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

Total Synthesis of (+)-Cassaine Utilizing an Anionic Polycyclization Strategy

A stereoselective total synthesis of (+)-cassaine (<b>1</b>) via an anionic polycyclization methodology is described. Commercially available (+)-carvone (<b>5</b>), the only chiral source, was used to fix the entire stereochemistry of the natural product. Anionic polycyclization of a new substituted 2-(methoxycarbonyl)cyclohex-2-en-1-one (<b>4</b>) with known 1-phenylysulfinyl-3-penten-2-one (<b>3</b>) provided the versatile tricycle (<b>2</b>) with requisite stereochemistry. A sequence of functional group manipulations of tricycle (<b>2</b>) furnished the natural product <b>1</b>

Synthesis of Furo[2,3‑<i>b</i>]pyran-2-ones through Ag(I)- or Ag(I)–Au(I)-Catalyzed Cascade Annulation of Alkynols and α‑Ketoesters

Ag­(I)- or Ag­(I)–Au­(I)-catalyzed cascade annulation of alkynols (5-hexyn-1-ol systems) with α-ketoesters involving a dual activation process (π and σ) has been developed for the first time. This reaction proceeds through cycloisomerization of alkynol to give the 6-<i>endo</i>-enol ether followed by annulation with an α-ketoester to furnish furo­[2,3-<i>b</i>]­pyran-2-ones in good yields. Chemical structures of all products were rigorously confirmed by single crystal X-ray analysis and analogy

Anionic Polycyclization Entry to Tricycles Related to Quassinoids and Terpenoids: A Stereocontrolled Total Synthesis of (+)-Cassaine

A full account of our anionic polycyclization approach to access highly functionalized tricycles related to quassinoids and terpenoids from several optically active bicyclic enone systems and Nazarov reagents is presented. (+)-Carvone is the only chiral source used to fix the entire stereochemistry of all of the tricycles, and the stereochemical outcome of this process was unambiguously determined by X-ray crystallographic analysis. The utility of this strategy was demonstrated by the stereocontrolled construction of advanced tricycles related to the highly potent anticancer natural product bruceantin, a member of quassinoid family, and the total synthesis of the cardioactive terpenoid (+)-cassaine, a nonsteroidal inhibitor of Na⁺-K⁺-ATPase

Total Synthesis of (+)-Cassaine Utilizing an Anionic Polycyclization Strategy

A stereoselective total synthesis of (+)-cassaine (<b>1</b>) via an anionic polycyclization methodology is described. Commercially available (+)-carvone (<b>5</b>), the only chiral source, was used to fix the entire stereochemistry of the natural product. Anionic polycyclization of a new substituted 2-(methoxycarbonyl)cyclohex-2-en-1-one (<b>4</b>) with known 1-phenylysulfinyl-3-penten-2-one (<b>3</b>) provided the versatile tricycle (<b>2</b>) with requisite stereochemistry. A sequence of functional group manipulations of tricycle (<b>2</b>) furnished the natural product <b>1</b>

Four-Step Total Synthesis of (+)-Yaoshanenolides A and B

A highly concise bioinspired four-step total synthesis of yaoshanenolides A and B possessing tricyclic spirolactone with an unusual 5′<i>H</i>-spiro-[bicyclo­[2.2.2]-oct­[2]­ene-7,2′-furan]-5′-one scaffold is reported. This synthesis features high-yielding aldol-type addition of γ-butyrolactone on to the aldehyde, exocyclic olefination of lactone derivative using Eschenmoser’s salt, and highly facial- and endo-selective [4 + 2]-cycloaddition of fully functionalized 5-methylene-2­(5<i>H</i>)-furanone with natural <i>R</i>-(−)-α-phellandrene. The approach allows access to yaoshanenolides A and B in four linear steps in 11 and 13% overall yield

The stereoselective total synthesis of (6S)-5, 6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one via Prins cyclization

The stereoselective total synthesis of an antiproliferative and antifungal α-pyrone natural product (6S)-5,6-dihydro-6-[(2R)-2-hydroxy-6-phenylhexyl]-2H-pyran-2-one is described. The key steps involved are the Prins cyclization, Mitsunobu reaction, and ring-closing metathesis reaction

Total synthesis of aculeatins A and B from L-malic acid

An efficient total synthesis of the cytotoxic spiroketal natural products aculeatin A and B is described. The synthesis of the 1,3,5-triol moiety with appropriate configuration was accomplished from the commercially available L-malic acid. The key steps in this synthesis are the Barbier allylation, LiAlH4/LiI-mediated syn-stereoselective 1,3-asymmetric reduction, and phenyliodine bis(trifluoroacetate) (=[bis(trifluoroacetoxy)iodo]benzene; PIFA) mediated oxidative spirocyclization

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>