A Novel Class of <i>N</i>‐Sulfonyl and <i>N</i>‐Sulfamoyl Noscapine Derivatives that Promote Mitotic Arrest in Cancer Cells

Yong, Cassandra; Devine, Shane M.; Gao, Xue; Yan, Angelina; Callaghan, Richard; Capuano, Ben; Scammells, Peter J.

doi:10.1002/cmdc.201900477

Cited by 10 publications

(14 citation statements)

References 39 publications

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“…Interestingly, at 5 and 2.5 μM, compound 4 i also showed a reduction of the maximum initial velocity ( V max =11.0±1.0 and 13.0±0.0 mOD/min, respectively). Even at lower concentrations, compound 4 i has similar or higher tubulin polymerization inhibitory activity than other TDAs reported in the literature . It should be mentioned that none of the other synthesized compounds induced significant changes in tubulin polymerization (Figure S28).…”

Section: Resultsmentioning

confidence: 58%

Design, Synthesis and Evaluation of 2,4‐Diaminoquinazoline Derivatives as Potential Tubulin Polymerization Inhibitors

et al. 2020

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Microtubules are highly dynamic polymers composed of αand β-tubulin proteins that have been shown to be potential therapeutic targets for the development of anticancer drugs. Currently, a wide variety of chemically diverse agents that bind to β-tubulin have been reported. Nocodazole (NZ) and colchicine (COL) are well-known tubulin-depolymerizing agents that have close binding sites in the β-tubulin. In this study, we designed and synthesized a set of nine 2,4-diaminoquinazoline derivatives that could occupy both NZ and COL binding sites. The synthesized compounds were evaluated for their antiproliferative activities against five cancer cell lines (PC-3, HCT-15, MCF-7, MDA-MB-231, and SK-LU-1), a noncancerous one (COS-7), and peripheral blood mononuclear cells (PBMC). The effect of compounds 4 e and 4 i on tubulin organization and polymerization was analyzed on the SK-LU-1 cell line by indirect immunofluorescence, western blotting, and tubulin polymerization assays. Our results demonstrated that both compounds exert their antiproliferative activity by inhibiting tubulin polymerization. Finally, a possible binding pose of 4 i in the NZ/COL binding site was determined by using molecular docking and molecular dynamics (MD) approaches. To our knowledge, this is the first report of non-N-substituted 2,4-diaminoquinazoline derivatives with the ability to inhibit tubulin polymerization.

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Section: Resultsmentioning

confidence: 58%

Design, Synthesis and Evaluation of 2,4‐Diaminoquinazoline Derivatives as Potential Tubulin Polymerization Inhibitors

et al. 2020

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“…The biosynthesis of noscapine ( 5 ) starts from l ‐tyrosine ( 6 ) and proceeds via the intermediate reticuline ( 7 ). Residues that were successfully modified in reticuline and noscapine by biotechnological or semisynthetic methods are highlighted [90–102,105,106,108] …”

Section: Engineering Anti‐inflammatory Natural Productsmentioning

confidence: 99%

“…In the past 10 years, several attempts have been made to generate noscapine analogues with favorable properties. [91][92][93][94][95][96][97][98][99][100][101][102] As a consequence of the complex stereochemistry, total chemical syntheses of noscapinoids are hard to realize. Therefore, semisynthesis has become the method of choice.…”

Section: Noscapinementioning

confidence: 99%

“…Residues that were successfully modified in reticuline and noscapine by biotechnological or semisynthetic methods are highlighted. [90][91][92][93][94][95][96][97][98][99][100][101][102]105,106,108] The biotechnological production of noscapine analogues became possible following the discovery and characterization of its biosynthesis gene cluster in the opium poppy. [103,104] The natural assembly of 5 is extremely complex.…”

Section: Noscapinementioning

confidence: 99%

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Bioengineering of Anti‐Inflammatory Natural Products

2020

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Inflammatory processes occur as a generic response of the immune system and can be triggered by various factors, such as infection with pathogenic microorganisms or damaged tissue. Due to the complexity of the inflammation process and its role in common diseases like asthma, cancer, skin disorders or Alzheimer's disease, anti‐inflammatory drugs are of high pharmaceutical interest. Nature is a rich source for compounds with anti‐inflammatory properties. Several studies have focused on the structural optimization of natural products to improve their pharmacological properties. As derivatization through total synthesis is often laborious with low yields and limited stereoselectivity, the use of biosynthetic, enzyme‐driven reactions is an attractive alternative for synthesizing and modifying complex bioactive molecules. In this minireview, we present an outline of the biotechnological methods used to derivatize anti‐inflammatory natural products, including precursor‐directed biosynthesis, mutasynthesis, combinatorial biosynthesis, as well as whole‐cell and in vitro biotransformation.

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“…N-Substituted noscapine and multi-functionalised derivatives 6 a-e and 7-9. [12,26] terpenes, safrole, benzylisoquinoline and aporphine alkaloids. [27] The 1,3-benzodioxole moiety can also be found in clinical agents such as stiripentol and paroxetine for the treatment of epilepsy and depression, respectively.…”

Section: Introductionmentioning

confidence: 99%

1,3‐Benzodioxole‐Modified Noscapine Analogues: Synthesis, Antiproliferative Activity, and Tubulin‐Bound Structure

et al. 2021

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Since the revelation of noscapine's weak anti-mitotic activity, extensive research has been conducted over the past two decades, with the goal of discovering noscapine derivatives with improved potency. To date, noscapine has been explored at the 1, 7, 6', and 9'-positions, though the 1,3-benzodioxole motif in the noscapine scaffold that remains unexplored. The present investigation describes the design, synthesis and pharmacological evaluation of noscapine analogues consisting of modifications to the 1,3-benzodioxole moiety. This includes expansion of the dioxolane ring and inclusion of metabolically robust deuterium and fluorine atoms. Favourable structural modifications were subsequently incorporated into multifunctionalised noscapine derivatives that also possessed modifications previously shown to promote anti-proliferative activity in the 1-, 6'-and 9'-positions. Our research efforts afforded the deuterated noscapine derivative 14 e and the dioxino-containing analogue 20 as potent cytotoxic agents with EC 50 values of 1.50 and 0.73 μM, respectively, against breast cancer (MCF-7) cells. Compound 20 also exhibited EC 50 values of < 2 μM against melanoma, non-small cell lung carcinoma, and cancers of the brain, kidney and breast in an NCI screen. Furthermore, compounds 14 e and 20 inhibit tubulin polymerisation and are not vulnerable to the overexpression of resistance conferring Pgp efflux pumps in drug-resistant breast cancer cells (NCI ADR/RES ). We also conducted X-ray crystallography studies that yielded the high-resolution structure of 14 e bound to tubulin. Our structural analysis revealed the key interactions between this noscapinoid and tubulin and will assist with the future design of noscapine derivatives with improved properties.

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A Novel Class of N‐Sulfonyl and N‐Sulfamoyl Noscapine Derivatives that Promote Mitotic Arrest in Cancer Cells

Cited by 10 publications

References 39 publications

Design, Synthesis and Evaluation of 2,4‐Diaminoquinazoline Derivatives as Potential Tubulin Polymerization Inhibitors

Design, Synthesis and Evaluation of 2,4‐Diaminoquinazoline Derivatives as Potential Tubulin Polymerization Inhibitors

Bioengineering of Anti‐Inflammatory Natural Products

1,3‐Benzodioxole‐Modified Noscapine Analogues: Synthesis, Antiproliferative Activity, and Tubulin‐Bound Structure

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