Kill the Bugs, Selectively

“Today, we have tuberculosis drugs you have to take for nine months, why can’t we find one that works in three days” - Bill Gates. 

Tuberculosis (TB) is a chronic contagious disease caused by  Mycobacterium tuberculosis (M.tb), one of the leading causes of death worldwide. The WHO estimates about one-third of the world’s population is infected with M.tb, 10% of those infected will progress to active TB disease during their lifetime. The tuberculosis pandemic has been declared a global health emergency as the growing resistance of M.tb to Antibiotics coincides with the spread of risk factors such as HIV/AIDS and diabetes. TB is a complex disease. The current TB drug regimen, a product of scientific advances of the 1960s, requires six to nine months of treatment for active, drug-susceptible TB. Unfortunately, many patients do not or cannot complete this treatment. Poor adherence and prescribing practices have led to the emergence of multi- and extensively drug-resistant strains of TB (MDR-TB and XDR-TB) that increasingly defy current medicines and spread throughout many regions of the globe. The incidence of MRD- and XRD- TB demands renewed efforts to develop a novel class of fast-acting anti TB chemotherapeutics.

 

Mycobacterium tuberculosis is one of the few bacterial species with a proteasome. A team of scientists led by researchers from Weill Cornell Medical College  has found that some oxathiazolone compounds kill tuberculosis-causing bacteria by selectively inhibiting mycobacterial proteasomes without affecting human proteasomes. These compounds were showing no apparent toxicity to mammalian cells. The oxathiazolone compounds are the first example of an anti-tubercular agent that inhibits protein breakdown. The ability of brief exposure to oxathiazol-2-one compounds to inhibit M.tb proteasomes permanently makes it a potential target for anti-TB therapy. These  findings  may lead to drugs that destroy TB in the dormant stage of the lifecycle.

Tamiflu

A new strain of swine flu, an H1N1influenza virus, is spreading around the globe. The WHO has declared the novel H1N1 influenza virus (swine flu - 2009) outbreak a global pandemic - First Phase 6 Influenza pandemic since 1968.

(_)-Oseltamivir phosphate (Tamiflu), a neuraminidase inhibitor used to treat both type A and type B human influenza. Currently, it is the most effective drug for the treatment of Influenza. However, the unmet supply of this drug demands urgent solutions. The manufacture of Tamiflu by Roche Company utilizing naturally occurring shikimic acid as the starting material. Getting stable quality of pure shikimic acid may be problematic. 

The Tamiflu supply problem has piqued the attention of academic chemists. Several labs have already reported new methods for making Tamiflu without shikimic acid. However, it is challenging to evaluate academic syntheses from the standpoint of potential as a manufacturing process because they have not been developed for large-scale operation. Considering the amount of Tamiflu required worldwide, there is an urgent demand to improve the production process.

Here is the retrosynthetic analysis for the shortcut synthesis of Tamiflu. This synthesis initiated by oxa-Michael addition of alcohol to acrolin, which was reported by Zhang et al,

Going Right-handed

Why are we made of only right-handed sugars? That has long been one of the biggest puzzles in understanding how life began, and this origin of homochirality in sugars and amino acids has been intrigued researchers for decades. So for convincing theory and experiment on the origin of homochirality are still lacking.

Armando Co´rdova and coworkers at Stockholm University, Sweden, used amino acid as a catalyst for the formation of hexoses sugars with >99 ee. Hexose’s have been suggested as building blocks of ancient RNA. It may be an example of the theoretical basis for the evolution of sugars' homochirality (right-handed configuration) in the prebiotic world.

Andrew Pohorille and Chenyu Wei at NASA Ames Research Center found that ribose permeates membranes an order of magnitude faster than its diastereomers. On this basis, it was hypothesized that differences in membrane permeability to aldopentoses provide a basis for preferential delivery of ribose to primitive cells for subsequent selective incorporation into nucleotides and their polymers.

D ribose (right-handed sugar) polynucleotide tends to form right-handed helices; what is the neutral macroscopic cause that gave rise to the preference of both right-handed helical nucleic acids and proteins on Earth? 

Y J He et al suggested that a net natural chiral right-handed helical force field, produced by the Earth’s orbital chirality (EOC) could affect the stability of molecule helical enantiomers and make the right-handed helical enantiomers more stable than their left-handed enantiomers. So, terrestrial living systems must select right-handed nucleic acids based on D-sugars and right-handed proteins based on L-amino acids.

This homochirality can be observed on the macroscopic scale, for example, the helical chirality of snail shells (preferred right-handed) and the helical winding of some kind of plants. 

Maybe a complete understanding of life and its evolution will never be possible. However, this will not certainly stop scientists from seeking the secret of the origin of life. Whitesides recently expressed the current state of understanding of the origin of life in frank words,

"Most chemists believe, as do I, that life emerged spontaneously from mixtures of molecules in the prebiotic Earth. How? I have no idea. Perhaps it was by the spontaneous emergence of “simple” autocatalytic cycles and then by their combination. On the basis of all the chemistry that I know, it seems to me astonishingly improbable." 

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GABA receptors as RA and Pain Targets? The Missing Link

Kelley et al. proposed a hypothesis for an inefficient GABA signaling system that resulted in unchecked pro-inflammatory cytokine production via the p38 MAP kinase pathway. p38 is a kinase target that regulates the production of inflammatory cytokines TNF, IL-1, IL-6, and PGE2. TNF, IL-1, and IL-6 are well-validated cytokines for controlling inflammation in rheumatoid arthritis (RA), and PGE2 is an essential mediator for inflammatory pain. However, most of the p38 projects failed to deliver drugs due to CNS toxicity. Are these CNS side effects linked to GABA? 

The research team led by Ulrich Zeilhofer used genetically altered mice in experiments to target the GABA receptors that control spinal pain relay. They showed that the non-sedative benzodiazepine ligand L- 838417 (a GABA receptor ligand) is highly effective against inflammatory and neuropathic pain. Clomethiazole edisilate is a drug that acts on GABA receptor, which inhibits the p38 MAPK too. This small molecule does not have other p38 inhibitors' structural features, which seems to support this hypothesis. The task is to find which subtype of GABA responsible for the chronic pain. However, no direct link has been reported between GABA and p38 MAPK. The role of GABA in RA and pain development will encourage further integration of Immunology in clinical neuroscience. These findings may provide a rational basis for developing subtype-selective GABAergic drugs to treat RA and chronic pain.

Drug Optimization

 

Pharmaceutical companies are trying to fill their drug portfolio by optimizing the marketed drugs. Most recently launched drugs are structurally similar to already known drugs, with only minor differences. The most common drug optimization methods are:

1. Reactive metabolites: 

An excellent example of this is venlafaxine (Effexor) and desvenlafaxine ( Pristiq). Desvenlafaxine is the metabolite of venlafaxine. The difference is that desvenlafaxine having O-H instead of O-Me. 

2. Deuterated Drugs: 

Switching a hydrogen atom with a heavier isotope such as deuterium, pharma companies hope that the deuterated drug survives longer in the body and fewer side effects because it can make a stronger chemical bond than hydrogen. 

3. Racemic switching: 

Racemic switching is the redevelopment in a single enantiomer from a first approved drug as a racemate; a better example is the Nexium. It is a predecessor Prilosec, a mixture of both S and R isomers. When Prilosec’s patent expired in 2001, the drugmaker was ready with Nexium, which contains only the S-isomer. 

The proliferation of "me-too" drugs leads to beneficial cost reductions. However, in the end, the real question is about pharmaceutical innovation. While “me too” fills the development pipeline, the creativity is fading away in the art of drug discovery?

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.