Heat shock proteins (Hsps) are molecular chaperones that also play important roles in the activation of the heat shock response (HSR). The HSR is an evolutionary conserved and protective mechanism that is used to counter abnormal physiological conditions, stressors, and disease states, such as those exemplified in cancer and/or neurodegeneration. In normal cells, heat shock factor‐1 (HSF‐1), the transcription factor that regulates the HSR, remains in a dormant multiprotein complex that is formed upon association with chaperones (Hsp90, Hsp70, etc.), co‐chaperones, and client proteins. However, under cellular stress, HSF‐1 dissociates from Hsp90 and induces the transcriptional upregulation of Hsp70 to afford protection against the encountered cellular stress. As a consequence of both peripheral and central neuropathies, cellular stress occurs and results in the accumulation of unfolded and/or misfolded proteins, which can be counterbalanced by activation of the HSR. Since Hsp90 is the primary regulator of the HSR, modulation of Hsp90 by small molecules represents an attractive therapeutic approach against both peripheral and central neuropathies.
The A-D fragment of gambieric acids A and C has been synthesized using an asymmetric Tsuji-Trost allylation reaction to couple the two key segments. The A ring fragment has been prepared by a short and highly efficient route involving diastereoselective Lewis acid mediated alkylation of an acetal. Iterative ring-closing metathesis reactions have been used to construct cyclic ethers and assemble the tricyclic B-D fragment.
Abstract:Complexation of (tricarbonyl)iron to an acyclic diene serves to protect the ligand against oxidation, reduction and cycloaddition reactions while the steric bulk of this adjunct serves to direct the approach reagents to unsaturated groups attached to the diene onto the face opposite to iron. Furthermore, the Fe(CO)3 moiety can serve to stabilize carbocation centers adjacent to the diene (i.e. pentadienyl-iron cations). Recent applications of these reactivities to the synthesis of polyene, cyclopropane, cycloheptadiene and cyclohexenone containing natural products or analogs will be presented.
2-Phenylbenzimidazoles, 2-benzylbenzimidazoles, 2-phenyl-1H-naphtho[1,2-d]imidazole, and 2-benzyl-1H-naphtho[1,2-d]-imidazole have been synthesized in excellent yields (77–98%) by lead tetraacetate oxidation of suitable N-arylbenzamidines, N-arylphenylacetamidines, N-α-naphthylbenzamidine, and N-α-naphthylphenylacetamidine respectively. The mechanism of nitrene insertion and intramolecular competitive nitrene insertion leading to these heterocycles has also been discussed.
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