Cytotoxicity of phenylpironetin analogs and the metabolic fate of pironetin and phenylpironetin.

To improve pironetin's metabolic stability we prepared four analogs by replacing its C12-14 segment with an aryl group. The antiproliferative activity of phenyl analog 4 was reduced two-fold and dihydroxy-4-fluorophenyl analog 5 was slightly more effective against OVCAR5 and A2780 ovarian cancer cell lines compared with the parent compound pironetin (1). The activity of 4-fluorophenyl analog 6 was reduced 3-fold in both cell lines.

Revisiting microtubule targeting agents: α-Tubulin and the pironetin binding site as unexplored targets for cancer therapeutics.

Molecules that bind to tubulin and disrupt tubulin dynamics are known as microtubule targeting agents. Treatment with a microtubule targeting agent leads to cell cycle arrest followed by apoptosis. Tubulin inhibitors have been highly effective in the clinical treatment of a variety of tumors and are being investigated for treatment of several other diseases.

Identification of the Metabolic Profile of the α-Tubulin-Binding Natural Product (-)-Pironetin.

Pironetin, the only crystallographically confirmed natural product to target α-tubulin, displays potent cytotoxic activity against sensitive and resistant A2780 ovarian cancer cell lines but is only marginally active in vivo. We now report that pironetin has a short half-life (<7 min) in human liver microsomes, suggesting that its limited in vivo efficacy is due to rapid metabolism. Further, we describe the discovery of epoxypironetin as pironetin's major metabolite in human liver microsomes.

TLR4-dependent fibroblast activation drives persistent organ fibrosis in skin and lung.

Persistent fibrosis in multiple organs is the hallmark of systemic sclerosis (SSc). Recent genetic and genomic studies implicate TLRs and their damage-associated molecular pattern (DAMP) endogenous ligands in fibrosis. To test the hypothesis that TLR4 and its coreceptor myeloid differentiation 2 (MD2) drive fibrosis persistence, we measured MD2/TLR4 signaling in tissues from patients with fibrotic SSc, and we examined the impact of MD2 targeting using a potentially novel small molecule.

Saccharin derivatives as inhibitors of interferon-mediated inflammation.

A series of novel, saccharin-based antagonists have been identified for the interferon signaling pathway. Through in vitro high-throughput screening with the Colorado Center for Drug Discovery (C2D2) Pilot Library, we identified hit compound 1, which was the basis for extensive structure-activity relationship studies. Our efforts produced a lead anti-inflammatory compound, tert-butyl N-(furan-2-ylmethyl)-N-{4-[(1,1,3-trioxo-2,3-dihydro-1λ(6),2-benzothiazol-2-yl)methyl]benzoyl}carbamate CU-CPD103 (103), as a potent inhibitor using an established nitric oxide (NO) signaling assay.

Multivalency amplifies the selection and affinity of bradykinin-derived peptides for lipid nanovesicles.

The trimer of a bradykinin derivative displayed a more than five-fold increase in binding affinity for phosphatidylserine-enriched nanovesicles as compared to its monomeric precursor. The nanovesicle selection is directly correlated with multivalency, which amplifies the electrostatic attraction. This strategy may lead to the development of novel molecular probes for detecting highly curved membrane bilayers.