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Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemical assays. Characterization of the library in terms of physicochemical properties, structural diversity, and similarity to compounds in publicly available libraries indicates that the Canvass library contains many structural elements in common with approved drugs. The assay data generated were analyzed using a variety of quality control metrics, and the resultant assay profiles were explored using statistical methods, such as clustering and compound promiscuity analyses. Individual compounds were then sorted by structural class and activity profiles. Differential behavior based on these classifications, as well as noteworthy activities, are outlined herein. One such highlight is the activity of (-)-2(S)-cathafoline, which was found to stabilize calcium levels in the endoplasmic reticulum. The workflow described here illustrates a pilot effort to broadly survey the biological potential of natural products by utilizing the power of automation and high-throughput screening.

Conformational properties of epothilone are discussed. Epothilones are produced by myxobacterium Sorangium cellulosum and are macrolide nitural products. They mimic the biological activity of the anticancer agent Taxol and bind tubulin. Better understanding of epothilone and analogues may lead to rational design of microtubule-stabilizing new compounds.

A study was conducted to analyze the preparation of epothilone A. Reactions were carried out under an atmosphere of nitrogen or argon using flame-dried glassware. The acetate was then dissolve din anhydrous diethyl ether. Experimental results indicated practical pathways to two synthetic precursors to epothilone A. The compounds support critical information on the conformation of epothilones bound to microtubules.

Diastereoselective chelation of the enolate containing the remote chiral auxiliary (S)-2-(methoxymethyl)pyrrolidine facilitated the controlled ester enolate alkylation leading to the synthesis 3-substituted 3-carbomethoxy-2-exo-methylenecyclohex-5-en-1-ones. The alkylations of the corresponding hexadienes proceeded via a bimolecular nucleophilic substitution process. Furthermore, the coordination between the enolate's alkali metal cation and the chiral auxiliary's nitrogen and oxygen atoms generated the observed stereocontrol.

An efficient, convergent synthetic strategy is developed that has enabled the preparation of a series of naturally occurring isotactic polymethoxy compounds. Ether transfer followed by a hydride workup has enabled simultaneous, diastereoselective production of two methoxy centers in a single step.

A study was done on an asymmetric control involving photochemistry of a 4-(3'-butenyl)-2,5-cyclohexadien-1-one in the solid state. It was shown that that competing and nearly isoenergetic unimolecular photocycloadditions can be selectively partitioned in the solid state as a result of the availability of effective reaction volumes. Installation of a chiral auxiliary provides an opportunity for desymmetrization of the 2,5-cyclohexadien-1-one ring.

Stereoselective synthesis of trans-2,6-disubstituted-3,4-dihydropyrans is achieved from a simple homoallylic alkoxyether through a three-step sequence, including electrophile-induced ether transfer, cyclization and functionalization. This method is implemented for the asymmetric synthesis of a C7-C17 fragment of swinholide A.

A design for analogues of complex polyketide macrolides to investigate the effect of conformation on biological activity is proposed. A combination of computational methods and high field NMR experiments were carried out to study the conformational properties of the epothilones.

The synthesis of two deoxygenated analogues of potent epothilones is reported in an effort to analyze the relative importance of molecular conformation and ligand-target interactions to biological activity. 7-deoxy-epothilone D and 7-deoxy-(S)-14-methoxy-epothilone D were prepared through total synthesis and shown to maintain the conformational preferences of their biologically active parent congeners through computer modeling and nuclear magnetic resonance (NMR) studies. The significant decrease in observed potency for each compound suggests that a hydrogen bond between the C7-hydroxyl group and the tubulin binding site plays a critical role in the energetics of binding in the epothilone class of polyketides. [ABSTRACT FROM AUTHOR]

Author(s): Richard E. Taylor [1] Organic Letters American Chemical Society. Biweekly. $2,926 (), $2,560 (), $25 (), $154 () [illus. 1] Interdisciplinary research has led to the creation of new [...]

A method for the synthesis of a general taxane precursor, an aldehyde bearing the complete carbon framework and oxygenation pattern of the A- and B-rings of Taxol, was developed. The technique utilizes verbenone as the starting material and completes the synthesis in 14 steps. The resulting aldehyde was characterized as having fully differentiated functionalities which allow the addition of side chains at C13, esters at C2 and a range of C-ring or seco C-ring variants at the C4 carbonyl.

A novel 37-step procedure for the elaboration of taxanes was developed. The method utilizes pinene which provides the complete A- and B-ring fragments and an aldol closure which establishes the C-ring. The technique results to the formation of taxol in the correct enantiomeric form with the use of verbenone, the air-oxidation product of pinene as the starting material. The new method is the shortest one available to date which offers the advantage of giving more concise access to key analogues.