Bioisosteric Replacements

Phosphate Bioisosteres

Phosphates play a critical role in biology, from critical structural elements of DNA and RNA, essential components of energy transfer to an important role in cell signalling via protein phosphorylation modulated by a vast array of kinases and phosphatases. As such they are important targets for a wide variety of therapeutic targets.

The Phosphate group provides a number of critical challenges for bioisosteric replacements, perhaps most notably simple alkyl phosphates have two ionisations relevant at physiological pH. The first ionisation is around 1.5 and the second around 6.3. Dialkyl phosphates have a single ionisation with a pKa of around 1.3. Thus these groups are always negatively charged at physiological pH.

The simplest bioisosteric replacement is to replace phosphate with phosphonate, in which the ether oxygen is replaced by carbon, this change has a small but significant effect on pKa, and the effect on the second ionisation may be critical for biological recognition, but does improve metabolic stability.

The replacement of oxygen by carbon has also been explored in a series of analogues of Adenosine Triphosphate (ATP) by Blackburn et al DOI. Whilst replacement of the ether oxygen improved stability it was felt that replacing a polar oxygen with methylene was not optimal. A series of analogues were prepared in which the methylene was substituted by halo, these analogues certainly modulated the pKa closer to that found in ATP.

This approach has been used to investigate the role of phosphoserine DOI in kinase mediated signal transduction, the pCF2-Ser results in a constitutive phosphorylation.

Acyclovir is a guanosine analogue antiviral agent, It is selectively converted into acyclo-guanosine monophosphate (1, acyclo-GMP) by viral thymidine kinase, is further phosphorylated into the active triphosphate form, acyclo-guanosine triphosphate (2, acyclo-GTP), by cellular kinases which has approximately 100 times greater affinity for viral than cellular polymerase. As a substrate, 2, acyclo-GTP is incorporated into viral DNA, resulting in premature chain termination. The phosphonate analogue 3 has been prepared and shown to have significant antiviral activity, it is assumed to be that they are phosphorylated further in cells to their diphosphates. http://www.ncbi.nlm.nih.gov/pubmed/1648622

The tetrahedral sulphates, and sulphonates have been used as phosphate bioisosters, the simple alkyl analogues have pKas in the range -3.4 to -1.9 and are thus fully ionised at physiological pH. Sulphamates are much weaker bases pKa = 15, but convertion to an acyl sulphamate increases the acidity.

This has been used for a series of PTP 1B inhibitors DOI

These have been extended to cyclic analogues such as isothiazolidinone DOI and thioureas DOI

Alendronic Acid is an example of a bisphosphonate drug used to prevent bone mass, they are thought to mimic pyrophosphate, bisphosphonates act on bone metabolism by binding and blocking the enzyme farnesyl diphosphate synthase (FPPS).

L-690330 is a bisphosphonate-containing inhibitor of inositol monophosphatase that has been evaluated in vitro and in vivo (http://www.ncbi.nlm.nih.gov/pubmed/8380439).

Carboxylic acids have also been used as replacements for phosphates, however they are planer rather than tetrahedral in geometry. Other carboxylic acid bioisosteres may also be useful.

Worth reading,

The use of phosphate bioisosteres in medicinal chemistry and chemical biology DOI

Structure-based drug design of new leads for phosphatase research (http://www.ncbi.nlm.nih.gov/pubmed/17285463)

Last Update 18 June 2012