Suppression of eukaryotic initiation factor 4E prevents chemotherapy-induced alopecia

BACKGROUND: Chemotherapy-induced hair loss (alopecia) (CIA) is one of the most feared side effects of chemotherapy among cancer patients. There is currently no pharmacological approach to minimize CIA, although one strategy that has been proposed involves protecting normal cells from chemotherapy by transiently inducing cell cycle arrest. Proof-of-concept for this approach, known as cyclotherapy, has been demonstrated in cell culture settings. METHODS: The eukaryotic initiation factor (eIF) 4E is a cap binding protein that stimulates ribosome recruitment to mRNA templates during the initiation phase of translation. Suppression of eIF4E is known to induce cell cycle arrest. Using a novel inducible and reversible transgenic mouse model that enables RNAi-mediated suppression of eIF4E in vivo, we assessed the consequences of temporal eIF4E suppression on CIA. RESULTS: Our results demonstrate that transient inhibition of eIF4E protects against cyclophosphamide-induced alopecia at the organismal level. At the cellular level, this protection is associated with an accumulation of cells in G1, reduced apoptotic indices, and was phenocopied using small molecule inhibitors targeting the process of translation initiation. CONCLUSIONS: Our data provide a rationale for exploring suppression of translation initiation as an approach to prevent or minimize cyclophosphamide-induced alopecia.1U01 CA168409 - NCI NIH HHS; P01 CA 87497 - NCI NIH HHS; P30 CA008748 - NCI NIH HHS; MOP-106530 - Canadian Institutes of Health Research; P01 CA013106 - NCI NIH HH

The stereoselective total synthesis of (+)-stagonolide B

The stereoselective total synthesis of the nonenolide, (+)-stagonolide B is described. The key steps involve epoxide homologation, hydrolytic kinetic resolution and ring-closing metathesis

Stereoselective total synthesis of goniothalesdiol A via chiron approach

The stereocontrolled synthesis of goniothalesdiol A, a dihydroxylated tetrahydropyran compound, has been accomplished using D-ribose as chiral precursor. The key steps involved are aryl Grignard reaction, stereoselective alkoxy-directed keto reduction, and intramolecular oxy-Michael addition

Synthesis of the Antiproliferative Agent Hippuristanol and Its Analogues from Hydrocortisone via Hg(II)-Catalyzed Spiroketalization: Structure–Activity Relationship

An efficient synthesis of hippuristanol (<b>1</b>), a marine-derived highly potent antiproliferative steroidal natural product, and nine closely related analogues has been accomplished from the commercially available hydrocortisone utilizing Hg­(II)-catalyzed spiroketalization of 3-alkyne-1,7-diol motif as a key strategy. This practical synthetic sequence furnished <b>1</b> in 11% overall yield from hydrocortisone in 15 linear steps. Modifications to the parent molecule <b>1</b> encompassed changing the functional groups on rings A and E. Each analogue was screened for their effects on inhibition of cap-dependent translation, and the assay results were used to establish structure–activity relationships. These results suggest that the stereochemistry and all substituents of spiroketal portion (rings E and F) and C3-α and C11-β hydroxyl functional groups on rings A and C, respectively, are critical for the inhibitory activity of natural product <b>1</b>