Inhibition of Hsp90 with Resorcylic Acid Macrolactones: Synthesis and Binding Studies

A series of resorcylic acid macrolactones, analogues of the natural product radicicol has been prepared by chemical synthesis, and evaluated as inhibitors of heat shock protein 90 (Hsp90), an emerging attractive target for novel cancer therapeutic agents. The synthesis involves acylation of an ortho‐toluic acid dianion, esterification, followed by a ring‐closing metathesis to form the macrocycle. Subsequent manipulation of the protected hydroxymethyl side chain allows access to a range of new analogues following deprotection of the two phenolic groups. Co‐crystallization of one of the new macrolactones with the N‐terminal domain of yeast Hsp90 confirms that it binds in a similar way to the natural product radicicol and to our previous synthetic analogues, but that the introduction of the additional hydroxymethyl substituent appears to result in an unexpected change in conformation of the macrocyclic ring. As a result of this conformational change, the compounds bound less favorably to Hsp90.     

Synthesis of 1-deoxysphingosine derivatives with conformationally restricted pyrrolidinediol head groups

[structure: see text] A family of cyclic 1-deoxysphingolipid derivatives of structure 4 has been designed and synthesized, which may serve as tumorigenesis suppressors for various cancers. Compound 4 is a second-generation analogue developed from sphingosine (1), in which a hydroxyl substituent is moved from C1 to C5 and a methylene is added for conformational rigidity between the C2-nitrogen substituent and C4. The synthetic chemistry for pyrrolidine ring closure at C3-C4 features ring-closing metathesis followed by hydroboration-oxidation.     

The synthetic challenge of diazonamide A, a macrocyclic indole bis-oxazole marine natural product

The complex structure of the marine metabolic diazonamide A comprises a dichlorinated indole bis-oxazole heteroaromatic fragment, and a [b]-fused dihydrobenzofuran-dihydroindole unit containing an animal carbon, all incorporated within a strained double macrocyclic array. This review details the synthetic studies on this fascinating natural product starting from early studies on the original structure (1991-2001), through the synthesis of the originally proposed structure and the subsequent structural revision, to the eventual successful syntheses of the natural product itself. Throughout we focus on the innovative ways in which synthetic chemists have approached the challenges posed by this natural product.     

Irreducible representations of Virasoro-toroidal Lie algebras

Toroidal Lie algebras and their vertex operator representations were introduced in [MEY] and a class of indecomposable modules were investigated. In this work, we extend the toroidal algebra by the Virasoro algebra thus constructing a semi-direct product algebra containing the toroidal algebra as an ideal and the Virasoro algebra as a subalgebra. With the use of vertex operators and certain oscillator representations of the Virasoro algebra it is proved that the corresponding Fock space gives rise to a class of irreducible modules for the Virasoro-toroidal algebra.To A. John Coleman on the occasion of his 75th birthday     

Frequency discrimination in the monkey

This study evaluated frequency discrimination ability in 11 monkeys over an extended period of time using a repeating-standard procedure and the method of constant stimuli. The intersubject variability of the difference limens for frequency (delta F) was large, as reported by other investigators, but similar in magnitude to the variability of the difference limens for intensity (delta I) from three of the same subjects in an intensity discrimination experiment. Continued training generally resulted in a rapid decrease in delta F's, followed by a longer-term, slower decrease. For one subject delta F's slowly decreased throughout a 190-week time period. This long-term training effect was specific to frequency discrimination; a similar effect was not observed for the same subject tested in an intensity discrimination experiment. Finally, delta F's from the well-trained monkeys of this study were larger than monkey delta F's from this laboratory reported in an earlier study, and than human delta F's. An anatomical explanation for the human/monkey delta F magnitude difference is explored.