Potential antitumor agents. 64. Synthesis and antitumor evaluation of dibenzo[1,4]dioxin-1-carboxamides: a new class of weakly binding DNA-intercalating agents.

doi:10.1021/JM00080A009

Paper

Potential antitumor agents. 64. Synthesis and antitumor evaluation of dibenzo[1,4]dioxin-1-carboxamides: a new class of weakly binding DNA-intercalating agents.

Published Jan 24, 1992 · H. H. Lee, B. Palmer, M. Boyd

Journal of medicinal chemistry

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33

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0

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Abstract

A series of substituted dibenzo[1,4]dioxin-1-carboxamides has been synthesized and evaluated for in vitro and in vivo antitumor activity. The required substituted dibenzo[1,4]dioxin-1-carboxylic acids were prepared by a variety of methods. No regiospecific syntheses were available for many of these, and separation of the mixtures of regioisomers obtained was sometimes difficult. The dibenzo[1,4]dioxin-1-carboxamides are active against wild-type P388 leukemia in vitro and in vivo, with structure-activity relationships resembling those for both the acridine-4-carboxamide and phenazine-1-carboxamide series of DNA-intercalating antitumor agents. In all three series, substituents placed peri to the carboxamide sidechain (the 5-position in the acridines, and the 9-position in the phenazines and dibenzo[1,4]dioxins) enhance activity and potency. The 9-chlorodibenzodioxin-1-carboxamide was also curative against the remotely sited Lewis lung carcinoma. Several of the compounds showed much lower levels of cross-resistance to the P388/AMSA line than classical DNA-intercalating agents, which suggests that their primary mechanism of action may not be via interference with topoisomerase II alpha. This is of interest with regard to the development of drugs to combat resistance mechanisms which arise by the expression of the topo II beta isozyme.

In Vitro Study

Study Snapshot

Dibenzo[1,4]dioxin-1-carboxamides show potential as weakly binding DNA-intercalating agents, with potential antitumor activity against wild-type P388 leukemia and Lewis lung carcinoma, with potential for developing drugs to combat topo II beta resistance mechanisms.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Potential antitumor agents. 64. Synthesis and antitumor evaluation of dibenzo[1,4]dioxin-1-carboxamides: a new class of weakly binding DNA-intercalating agents.

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References

Citations

Inhibitory Potential of Benzo[a]phenazin-5-ol Derivatives Against C-Kit Kinase: Molecular Docking and Prediction of ADME/Drug-Likeness Properties

Compounds A and C show promising inhibitory effects against C-kit kinase, with compound A showing the closest pharmacological match to Sunitinib and a potential P-gp substrate.

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Dibenzodioxins with high cytotoxicity also have high DNA-binding affinity, suggesting DNA could be a likely target for these compounds.

Spectroscopic and viscometric determination of DNA-binding modes of some bioactive dibenzodioxins and phenazines

Push-pull dibenzodioxins and phenazines show strong anti-tumor activity, with groove binding being the preferred mode of binding to DNA, influenced by subtle structural differences in their analogues.

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Aza-dihydrotetracene 18H is a strong fluorescent agent for microscopy, aiding in the detection of HeLa cells with strong cytotoxicity.

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