Design, synthesis and biological evaluation of tetrahydroquinoxaline sulfonamide derivatives as colchicine binding site inhibitors

Dong, Haiyang; Lu, Lu; Song, Xueting; Li, Youkang; Zhou, Jinguang; Xu, Yungen; Zhang, Yahong; Qi, Jianguo; Liang, Tingting; Wang, Jianhong

doi:10.1039/d3ra05720h

Cited by 3 publications

(1 citation statement)

References 36 publications

(86 reference statements)

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“…An aberrant phosphorylation of the tau protein causes its dissociation from the microtubules and the formation of neurofibrillary tangles directly implicated in the progression of the neurodegenerative disorder [11]. For these different reasons, the search for novel MTAs remains very active using different strategies: (i) via the rational design and synthesis of new compounds, small molecules, and peptides (e.g., indazole derivatives [12], quinoxaline derivatives [13], and cyclic peptides [14]), (ii) via the repositioning of known drugs characterized as MTAs [15,16], and (iii) the identification of novel natural products targeting tubulin and/or microtubules [17]. The search for new tubulin binders can be performed using medium/high-throughput drug screening methodologies with defined chemical libraries of natural products, synthetic compounds, and small fragments [18], and also using computational methods and platforms to guide the selection of new compounds [19,20].…”

Section: Introductionmentioning

confidence: 99%

Interaction of norsecurinine-type monomeric and dimeric alkaloids with α-tubulin: a molecular docking study

Vergoten,

Bailly

2024

Explor Drug Sci

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Aim: New microtubule-targeting agents are needed to improve cancer treatment. The recent characterization of the anticancer alkaloid securinine as a tubulin-binding agent prompted us to explore the interaction of related monomeric and dimeric analogues with tubulin. The interaction between the α/β-tubulin dimer and alkaloids fluevirines A–F and flueggenines A–I, isolated from the bush Flueggea virosa (Roxb. ex Willd.) Royle, was investigated using molecular docking. Methods: Two molecular models were initially compared for the binding of securinine to α/β-tubulin. The pironetin-binding site model (5FNV) was selected for the subsequent docking analysis with all compounds. Empirical energies of interaction (ΔE) were measured and compared. Results: Fluevirine A has been identified as a potent tubulin binder. This dimeric alkaloid formed more stable complexes with tubulin than the monomeric counterparts, such as fluevirines B–D. The bis-indole derivative fluevirine E also provided more stable complexes than (nor)securinine. The study was extended to the dimeric alkaloids flueggenines A–I and three compounds were identified as potential tubulin binders: the polycyclic product flueggenine B, the norsecurinine-indole hybrid flueggenine E, and the norsecurinine dimer flueggenine I. This later compound proved to be well adapted to fit into the pironetin site of tubulin, extending its two norsecurinine units between the colchicine-binding area and the pironetin site, in close proximity to the pironetin-reactive cysteine-316 residue. Structure-binding relationships were delineated. Conclusions: The study identifies the dimeric alkaloids fluevirine A and flueggenine I as potential α-tubulin binding agents. For the first time, dimeric alkaloids including two C-C connected norsecurinine units are characterized as tubulin ligands. The study contributes to a better understanding of the mechanism of action of Flueggea alkaloids and should help the design of anticancer analogues targeting the pironetin site of α-tubulin.

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Section: Introductionmentioning

confidence: 99%

Interaction of norsecurinine-type monomeric and dimeric alkaloids with α-tubulin: a molecular docking study

Vergoten,

Bailly

2024

Explor Drug Sci

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Design, synthesis and biological evaluation of novel tubulin-targeting agents with a dual-mechanism for polymerization inhibition and protein degradation

Wang,

et al. 2024

European Journal of Medicinal Chemistry

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Novel Antimitotic Agent SP-1-39 Inhibits Head and Neck Squamous Cell Carcinoma

Adeleye,

Li,

Xie

et al. 2024

J Dent Res

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Effective management of head and neck cancer (HNC) poses a significant challenge in the field of oncology, due to its intricate pathophysiology and limited treatment options. The most common HNC malignancy is head and neck squamous cell carcinoma (HNSCC). HNSCC treatment includes a combination of surgery, radiation, and chemotherapy. While HNSCC is treatable if diagnosed early, this is often not the case and is considered incurable once in its late stages and metastatic disease has developed. Therapies are also limited once resistant disease has occurred. SP-1-39, a novel colchicine-binding site inhibitor (CBSI), has been recently reported for its potential efficacy in a variety of cancer cell lines including breast, melanoma, pancreatic, and prostate. SP-1-39 also shows abilities to overcome paclitaxel resistance in a paclitaxel-resistant prostate cancer xenograft model. To evaluate the potential of SP-1-39 as a new HNSCC treatment option, herein we systematically performed preclinical studies in HNSCC models using SP-1-39 and demonstrated that, in vitro, SP-1-39 inhibits the proliferation of 2 HNSCC cell lines with low nanomolar IC50 values (1.4 to 2.1 nM), induces HNSCC cell apoptosis in a dose-dependent manner, interferes with migration of HNSCC cells, and leads to HNSCC cell cycle arrest in the G2/M phase. In vivo, SP-1-39 suppresses the primary tumor growth of a Detroit 562 subcutaneous xenograft mouse model in 6- to 8-wk-old, male NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mice, with no detectable cytotoxic effects at a low dose of 2.5 mg/kg. This efficacy of SP-1-39 is better when compared with the treatment using a reference chemotherapy drug, paclitaxel at 10 mg/kg. Collectively, these data demonstrate that SP-1-39 is a promising candidate for further development for more efficacious HNSCC treatment.

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Design, synthesis and biological evaluation of tetrahydroquinoxaline sulfonamide derivatives as colchicine binding site inhibitors

Abstract: (1) 26 derivatives were synthesized and evaluated for their antiproliferative activities against HT-29 cells. (2) I-7 inhibited tubulin polymerization, arrested cell cycle at G2/M phase. (3) I-7 is located at the colchicine binding site.

Cited by 3 publications

References 36 publications

Interaction of norsecurinine-type monomeric and dimeric alkaloids with α-tubulin: a molecular docking study

Interaction of norsecurinine-type monomeric and dimeric alkaloids with α-tubulin: a molecular docking study

Design, synthesis and biological evaluation of novel tubulin-targeting agents with a dual-mechanism for polymerization inhibition and protein degradation

Novel Antimitotic Agent SP-1-39 Inhibits Head and Neck Squamous Cell Carcinoma

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