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

The Food and Drug Administration-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 anticancer chemotherapeutic against several Hh-depen...

Full description

Saved in:
Bibliographic Details
Published inJournal of medicinal chemistry Vol. 62; no. 8; pp. 3873 - 3885
Main Authors Pace, Jennifer R, Teske, Kelly A, Chau, Lianne Q, Dash, Radha Charan, Zaino, Angela M, Wechsler-Reya, Robert J, Hadden, M. Kyle
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 25.04.2019
Amer Chemical Soc
Subjects
Animals
Binding Sites
Cell Line
Cell Proliferation
Chemistry, Medicinal
Drug Design
Hedgehog Proteins - antagonists & inhibitors
Hedgehog Proteins - metabolism
Humans
Itraconazole - chemistry
Itraconazole - metabolism
Itraconazole - pharmacology
Life Sciences & Biomedicine
Mice
Molecular Dynamics Simulation
Pharmacology & Pharmacy
Science & Technology
Signal Transduction - drug effects
Structure-Activity Relationship
Triazoles - chemistry
AGENT
RESISTANCE
POTENT
ANTIFUNGAL
MEDULLOBLASTOMA
Online AccessGet full text

Cover

More Information
Summary:The Food and Drug Administration-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 anticancer chemotherapeutic against several Hh-dependent malignancies. We have extended our studies on ITZ analogues as Hh pathway inhibitors through the design, synthesis, and evaluation 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 functionalities (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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
K.A.T. Current Address: Western Michigan University Department of Chemistry, Kalamazoo, MI, 49008
J.R.P. Current Address: Tufts University Department of Chemistry, 62 Talbot Avenue, Medford MA, 02155
Author Contributions
J.R.P. and K.A.T. synthesized ITZ analogues and performed biological evaluations. L.Q.C. performed compound evaluation in the Ptch-CKO cells. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.8b01283