Novel derivatives of pyridylbenzo[b]thiophene-2-carboxamides and benzo[b]thieno[2,3-c]naphthyridin-2-ones: minor structural variations provoke major differences of antitumor action mechanisms.

doi:10.1021/jm801573v

Paper

Novel derivatives of pyridylbenzo[b]thiophene-2-carboxamides and benzo[b]thieno[2,3-c]naphthyridin-2-ones: minor structural variations provoke major differences of antitumor action mechanisms.

Published Apr 23, 2009 · K. Ester, M. Hranjec, I. Piantanida

Journal of medicinal chemistry

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Abstract

Novel cyano- and 2-imidazolinyl-substituted derivatives of pyridylbenzo[b]thiophene-2-carboxamides 4, 5, 10-13 and benzo[b]thieno[2,3-c]naphthyridin-2-ones 6, 7, 14-17 were prepared. All derivatives showed a prominent antiproliferative effect. Extensive DNA binding studies and additional biological evaluations point to various modes/targets of action. The results strongly support intercalation into DNA as a dominant binding mode of fused analogues, which was substantiated using topoisomerase I inhibition assay. Most intriguingly, only minor structural difference between "nonfused" compounds 12 and 13 has strong impact on the interactions with DNA; while 13 binds within the DNA minor groove in the form of dimer, 12 does not form significant interactions with DNA. The assumption that severe mitotic impairment (G2/M phase arrest) induced by 12 could point to tubulin, another important target, was confirmed by its obvious anti-tubulin activity observed in immunofluorescence assay, whereby treated cells showed disruption of microtubule formation comparable to the effect obtained by paclitaxel, a well-known tubulin antagonist chemotherapeutic.

In Vitro Study

Study Snapshot

Novel derivatives of pyridylbenzo[b]thiophene-2-carboxamides and benzo[b]thieno[2,3-c]naphthyridin-2-ones show strong antitumor effects, with DNA intercalation as a dominant binding

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Novel derivatives of pyridylbenzo[b]thiophene-2-carboxamides and benzo[b]thieno[2,3-c]naphthyridin-2-ones: minor structural variations provoke major differences of antitumor action mechanisms.

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References

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The 9-substituent in chalcogenoxanthylium dyes strongly impacts DNA binding modes, with selenoxanthylium derivatives showing higher binding constants than other chalcogen atoms.

Mana-Hox displays anticancer activity against prostate cancer cells through tubulin depolymerization and DNA damage stress

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Both fused and nonfused thiophene-containing imidazolyl derivatives show promising antitumor activity, with imidazolyl-substituted compound 11 showing the most activity and selectivity towards tumor cells.

Allosteric inhibitors of Akt1 and Akt2: a naphthyridinone with efficacy in an A2780 tumor xenograft model.

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Structural simplification of bioactive natural products with multicomponent synthesis. 2. antiproliferative and antitubulin activities of pyrano[3,2-c]pyridones and pyrano[3,2-c]quinolones.

Pyrano[3,2-c]pyridones and pyrano[3,2-c]quinolones show low nanomolar antiproliferative activity and induce apoptosis in human cancer cells, offering promising new leads in anticancer drug design.

Citations

Molecular structure, electronic properties, spectroscopic investigation and nonlinear optical properties of thianaphthene-2-carboxylic acid: A quantum chemical approach

This study presents a detailed theoretical analysis of Thianaphthene-2-carboxylic acid, a thiophene derivative, revealing its optimized geometric structure, electronic properties, and nonlinear optical characteristics.

Synthesis, antidiabetic activity and in silico studies of benzo[b]thiophene based small molecule α-amylase inhibitors

A novel class of benzo[b]thiophene-based -amylase inhibitors has been identified, showing potential for further lead optimization and development in antidiabetic drug discovery.

TFA-Promoted Cascade Sulfonylation/Rearrangement/Cyclization of 1,5-Diynols and Sodium Sulfinates to Construct Sulfonylated Benzo[b]fluorenes.

TFA-promoted cascade cyclization with sodium sulfinates efficiently converts 1,5-diynols into sulfonylated benzo[b]fluorenes in moderate to excellent yields under metal-free conditions.

Cascade Cyclization of 1,5-Diynols and (RO)2P(O)SH to Construct Benzo[b]fluorenyl S-Alkyl Phosphorothioates under Catalyst-Free Conditions.

This study developed an efficient cascade cyclization method for producing benzo[b]fluorenyl S-alkyl phosphorothioates under mild conditions, with water as the only byproduct.

Functionalized Sulfur-Containing Heterocyclic Analogs Induce Sub-G1 Arrest and Apoptotic Cell Death of Laryngeal Carcinoma In Vitro

Hydroxyl-containing benzo[b]thiophene analogs BP and EP show selective activity against laryngeal cancer cells, promoting apoptosis and enhancing antioxidant enzyme activity, potentially aiding in combination therapy.