Structure-Activity Relationships for Itraconazole-Based Triazolone Analogues as Hedgehog Pathway Inhibitors.

08:00 EDT 21st March 2019 | BioPortfolio

Summary of "Structure-Activity Relationships for Itraconazole-Based Triazolone Analogues as Hedgehog Pathway Inhibitors."

The FDA-approved antifungal agent, itraconazole (ITZ), has been increasingly studied for its novel biological properties. In particular, ITZ inhibits the hedgehog (Hh) signaling pathway and has the potential to serve as an anti-cancer chemotherapeutic against several Hh-dependent malignancies. We have extended our studies on ITZ analogues as Hh pathway inhibitors through the design, synthesis, and evaluate of novel des-triazole ITZ analogues that incorporate modifications to the triazolone/side chain region of the scaffold. Our overall results suggest that the triazolone/side chain region can be replaced with various functionality (hydrazine carboxamides and meta-substituted amides) resulting in improved potency when compared to ITZ. Our studies also indicate that the stereochemical orientation of the dioxolane ring is important for both potent Hh-pathway inhibition and compound stability. Finally, our studies suggest that the ITZ scaffold can be successfully modified in terms of functionality and stereochemistry to further improve its anti-Hh potency and physicochemical properties.


Journal Details

This article was published in the following journal.

Name: Journal of medicinal chemistry
ISSN: 1520-4804


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Medical and Biotech [MESH] Definitions

A quantitative prediction of the biological, ecotoxicological or pharmaceutical activity of a molecule. It is based upon structure and activity information gathered from a series of similar compounds.

The informal or formal organization of a group of people based on a network of personal relationships which is influenced by the size and composition, etc., of the group.

A frizzled-like, G-protein-coupled receptor that associates with PATCHED RECEPTORS to transduce signals from HEDGEHOG PROTEINS and initiate hedgehog signaling to ZINC FINGER PROTEIN GLI1. It may normally inhibit signaling in the absence of SONIC HEDGEHOG PROTEIN binding to PATCHED RECEPTOR-1.

A family of intercellular signaling proteins that play and important role in regulating the development of many TISSUES and organs. Their name derives from the observation of a hedgehog-like appearance in DROSOPHILA embryos with genetic mutations that block their action.

The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.

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