New Indole Tubulin Assembly Inhibitors Cause Stable Arrest of Mitotic Progression, Enhanced Stimulation of Natural Killer Cell Cytotoxic Activity, and Repression of Hedgehog-Dependent Cancer

Abstract

We designed 39 new 2-phenylindole derivatives as potential anticancer agents bearing the 3,4,5-trimethox-yphenyl moiety with a sulfur, ketone, or methylene bridging group at position 3 of the indole and with halogen or methoxy substituent(s) at positions 4–7. Compounds 33 and 44 strongly inhibited the growth of the P-glycoprotein-overexpressing multi-drug-resistant cell lines NCI/ADR-RES and Messa/Dx5. At 10 nM, 33 and 44 stimulated the cytotoxic activity of NK cells. At 20–50 nM, 33 and 44 arrested >80% of HeLa cells in the G2/M phase of the cell cycle, with stable arrest of mitotic progression. Cell cycle arrest was followed by cell death. Indoles 33, 44, and 81 showed strong inhibition of the SAG-induced Hedgehog signaling activation in NIH3T3 Shh-Light II cells with IC50 values of 19, 72, and 38 nM, respectively. Compounds of this class potently inhibited tubulin polymerization and cancer cell growth, including stimulation of natural killer cell cytotoxic activity and repression of Hedgehog-dependent cancer.

Copper-catalysed regioselective sulfenylation of indoles with sodium sulfinates

“…Recently, Miller et al reported a 3-sulfenylindole derivative that was a potent inhibitor of small-molecule autotaxin [ 4 ]. Furthermore, many 3-sulfenylindole derivatives have been proved to possess other biological activities, including anticancer activity [ 5 , 6 ], anti-HIV-1 activity [ 7 ], anti-allergy activity [ 8 ] and so on. The indole rings can be directly functionalized with electrophiles via carbon–carbon or carbon-hetero bonds because of their electron-rich nature.…”

Targeting the Pregnane X Receptor Using Microbial Metabolite Mimicry

“…FKK6 has been studied with respect to a limited number of cellular targets that relate to PXR. While we find that FKK effects in cells and human intestinal organoids (HIOs) correlates with changes in PXR target gene and NF-κB signaling, it is possible that some of its protective effects could come via other targets hitherto uncharacterized (e.g., tubulin) 43 . Loss of PXR studies in HIOs would be required to confirm these correlations; these studies are in progress using both LS174T cells and iPSC cells in which PXR is knocked out using CRISPR-Cas9.…”

Targeting the pregnane X receptor using microbial metabolite mimicry

“…We have studied a limited number of cellular targets that relate to PXR with respect to FKK6. While we find that FKK effects in cells and human intestinal organoids (HIOs) correlate with changes in PXR target genes and NF‐κB signaling, it is possible that some of its protective effects could be related to other targets (e.g., tubulin) (La Regina et al , ). Loss of PXR studies in HIOs would be required to confirm these correlations; these studies are in progress using both LS174T cells and iPSC cells, in which PXR is knocked out using CRISPR/Cas9.…”