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.

N-Methylation and Oral Bioavailability.

Inspired by the excellent pharmacokinetic profile of transplantation drug, cyclosporine A (a natural, N-methylated cyclic peptide), which can be administered orally, Kessler reported that multiple N-methylation is a promising way to rationally improve key pharmacokinetic characteristics in peptides.

N-methyl scan of the cyclopeptidic somatostatin analog cyclo(-PFwKTF-), known as the Veber−Hirschmann peptide, improves not only oral bioavailability but also receptor selectivity.

Another interesting question is to what extent might the N methylation contribute to the bioavailability (the ADMET profile) in the amide of small molecules rather than peptides? For example, Tubulin-binding taxanes such as paclitaxel and docetaxel are important cancer chemotherapeutic agents. However, these drugs suffer from limitations such as poor aqueous solubility and oral bioavailability, emerging drug resistance, and the lack of blood-brain barrier permeability.

N-methyltaxol C (methylation of the C3′ amide of taxol C), a potential impurity in clinically used taxanes, showed improved bioavailability. This result demonstrates the utility of N-methylation to improve key pharmacokinetic characteristics in amides.

The making of hERG free molecules (The Role of Fluorine)

The unwanted hERG affinity could be removed by moderating 

1) basicity (control pka),

2) lipophilicity of the compound, and 

3) steric environment of the central nitrogen 

A paper in BMCL from Pfizer reported the pka, lipophilicity, independent optimization of hERG affinity for the CCR5 antagonist ‘Maraviroc’. The steric demand and the dipole generated by the difluoro moiety of 4 4’difluoro cyclohexyl group in maraviroc are clearly not tolerated within the hERG channel.

 

Overcoming hERG affinity in kinesin spindle protein inhibitor MK-0731 for the treatment of Taxane Refractory Cancer was achieved by making axial fluorine in the piperidine ring.

Fluorination of aryl boronic acids

Replacement of C-H bond with fluorine (C-F) has unique advantages in drug development and tracers for Positron Emission Tomography (PET), a powerful technology for noninvasive molecular imaging.

Introducing fluorine group directly onto a saturated ring system is very difficult; also there may be functional groups that are not compatible with fluorination.

Recently, Ritter and co-workers reported a regioselective, functional group tolerant fluorination reaction of aryl boronic acids mediated by palladium complex. This process is ideally suited for introducing fluorine substituents at a late stage for aryl fluoride synthesis.

The rule of three and ADMET

Paul Gleeson from GSK has come up with a set of rules of thumb for the three crucial property of drug namely molecular weight, log P, and ionization state (which medicinal chemist comfortable and familiar with) that influence their ADMET behavior Such as Solubility, Permeability, Bioavailability, Volume of distribution, Plasma protein binding, CNS penetration, Brain tissue binding, P-gp efflux, hERG inhibition, and Cytochrome-P450. This study is vital for the pharmaceutical industry because up to 40 % of promising candidates fail in clinical trials due to unfavorable pharmacological properties in drug development. His study re-emphasizes the need to focus on a lower molecular weight and log P area of physicochemical property space to obtain improved ADMET parameters.