Rule of attraction

The role of fluorine in Ligand – Protein interaction has been well studied, but much less known about the non-bonding interaction of chlorine and bromine with protein.
A new paper (Angew. Chem. Int. Ed 2009, 48, 2911) from Matter demonstrates the non-covalent interaction between the chlorine or bromine and the aromatic ring in protein.



This Cl/Br…pi interaction might be general use in structure based design towards interaction for aromatic amino acids. It is clear that systematic halogen scan (F, Cl and Br) in the lead structure will be a useful strategy for the lead optimization, not only block the metabolic labile position but also to strengthen protein-ligand binding interaction.

Fluorine in Drug Development

The drug development process (fig. 2) is a lengthy, high risk and costly endeavor; many strategies exist to accelerate the target to clinical candidate selection as well as to provide the highest quality of the candidate. Fluorine and its isotope have many role in the different phases of drug development process. The number of fluorine containing drugs are growing rapidly which include the best selling drugs such as Atorvastatin, Prozac, Ciprobay and Pantoprazole (fig.1).

Target identification:

PET is a nuclear medicine imaging tool that allows three-dimensional quantitative determination of the distribution of radioactive with in the human body. The relatively long half-life, high % of β emission, and relatively low positron energy 18 F make it is most favorable for the Positron Emission Tomography (PET) studies. F MR - Fluorine Magnetic Resonance. allows detection of the presence of the target, in vivo, including assessment of the presence of targets, as well as quantification of their spatial and temporal distribution.

F MR - Fluorine Magnetic Resonance. 

PET- Positron Emission Tomography. 

Lead Finding: Once the target is chosen and identified, and the next stage is typically high-throughput screening of large libraries of chemicals for their ability to modulate the target. F M R allows compound screening using cell-based and animal-based assays (whereas HTS is restricted to cell-based assays). Fluorine plays an important role in the physicochemical properties (see lead optimization) of the molecule, so the HTS screening of fluorine-containing libraries will help for the lead finding. 

Lead Optimization: The small and highly electronegative fluorine atom can play a role in medicinal chemistry. Systematic fluorine scan of ligands is a promising strategy in lead optimization. It not only helps to enhance the physicochemical properties but also to strengthen Protein-Ligand binding interaction. This would make the molecule a safer candidate. 

The current strategies for introducing fluorine atoms into molecules are centered to 

1. Improve metabolic stability,

2. Alter physicochemical properties such as pKa and lipophilicity, dipole moment, and even the chemical reactivity and stability of the neighboring functional groups,

3. Enhance the binding efficacy and selectivity in pharmaceuticals, and

4. Bioisosterism. 

Preclinical and Clinical Studies: The suboptimal pharmacokinetics and pharmacodynamic can lead up to 40% of the drug candidate failing to make it to phase 1 trial. PET can allow assessment of parameters such as drug absorption biodistribution, metabolism, delivery, and dose uses in preclinical studies and can help in systematic planning latter phases. The estimation of pharmacological agents to reach their targets is important in drug trials. This can be done by the ADME techniques based on blood or tissue harvesting and subsequent drug and metabolite analysis. This approach is less than perfect because plasma levels of the compound often do not reflect concentrations in a specific tissue because of the presence of physicochemical barriers such as between blood and brain. Proton Emission tomography provides a reliable measure of tissue drug concentration. 

References 

1) Muller. K et al., Science. 317, 2007, 1881. 

2) Reid G. D et al., Drug discovery today. 13, 2008, 473. 

3) Willmann J. K. et al., Nature reviews drug discovery. 7, 2008, 591.

The rule 2-0

Recently, Aronov from Vertex pharmaceuticals proposed a general ‘rule of thumb’ termed the 2-0 rule for kinase likeness to discriminating kinase inhibitors from the nonkinase molecules.

For kinase activity, the molecule should have

1) One or more heteroaromatic nitrogen’s,

2) One or more heteroaromatic NH group,

3) It contains one or more aniline, and 

4) It contains one or more nitriles.

Around 78% of the kinase compound passes the 2-0 rule.

Are Protein Kinases Drug Targets?

Kinases catalyze the transfer of phosphate groups from phosphate-donating molecules (like ATP) to other molecules. They have been intensively investigated as drug targets for many years. Around 20-25% of the druggable genome consists of kinases, and this target accounts for 20-30% of many companies' drug discovery programs.

Several protein kinase inhibitors have been approved by FDA and available in the market which includes Tykerb®, Sprycel®, Sutent®, Nexavar®, Tarceva®, Iressa®, and Gleevec®. Many other kinase inhibitors are currently undergoing clinical development. This accelerated the research and development in this area, reflecting the number of search results for 'kinase inhibitors'. Sci-finder keyword search resulted in 1281 patents, which is filed in 2007 alone. Drug and Market Development’s (D&MD) report (2005) shows that kinase targeted therapies growing from $12.7 billion in 2005 to $58.6 billion in 2010. 

 

So what is the problem with kinases? The lack of selectivity for targeting a specific kinase is the issue due to the similarity of other kinase targets. For example, the natural product substrate Staurosporine hits almost every kinase out there will be gratuitously toxic. However, the real problem with kinase inhibitors is the toxic outcomes may result from tissue distribution of orally administered kinase inhibitors.

 

Kinases are drug targets. But, difficult ones.

Phosphonium Coupling

A recent review article,Eur. J. Org. Chem. 2009, 461-479 by Kang F. et al., describes a new, efficient, chemoselective and versatile phosphonium mediated tautomerization-activation methodology for tautomerizable heterocycles.

Phosphonium Coupling affords the direct C-N, C-S, C-O and C-C bond formation of electron deficient heterocycles with various nucleophiles (with boronic acid for C-C) via C-OH bond activation using phosphonium salts.
The author believes that the reactivity of the C-OP+ is similar to that of C-Br, so that direct bond formation can be achieved via either SNAr displacement or transition metal catalyzed cross coupling under mild condition.


This Phosphonium Coupling leads to the most efficient synthesis of biologically important nucleosides from unactivated, unprotected, commercially available starting materials.