Chemistry Unprotected

The ideal total synthesis of a natural product would proceed in one step and in 100% yield from commercially available starting material- this dream is increasingly driving natural product synthesis as a science.

Dr. Phil Baran and colleagues at Scripps Institute, La Jolla, California, promises to generate natural products in much larger amounts than conventional methods, making biological testing much easier for drug discovery scientists. Most total syntheses make liberal use of protecting groups. Adding and removing protecting groups can add many steps to a synthesis, cutting overall yields drastically.

Baran's team have now made a collection of marine natural products without using a single protecting group. Instead, they take advantage of the intrinsic reactivity of the molecule's different functional groups.

Fig(-)-fisherindole to (+)- welwitindolinone.

The reactions were enatioselective and they made only the preferred mirror-image form, or enantiomer, of the molecule, instead of a racemic mixture containing equal amounts of both enantiomers. This methodology takes advantage of the intrinsic reactivity of the molecule's different functional groups.

Why are we made of only left-handed amino acids? A molecular concept of Life.

Most biomolecules are "chiral", that is to say, they exist in two left and right-handed mirror-image forms. However, biology only uses one hand, i.e., it is "homochiral". Life on Earth is made of left-handed amino acids, almost exclusively. One of the greatest puzzles in biophysics is the question of why life on Earth is based on left-handed (L) amino acids? Moreover, the synthesis of single enantiomers (ee ~100%) is one of the most critical industry demands.

Recently Prof. Pedro Cintas described that fractional sublimation of chiral organic compounds improves ee substantially.

The reported results provide a beneficial protocol for the resolution of racemates. Additionally, it suggests that improvement of optical activity by such a thermal process could be more efficient than or at least an alternative to spontaneous crystallization of suitable compounds.

He conclude that sublimation should be regarded as a reasonable mechanism for the formation of optically active crystals in the prebiotic world. Subsequent stochastic sorting of crystals of enantiopure compounds by natural agents might have generated highly enantiopure niches, which might be responsible for the prevalence of homochirality in nature.

Molecular evolution might lead to life, but it is not scientifically valid because life is a non-physical, non-chemical entity.

The Histamine H4 Receptor: Drug Discovery in the Post-genomic Era

The Histamine H4R receptor is the most recently identified G-protein coupled receptor, with little homology to the classical pro-inflammatory histamine H1 or the histamine H2 receptor, and some 35% homology with H3 receptor.

 The high expression of the histamine H4 receptor in cells of hemopoietic lineage and immune cells suggests that this new histamine receptor plays a role in inflammatory and immune responses. Activation of the Histamine receptor can mediate calcium mobilization and chemotaxis in mast cells.

Preliminary studies on the H4R and specific antagonist (JNJ 7777120 - Johnson & Johnson, VUF6002-Janssen Pharma.) suggest another rich vein of histamine receptors therapeutics, likely to generate more blockbusters and medical breakthroughs, could be on the horizon.

Ref: Nature Reviews Drug Discovery, 7, 41-53, 2008, Trends Pharmacol. Sci. 26, 462-469, 2005.

Novel Reactions: Are anymore waiting to be Discovered?

Inspired by Barton's landmark total synthesis of Usnic acid, a method was devised by Baran for the direct oxidative coupling of indoles and pyrroles to a range of carbonyl compounds (Baran et al., J. Am. Chem. Soc. 2007, 129, 12857-69).

When one examines the piece of work to which such a description has been applied, it often contains only a minor improvement on a well-known reaction or a new application of an old technique.

Fluorine in Drug Discovery

The importance of Fluorine in medicinal chemistry is well recognized. Indeed, an increasing number of drugs on the market contain Fluorine, the presence which often is of major importance to activity. A recent review article (Chem. Soc. Rev., 2008, 37, 320) by Sophie Purser describes the role of Fluorine in medicinal chemistry.

Replacement of hydrogen with Fluorine (F) in a pharmacologically active molecule can profoundly change the conformational preference due to its size difference and stereoelectronic effects.

1) F can enhance binding efficacy and selectivity in pharmaceuticals.

2) F substituents on ligands prefer to orient toward electropositive regions of receptor sites.

3) Distinct fluorofilic environment in proteins includes the ubiquitous peptide bonds, which undergo multipolar C-F…H-N, C-F..C=O and C-F..H-C interaction.

Systematic fluorine scans of ligands is a promising strategy during the lead optimization stage of drug discovery. Fluorine substitution enhances physicochemical and adsorption, distribution, metabolism, and excretion properties and strengthens protein-ligand binding interaction.

The effects of Fluorine substitution expands, further applications in drug discovery will emerge. 

Modern fluorine organic chemistry has dramatically widened the synthetic repertoire for the specific introduction of Fluorine in an organic molecule.