Three-Component Combinatorial Synthesis of a Substituted 6H-Pyrido[2‘,1‘:2,3]imidazo- [4,5-c]isoquinolin-5(6H)-one Library with Cytotoxic Activity

Meng, Tao; Zhang, Zhixiang; Hu, Dawei; Lin, Liping; Ding, Jian; Wang, Xin; Shen, Jingkang

doi:10.1021/cc0700593

Cited by 44 publications

(15 citation statements)

References 11 publications

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“…MT119 was readily prepared by three component condensation of 2‐amino‐5‐bromopyridine, phthaldehydic acid and 1‐(2‐isocyanoethyl)‐4‐methoxybenzene according to our previous publication,5 followed by the Ullmann condensation with 3‐(aminomethyl)pyridine. Its purity (more than 99%) was determined by RP‐HPLC at two wavelengths of 214 nm and 254 nm.…”

Section: Methodsmentioning

confidence: 99%

“…We previously reported a combinatorial library of 6 H ‐Pyrido[2′,1′:2,3]imidazo [4,5‐ c ]isoquinolin‐5(6 H )‐ones that possessed potent antitumor activities in vitro. 5 From this library, we found a compound, designated as MT7 [6‐(4‐methoxybenzyl) pyrido[2',1':2,3]imidazo[4,5‐c]isoquinolin‐5(6H)‐one], to destabilize cellular microtubules and arrest mitosis, suggesting that this library might represent a new class of microtubule‐targeted scaffolds 6. However, the relatively weak activity of MT7 prevents us to further characterize how it acts on microtubule.…”

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confidence: 99%

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MT119, a new planar‐structured compound, targets the colchicine site of tubulin arresting mitosis and inhibiting tumor cell proliferation

Zhang

Meng

Yang

et al. 2010

Intl Journal of Cancer

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Microtubule-targeted drugs are now indispensable for the therapy of various cancer types worldwide. In this article, we report MT119 [6-[2-(4-methoxyphenyl) -ethyl]-9-[(pyridine-3-ylmethyl)amino]pyrido[2 0 ,1 0 :2,3]imida-zo [4,5-c]isoquinolin-5(6H)-one] as a new microtubule-targeted agent. MT119 inhibited tubulin polymerization significantly both in tumor cells and in cell-free systems, which was followed by the disruption of mitotic spindle assembly. Surface plasmon resonance-based analyses showed that MT119 bound to purified tubulin directly, with the K D value of 10.6 lM. The binding of MT119 in turn caused tubulin conformational changes as evidenced by the quenched tryptophan fluorescence, the reduction of the bis-ANS reactivity and the decreased DTNB-sulfhydryl reaction rate. Competitive binding assays further revealed that MT119 bound to tubulin at its colchicine site. Consequently, by inhibiting tubulin polymerization, MT119 arrested different tumor cells at mitotic phase, which contributed to its potent antitumor activity in vitro. MT119 was also similarly cytotoxic to vincristine-, adriamycin-or mitoxantrone-resistant cancer cells and to their corresponding parental cells. Together, these data indicate that MT119 represents a new class of colchicine-site-targeted inhibitors against tubulin polymerization, which might be a promising starting point for future cancer therapeutics.Microtubule is composed of a-and b-tubulin heterodimers, whose dynamics is crucial for the proper function of spindles and guarantees the mitotic progression. 1 By interfering with microtubule dynamics, tubulin inhibitors cause mitosis arrest and ultimately lead to tumor cell death. Since the approval of vinca alkaloids in 1960s and then taxol in 1990s for cancer therapy, targeting microtubule has been recognized as the most effective strategy against different types of malignancies, including hematological, ovarian, mammary and lung cancers. 2 According to the differential impacts on microtubule polymer mass, tubulin inhibitors could be classified into microtubule destabilizers, such as vinca alkaloids, colchicine and combretastatins and microtubule stabilizers, such as taxol and epothilones. Regardless of their distinct structural types, these inhibitors bind to microtubules mainly at one of the three sites: the vinblastine site, the colchicine site or the taxol site. Despite of their proven therapeutic success, some drawbacks such as limited natural sources, high neurotoxicity and poor solubility have rendered serious questions onto the extensive use of current microtubule-targeted drugs in clinic. 3,4 Therefore, it is urgent to find more structurally-diverse compounds with tubulin inhibitory functions for future antitumor therapy.We previously reported a combinatorial library of 6H-Pyrido

