25 research outputs found
Structure–Activity Relationships for Vitamin D3-Based Aromatic A‑Ring Analogues as Hedgehog Pathway Inhibitors
A structure–activity
relationship study for a series of
vitamin D3-based (VD3) analogues that incorporate aromatic A-ring
mimics with varying functionality has provided key insight into scaffold
features that result in potent, selective Hedgehog (Hh) pathway inhibition.
Three analogue subclasses containing (1) a single substitution at
the <i>ortho</i> or <i>para</i> position of the
aromatic A-ring, (2) a heteroaryl or biaryl moiety, or (3) multiple
substituents on the aromatic A-ring were prepared and evaluated. Aromatic
A-ring mimics incorporating either single or multiple hydrophilic
moieties on a six-membered ring inhibited the Hh pathway in both Hh-dependent
mouse embryonic fibroblasts and cultured cancer cells (IC<sub>50</sub> values 0.74–10 μM). Preliminary studies were conducted
to probe the cellular mechanisms through which VD3 and <b>5</b>, the most active analogue, inhibit Hh signaling. These studies suggested
that the anti-Hh activity of VD3 is primarily attributed to the vitamin
D receptor, whereas <b>5</b> affects Hh inhibition through a
separate mechanism
Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic
Itraconazole
(ITZ) is an FDA-approved member of the triazole class
of antifungal agents. Two recent drug repurposing screens identified
ITZ as a promising anticancer chemotherapeutic that inhibits both
the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized
and evaluated first- and second-generation ITZ analogues for their
anti-Hh and antiangiogenic activities to probe more fully the structural
requirements for these anticancer properties. Our overall results
suggest that the triazole functionality is required for ITZ-mediated
inhibition of angiogenesis but that it is not essential for inhibition
of Hh signaling. The synthesis and evaluation of stereochemically
defined <i>des</i>-triazole ITZ analogues also provides
key information as to the optimal configuration around the dioxolane
ring of the ITZ scaffold. Finally, the results from our studies suggest
that two distinct cellular mechanisms of action govern the anticancer
properties of the ITZ scaffold
Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic
Itraconazole
(ITZ) is an FDA-approved member of the triazole class
of antifungal agents. Two recent drug repurposing screens identified
ITZ as a promising anticancer chemotherapeutic that inhibits both
the angiogenesis and hedgehog (Hh) signaling pathways. We have synthesized
and evaluated first- and second-generation ITZ analogues for their
anti-Hh and antiangiogenic activities to probe more fully the structural
requirements for these anticancer properties. Our overall results
suggest that the triazole functionality is required for ITZ-mediated
inhibition of angiogenesis but that it is not essential for inhibition
of Hh signaling. The synthesis and evaluation of stereochemically
defined <i>des</i>-triazole ITZ analogues also provides
key information as to the optimal configuration around the dioxolane
ring of the ITZ scaffold. Finally, the results from our studies suggest
that two distinct cellular mechanisms of action govern the anticancer
properties of the ITZ scaffold