Effect of Phosphate Group Druggability of Compounds

Phosphate is an important part of nucleic acid, a large number of which exists in the human body, it is a kind of harmless endogenous substances, which can help drugs to improve water solubility and transport to cells, so it is an excellent small molecular carrier. It can even improve the biological and physical properties of the drug, reduce toxic and side effects, so as to improve the medicinal properties of the drug. At present, the main prodrugs of phosphate on the market include adefovir dipivoxil, tenofovir disoproxil fumarate and so on, as shown in figure 1.

Fig 1. Structure of adefovir dipivoxil and tenofovir disoproxil fumarate

This paper introduces the effect of phosphate group on drug properties from the following aspects.

  • Improve drug selection.

Traditional antineoplastic drugs not only kill tumor cells, but also attack the surrounding normal tissue cells, so they generally have greater toxic and side effects. Studies have shown that the content of phosphatase in tumor cells is higher than that in normal cells, so pharmacologists assume to make antineoplastic drugs into phosphate prodrugs in order to improve the release of their target organs. When the antineoplastic drugs enter the tumor tissue, the active antineoplastic drugs are released after hydrolysis under the action of phosphatase, thus increasing the concentration of active components in the tumor tissue and reducing the concentration in the normal tissue. For example, the Estramustine has poor selectivity to prostate cancer. After the introduction of phosphate ester group, the selectivity to prostate cancer is significantly improved and the toxicity and side effects are reduced.

Fig 2. Structure of Estramustine and Estramustine phosphate

  • Improve drug compliance.
    On the basis of the original drug, the introduction of phosphate group to prepare the prodrug can also reduce the discomfort to the patients and improve the drug compliance to a certain extent. For example, clindamycin injection generally causes severe pain, and oral administration taste bitter, easy to cause gastrointestinal reactions, and clindamycin into clindamycin phosphate ester, water solubility can be improved, can be injected intravenously, alkaline phosphatase in the blood quickly hydrolyzed to clindamycin, to avoid oral medication caused by taste discomfort and gastrointestinal reactions.

Fig 3. Structure of clindamycin and clindamycin phosphate ester

  • Improve water solubility.

On the basis of phenytoin, phosphate group was introduced to obtain phenytoin sodium, which increased the water solubility of the original drug (140mg·mL-1). The aqueous solution of 50 mg·mL-1 could be injected intravenously or intramuscular injection, which greatly overcome the adverse reactions caused by the clinical application of phenytoin and eliminate the drug-drug interaction of phenytoin.

Fig 4. Structure of phenytoin and Fosphenytoin sodium

  • Improve bioavailability.

Amprenavir has strong antiviral activity and good drug resistance, and has strong inhibitory activity against HIV. However, the lipophilicity of Anrenavir is high, and its bioavailability is limited by the administration of crystalline solids. The preparation must contain a high proportion of organic excipients to promote its dissolution in the stomach. Therefore, the single dose of the drug is usually given in the form of soft capsule formula and multiple tablets, which brings inconvenience to the patients. However, after the introduction of phosphate group into its structure, the water solubility and solid stability of fosamprenavir were significantly improved. It could be quickly absorbed by gastrointestinal epithelial cells and transformed into amprenavir.

Fig 5. Structure of amprenavir and fosamprenavir

  • Improve fat solubility.

Stavudine (logP=-0.59) is a kind of anti-HIV drug with good selectivity. The drug needs to be converted to monophosphate under the action of adenosine kinase, and then diphosphorylation and triphosphorylation can achieve antiviral pharmacological activity. However, the polarity of stavudine and its phosphorylation products are relatively large, so it is difficult to reach the acting site. In order to improve its fat solubility, drug researchers introduced phosphate group into its structure, which greatly improved the fat solubility of the drug and the ability of the drug to penetrate the cell membrane (logP=2.15). At the same time, it also improved the phosphorylation degree and selectivity of stavudine.

Fig 6. Structure of stavudine and stavudine phosphate ester

The introduction of phosphate group on the basis of the original drug not only improves the selectivity of the drug, reduces its side effects, but also improves the solubility, provides a variety of ways of drug delivery, and greatly increases the druggability of compounds.


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