Design and Synthesis of Potent in Vitro and in Vivo Anticancer Agents Based on 1-(3′,4′,5′-Trimethoxyphenyl)-2-Aryl-1H-Imidazole

Romagnoli, Romeo; Baraldi, Pier Giovanni; Prencipe, Filippo; Oliva, Paola; Baraldi, Stefania; Tabrizi, Mojgan Aghazadeh; Cara, Carlota Lopez; Ferla, Salvatore; Brancale, Andrea; Hamel, Ernest; Ronca, Roberto; Bortolozzi, Roberta; Mariotto, Elena; Basso, Giuseppe; Viola, Giampietro

doi:10.1038/srep26602

Cited by 30 publications

(25 citation statements)

References 43 publications

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“…In vivo studies on a mouse model also demonstrated the potential of 8 for further preclinical evaluation. 25 In an earlier report, 1,2,5-selenadiazole was incorporated in CA-4 in place of the olefinic bond; the analogue 9 exhibited potent activity on the nanomolar level in three cancer cell lines and its mechanistic action was similar to that of CA-4. 26 Xu and coworkers reported substituted 1,5-diaryl pyrazoles as CA-4 analogues with significant antiproliferative and tubulin inhibition properties.…”

Section: Recent Developments In Ca-4 Based Analoguesmentioning

confidence: 96%

Recent advances in combretastatin based derivatives and prodrugs as antimitotic agents

et al. 2017

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The dynamic and crucial role of tubulin in different cellular functions rendered it a promising target in anticancer drug development. Combretastatin A-4 (CA-4), an inhibitor of tubulin polymerization isolated from natural sources, is a lead molecule with significant cytotoxicity against tumour cells. Owing to its non polar nature it exhibits low solubility in natural biological fluids, thereby prompting the development of new CA-4 based derivatives. The modification of this lead molecule was mostly carried out by keeping the crucial -orientation of the double bond intact, along with a trimethoxyphenyl aromatic ring, by employing different approaches. The issue of solubility was also addressed by the development of water soluble prodrugs of CA-4. The present review highlights the investigations into the parallel development of both new CA-4 based derivatives and prodrugs in the past few years.

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Section: Recent Developments In Ca-4 Based Analoguesmentioning

confidence: 96%

Recent advances in combretastatin based derivatives and prodrugs as antimitotic agents

et al. 2017

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“…Romagnoli et al [ 37 ] developed 2-substituted-1-(3,4,5-trimethoxyphenyl)-1H-imidazole (Scheme 17 ) and evaluated for anticancer activity against different cancer cell lines such as HeLa, HT-29, A549, MCF-7, Jurkat, and HL-60 using C-A4 as a reference standard. Compounds 28k, 28n , and 28o showed maximum cytotoxicity as compared to others.…”

Section: Main Textmentioning

confidence: 99%

Synthesis and therapeutic potential of imidazole containing compounds

2021

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Imidazole is a five-membered heterocyclic moiety that possesses three carbon, two nitrogen, four hydrogen atoms, and two double bonds. It is also known as 1, 3-diazole. It contains two nitrogen atoms, in which one nitrogen bear a hydrogen atom, and the other is called pyrrole type nitrogen. The imidazole name was reported by Arthur Rudolf Hantzsch (1857–1935) in 1887. 1, 3-diazole is an amphoteric in nature i.e. it shows both acidic and basic properties. It is a white or colorless solid that is highly soluble in water and other polar solvents. Due to the presence of a positive charge on either of two nitrogen atom, it shows two equivalent tautomeric forms. Imidazole was first named glyoxaline because the first synthesis has been made by glyoxal and ammonia. It is the basic core of some natural products such as histidine, purine, histamine and DNA based structures, etc. Among the different heterocyclic compounds, imidazole is better known due to its broad range of chemical and biological properties. Imidazole has become an important synthon in the development of new drugs. The derivatives of 1, 3-diazole show different biological activities such as antibacterial, antimycobacterial, anti-inflammatory, antitumor, antidiabetic, anti-allergic, antipyretic, antiviral, antioxidant, anti-amoebic, antihelmintic, antifungal and ulcerogenic activities, etc. as reported in the literature. There are different examples of commercially available drugs in the market which contains 1, 3-diazole ring such as clemizole (antihistaminic agent), etonitazene (analgesic), enviroxime (antiviral), astemizole (antihistaminic agent), omeprazole, pantoprazole (antiulcer), thiabendazole (antihelmintic), nocodazole (antinematodal), metronidazole, nitroso-imidazole (bactericidal), megazol (trypanocidal), azathioprine (anti rheumatoid arthritis), dacarbazine (Hodgkin's disease), tinidazole, ornidazole (antiprotozoal and antibacterial), etc. This present review summarized some pharmacological activities and various kinds of synthetic routes for imidazole and their derived products.

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“…To evaluate its antitumor effect in vivo, 6g was administered by the intraperitoneal route every other day, starting at day 9, at two different doses (3.0 and 7.5 mg/kg) in an allograft tumor model developed in mice. 50,51 As reference compound, CA-4P was used at 30 mg/kg. This model consists of the use of B16 murine melanoma cells that are injected in the flank of individual mice.…”

Section: Effectsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of 6-Substituted Thieno[3,2-d]pyrimidine Analogues as Dual Epidermal Growth Factor Receptor Kinase and Microtubule Inhibitors

et al. 2019

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The clinical evidence for the success of tyrosine kinase inhibitors in combination with microtubule-targeting agents prompted us to design and develop single agents that possess both epidermal growth factor receptor (EGFR) kinase and tubulin polymerization inhibitory properties. A series of 6-aryl/heteroaryl-4-(3′,4′,5′-trimethoxyanilino)thieno[3,2-d]pyrimidine derivatives were discovered as novel dual tubulin polymerization and EGFR kinase inhibitors. The 4-(3′,4′,5′-trimethoxyanilino)-6-(p-tolyl)thieno[3,2-d]pyrimidine derivative 6g was the most potent compound of the series as an antiproliferative agent, with half-maximal inhibitory concentration (IC50) values in the single- or double-digit nanomolar range. Compound 6g bound to tubulin in the colchicine site and inhibited tubulin assembly with an IC50 value of 0.71 μM, and 6g inhibited EGFR activity with an IC50 value of 30 nM. Our data suggested that the excellent in vitro and in vivo profile of 6g may be derived from its dual inhibition of tubulin polymerization and EGFR kinase.

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Design and Synthesis of Potent in Vitro and in Vivo Anticancer Agents Based on 1-(3′,4′,5′-Trimethoxyphenyl)-2-Aryl-1H-Imidazole

Cited by 30 publications

References 43 publications

Recent advances in combretastatin based derivatives and prodrugs as antimitotic agents

Recent advances in combretastatin based derivatives and prodrugs as antimitotic agents

Synthesis and therapeutic potential of imidazole containing compounds

Design, Synthesis, and Biological Evaluation of 6-Substituted Thieno[3,2-d]pyrimidine Analogues as Dual Epidermal Growth Factor Receptor Kinase and Microtubule Inhibitors

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