported as an anti-gastric cancer agent via activating the Hippo signalling pathway and might help foster a new strategy for the cancer treatment by activating the Hippo signalling pathway regulatory function to inhibit the activity of YAP.

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Bioactive heterocycles containing a 3,4,5-trimethoxyphenyl fragment exerting potent antiproliferative activity through microtubule destabilization

Cited by 30 publications

References 29 publications

Antiproliferative benzothiazoles incorporating a trimethoxyphenyl scaffold as novel colchicine site tubulin polymerisation inhibitors

Antiproliferative benzothiazoles incorporating a trimethoxyphenyl scaffold as novel colchicine site tubulin polymerisation inhibitors

Design and efficient synthesis of pyrazoline and isoxazole bridged indole C-glycoside hybrids as potential anticancer agents

Discovery of N-aryl sulphonamide-quinazoline derivatives as anti-gastric cancer agents in vitro and in vivo via activating the Hippo signalling pathway

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