3-(3-Phenoxybenzyl)amino-β-carboline: A novel antitumor drug targeting α-tubulin

Ikeda, Reiko; Kurosawa, Masaki; Okabayashi, Takazumi; Takei, Ayako; Yoshiwara, Masamichi; Kumakura, Tadashi; Sakai, Norio; Funatsu, Osamu; Morita, Akinori; Ikekita, Masahiko; Nakaike, Yumi; Konakahara, Takeo

doi:10.1016/j.bmcl.2011.06.061

Cited by 33 publications

(20 citation statements)

References 13 publications

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“…Finally, various 3indolyl azides with different electronic nature on the indole ring were screened, and the reaction furnished the desired products 3k-3n in mostly excellent yields ( Table 2, entries [11][12][13][14]. This transformation thus makes it an alternative way for the efficient construction of the valuable 3-amino-b-carbolines, known as the lead compounds for anti-tumor agents, that conventionally demand rather tedious synthesis [52][53][54][55][56]. Based on the above experimental results and our previous work [49], a plausible mechanism of this gold-catalyzed formal [4+2]…”

Section: Resultsmentioning

confidence: 99%

Gold-catalyzed intermolecular reaction of ynamides with 3-indolyl azides via an unexpected 1,2-alkyl migration

et al. 2017

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Section: Resultsmentioning

confidence: 99%

Gold-catalyzed intermolecular reaction of ynamides with 3-indolyl azides via an unexpected 1,2-alkyl migration

et al. 2017

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“…PAC (Fig. 1a) showed high anticancer activity in vitro [33], and is identified as a tubulin inhibitor [30]. PAC induced obvious G2/M phase cell cycle arrest on human cervical adenocarcinoma cell line HeLa and human colon colorectal carcinoma cell line Hct116 (Fig.…”

Section: Pac Selectively Downregulates the Protein Level Of Tubulin Heterodimersmentioning

confidence: 99%

mentioning

confidence: 99%

“…A synthetic compound, 3-(3-Phenoxybenzyl)amino-β-carboline (PAC, Fig 1a), belongs to the class of known anti-cancer natural products [27] denoted β-carboline derivatives [28][29][30]. PAC is a potent tubulin inhibitor with nanomolar IC50 values in several tumor cells [30]. Tubulin is a validated target for a wide range of tumors and several drugs, including paclitaxel, eribulin and vinca alkoloids, that inhibit the polymerization or depolymerization of tubulin are in clinical use [31,32].…”

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confidence: 99%

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A new role of low barrier hydrogen bond in mediating protein stability by small molecules

Yang

Qiu

et al. 2021

Preprint

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Low barrier hydrogen bond (LBHB) is a special type of hydrogen bond which occurs where two heteroatoms with similar pKa values share a single proton resulting in an unusually strong and short hydrogen bond. LBHBs in protein play important roles in enzyme catalysis and maintaining protein structural integrity but its other biochemical roles are unknown. Here we report a novel function of LBHB in selectively inducing tubulin protein degradation. A tubulin inhibitor, 3-(3-Phenoxybenzyl) amino-β-carboline (PAC), promotes selective degradation of αβ-tubulin heterodimers by binding to the colchicine site of β-tubulin. Biochemical studies have revealed that PAC specifically destabilizes tubulin, making it prone to aggregation that then predisposes it to ubiquitinylation and then degradation. Structural activity analyses have indicated that the destabilization is mediated by a single hydrogen bond formed between the pyridine nitrogen of PAC and βGlu198, which is identified as a LBHB. In contrast, another two tubulin inhibitors only forming normal hydrogen bonds with βGlu198 exhibit no degradation effect. Thus, the LBHB accounts for the degradation. Most importantly, we screened for compounds capable of forming LBHB with βGlu198 and demonstrated that BML284, a Wnt signaling activator, also promotes tubulin heterodimers degradation in a PAC-like manner as expected. Our study has identified a novel approach for designing tubulin degraders, providing a unique example of LBHB function and suggests that designing small molecules to form LBHBs with protein residues resulting in the highly specific degradation of a target protein could be a new strategy for drug development.

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“…A large number of β-carboline derivatives have been prepared in search of more potent antitumor agents. The structure–activity relationships (SARs) of these β-carbolines have been extensively investigated [3,4,5,6,7,8,9,10]. Research has indicated that this class of compounds exert their antitumor effects through multiple mechanisms of action, including intercalating into DNA [11,12,13] and inhibiting topoisomerases I and II [14,15], cyclin-dependent kinase (CDK) [16,17], polo-like kinase 1 (PLK1) [18], kinesin-like protein Eg5 [19], and IκB kinases [20].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Novel N-Acylhydrazone Bond Linked Heterobivalent β-Carbolines as Potential Anticancer Agents

Chen

Guo

Ma³

et al. 2019

Molecules

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Utilizing a pharmacophore hybridization approach, we have designed and synthesized a novel series of 28 new heterobivalent β-carbolines. The in vitro cytotoxic potential of each compound was evaluated against the five cancer cell lines (LLC, BGC-823, CT-26, Bel-7402, and MCF-7) of different origin—murine and human, with the aim of determining the potency and selectivity of the compounds. Compound 8z showed antitumor activities with half-maximal inhibitory concentration (IC50) values of 9.9 ± 0.9, 8.6 ± 1.4, 6.2 ± 2.5, 9.9 ± 0.5, and 5.7 ± 1.2 µM against the tested five cancer cell lines. Moreover, the effect of compound 8z on the angiogenesis process was investigated using a chicken chorioallantoic membrane (CAM) in vivo model. At a concentration of 5 μM, compound 8z showed a positive effect on angiogenesis. The results of this study contribute to the further elucidation of the biological regulatory role of heterobivalent β-carbolines and provide helpful information on the development of vascular targeting antitumor drugs.

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3-(3-Phenoxybenzyl)amino-β-carboline: A novel antitumor drug targeting α-tubulin

Cited by 33 publications

References 13 publications

Gold-catalyzed intermolecular reaction of ynamides with 3-indolyl azides via an unexpected 1,2-alkyl migration

Gold-catalyzed intermolecular reaction of ynamides with 3-indolyl azides via an unexpected 1,2-alkyl migration

A new role of low barrier hydrogen bond in mediating protein stability by small molecules

Design, Synthesis, and Biological Evaluation of Novel N-Acylhydrazone Bond Linked Heterobivalent β-Carbolines as Potential Anticancer Agents

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