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Synthesis and Small Molecule Exchange Studies of a …
Following Jourdan-Ullmann coupling, sodium borohydride was used in a reductive ring closure reaction to form phenazine- 1-carboxylic acids 2 and 21-32 that are either non-functionalized (i.e., PCA 2) or diversely functionalized in the 6-, 7-, 8- and/ or 9-position(s) of the phenazine heterocycle with fluoro-, chloro-, bromo-, alkyl-, methoxy- or carboxylic acid groups. The success rate of this sodium borohydride reductive ring closure was quite good as we were able to synthesize desired PCA analogues (2 and 21-32) from 13 of the 15 (87%) Jourdan-Ullmann substrates (6-20) synthesized. We were unable to obtain the desired PCA compounds from reductive ring closure of compounds 12 and 18. Substrates 12 and 18 surprisingly yielded PCA 2 as the only observed product due to over-reduction. The average yield for successful ring closing reactions was 44% with a large range of yields (between 1 and 84% yield) during our synthesis of PCA analogues 2 and 21-32.
Novel chiral oxazolyl alanine and homologues are synthesized and utilized as building blocks for the solid-phase parallel synthesis of novel trifunctional oxazole small molecules in good to excellent overall yields and with high purity. The orthogonal deprotection strategy of oxazolyl amino acids, prepared from serine methyl ester and amino acids such as aspartic and glutamic acids, allows multiple sites of diversification to make a variety of pharmacologically relevant small molecules. The general nature of this approach allows the preparation of a large number of small molecules and peptidomimetics.
Synthesis of Large Molecules : Abstract : Nature
The combination of addressable synthetic macromolecules with proteins of precise structure and function often leads to materials with unique properties, as is now shown by the efficient multi-site initiation of polymer growth inside the cavity of a virus capsid.
PCA amide small molecules in particular are promising lead structures for the discovery of new anticancer, anti-tuberculosis and antifungal agents. Future studies will include the screening of these diverse PCA-amide structures in various phenotype and target-based screens. Additionally, PCA-derived amides are ideal for parallel synthesis strategies as (1) several of the phenazine- 1-carboxylic acids we synthesized were scalable to >150 milligrams and (2) we can rapidly synthesize collections of PCA-derived amides from coupling diverse phenazine-1-carboxylic acids with commercially available amines.
Mark discussed “The Synthesis of Large Molecules”
Further diversification of the PCA scaffold was carried out by reacting diphenylphosphoryl azide (DPPA) with 8 PCA analogues, followed by reaction with water to yield 1-aminophenazine small molecules 43-50 (Figure 4) in one-pot. The average yield for the Curtius rearrangement reaction was 41% in our hands. We also acylated three Curtius products (i.e., 1-aminophenazines 43, 45 and 50) with either 3-bromobenzoyl chloride or 4-fluorobenzoyl chloride to give four PCA reverse amide structures 51-54 in 71% average yield.
We are currently using small aromatic molecules that are not expected to disrupt structural aspects of the unmodified RNA, i.e., thiophene, furan, pyrrole, or pyridyl.
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Evaluating enzymatic synthesis of small molecule …
The development of rapid approaches for the synthesis of privileged scaffold inspired chemical libraries is a driving force in drug discovery. Phenazines demonstrate a diverse array of biological activities (e.g. anticancer, antibacterial, antifungal, etc.) thus we consider the phenazine heterocycle to be a privileged scaffold of importance to drug discovery. Here, we have developed a synthetic approach that allows for the rapid preparation of four diverse derivatives of phenazine-1-carboxylic acid (PCA) in 3 to 4 linear synthetic steps from a single, commercially available aniline. This step-economy focused approach takes advantage of the Jourdan-Ullmann/sodium borohydride ring-closure pathway to synthesize a diverse set of PCA small molecules, followed by the rapid using Curtius rearrangements and a series of amidation reactions to generate a library of 35 diverse phenazines.
See also Carbohydrate synthesis Small molecules
Figure 1: Phenazine 1, PCA 2 and PCA derived small molecules 3-5 that demonstrate a diverse array of biological activities against various disease states.
How is custom synthesis performed for small molecules?
Considering the diverse array of biomedical applications for PCA-derived small molecules and the lack of phenazine libraries in drug discovery, we became interested in developing a rapid synthetic approach that focused primarily on the of PCA small molecules. Following careful examination of various synthetic approaches to generate diverse PCA analogues, we determined that using the copper-promoted Jourdan-Ullmann reaction between an appropriately functionalized aniline and 2-bromo-3-nitrobenzoic acid followed by reductive ring closure with sodium would be ideal . We were attracted to this route because of the opportunity to generate highly diverse PCA analogues at the 6-, 7-, 8- and 9-positions of the phenazine heterocycle from commercially available, cost effective aniline building blocks (Figure 2).
Small Molecules | Combichem | Custom Synthesis
Figure 2: Modular and step-economic approach to the synthesis of a diverse collection of PCA derived small molecules for discovery.
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