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

MT119, a new planar‐structured compound, targets the colchicine site of tubulin arresting mitosis and inhibiting tumor cell proliferation

Zhang

Meng

Yang

et al. 2010

Intl Journal of Cancer

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“…The prominent structural variety of GBBR is mainly due to the diversity of the aldehyde components which in turn used to access compounds with functionalization diversity at [42,70]. GBBR reaction is compatible with a wide range of aldehydes including aromatic (e.g., ortho-, meta-or para-substituted benzaldehyde, naphthaldehyde, anthracene-9-carbaldehyde, salicylaldehyde and phthalaldehydic esters), aliphatic (e.g., valeraldehyde, pivalaldehyde and 3-phenylpropiolaldehyde) and heteroaromatic (e.g., thiophenaldehyde, pyridoxal, nicotinaldehyde, picolinaldehyde and isonicotinaldehyde) aldehydes (Fig.…”

Section: Variations Of the Aldehyde Componentmentioning

confidence: 99%

“…On the other hand, aldehydes having electron-withdrawing groups are basically more reactive in GBBR than those having electronreleasing groups. Meng et al [42] reported the solution-phase combinatorial synthesis of substituted pyrido[2 , 1 : 2, 3]imidazo [4,5-c]isoquinolinones 2 in good yields (up to 82 %) employing 2-formylbenzoic (1) acid as the aldehyde component (Scheme 1).…”

Section: Variations Of the Aldehyde Componentmentioning

confidence: 99%

Groebke–Blackburn–Bienaymé multicomponent reaction: emerging chemistry for drug discovery

2015

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The Groebke-Blackburn-Bienaymé reaction (GBBR) is used for the one-pot synthesis of therapeutically relevant fused imidazoles bridgehead nitrogen heterocyclic compounds from readily available aldehyde, isocyanide and amidine building blocks. The reaction is driven by a wide range of catalysts and can be performed either under solvent or solvent-free conditions, or under microwave irradiation as heat source. The GBBR products can be used for the synthesis of a variety of more complex scaffolds via postmodification reactions. These include cyclization and nucleophilic substitution as well as further MCRs. The GBBR reaction has seen diverse applications in combinatorial and medicinal chemistry and its products are of great use in drug discovery. In this review, we summarize the efforts of the chemistry community in the progress and applications of GBBR since 1998. This review also includes some biological profiles and synthetic scopes of GBBR products. The component variations, postmodifications and secondary transformations will also be discussed throughout this review.

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“…[8] As part of our ongoing efforts to prepare novel fused imidazole ring systems, [9,10] which are of great interest to the pharmaceutical industry, we recently focused on the Groebke-Blackburn-BienaymØ multicomponent reaction or GBB-MCR (Scheme 1). [11] It involves the reaction of 2-aminopyridine, salicylaldehyde and ethyl isocyanoacetate, and is catalyzed by scandium triflate to afford 3-aminoimidazoA C H T U N G T R E N N U N G [1,2-a]pyridines in good yields (> 80%).…”

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confidence: 99%

Simple and Efficient Copper(I)‐Catalyzed Access to Three Versatile Aminocoumarin‐Based Scaffolds using Isocyanoacetate

et al. 2011

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Three-Component Combinatorial Synthesis of a Substituted 6H-Pyrido[2‘,1‘:2,3]imidazo- [4,5-c]isoquinolin-5(6H)-one Library with Cytotoxic Activity

Cited by 44 publications

References 11 publications

MT119, a new planar‐structured compound, targets the colchicine site of tubulin arresting mitosis and inhibiting tumor cell proliferation

MT119, a new planar‐structured compound, targets the colchicine site of tubulin arresting mitosis and inhibiting tumor cell proliferation

Groebke–Blackburn–Bienaymé multicomponent reaction: emerging chemistry for drug discovery

Simple and Efficient Copper(I)‐Catalyzed Access to Three Versatile Aminocoumarin‐Based Scaffolds using Isocyanoacetate

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