Prodrugs strategies

De Clercq E, Eield H J (2006) Antiviral prodrugs - the development of successful prodrug strategies for antiviral chemotherapy. Brit J Pharmacol 147 1-11 De Clercq E, Hol A, Rosenberg I, Sakuma T, Balzarini J, Maudgal PC (1986) A novel selective broad-spectrum anti-DNA virus agent. Nature 323 464 67 De Clercq E, Sakuma T, Baba M, Pauwels R, Balzarini J, Rosenberg I, Hol A (1987) Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines. Antiviral Res 8 261-272... 

Borchardt, R. T., Optimizing oral absorption of peptides using prodrug strategies, J. Controlled Release 1999,... 

Scheme 3 Releasable PEGylation based on 1,6-benzyl elimination prodrug strategy...

Fig. 2. Ligand substitution as a prodrug strategy for metallochem-otherapeutics (a) general scheme of prodrug activation by ligand substitution hydrolysis of a metal—halide bond is a typical activation pathway of metal-based anticancer drugs, as exemplified by the activation of cisplatin (b) and a ruthenium—arene complex (c).

Fig. 3. Photoactivation of Pt(IV) complexes as a prodrug strategy for metallochemotherapeutics (a) general scheme of prodrug activation by photoreduction (b) photosubstitution and photoisomerization are competing photoreaction pathways, which can result in different reactive species upon reduction (c) an example of a photoactive platinum(IV) diazido complex developed in our lab.

The oral absorption of an entirely different class of drugs, namely bisphosphonates, has also been improved by a peptide prodrug strategy [36]. The drugs pamidronate (6.13, n=2) and alendronate (6.13, n=3) were deriv-atized with the Pro-Phe-dipeptidyl unit to yield the prodrugs Pro-Phe-pamidronate (6.14, n=2) and Pro-Phe-alendronate (6.14, n=3), the ob-... 

Tumor cells express many hydrolytic enzymes, particularly peptidases, some of which are partially specific for certain tumor types, e.g., plasmin, plasminogen activator protease, and cathepsins. A number of prodrug strategies have been developed for the tumor-selective delivery of cytotoxic drugs [45-47], as illustrated below with a few representative examples. 

Coumarinic acid is another phenylpropanoic acid pro-moiety used to prepare double prodrugs of amines (in analogy with the phenylpropanamides shown in Fig. 8.23), as well as cyclic prodrugs of a number of peptides (8.189) [242-246], These studies confirm the considerable potential of the cyclic prodrug strategy, such compounds being characterized by metabolic stability to peptidases and good cellular permeation. 

Figure 13.12. Schematic representation of enzyme-mediated targeting of enkephalin using a prodrug strategy.

Chan, O.H., et al. 1998. Evaluation of a targeted prodrug strategy to enhance oral absorption of poorly water-soluble compounds. Pharm Res 15 1012. 

Hamstra, D. A., and Rehemtulla, A. Toward an enzyme/prodrug strategy for cancer gene therapy Endogenous activation of carboxypeptidase A mutants by PACE/furin family of propeptidases. Hum. Gene Ther. 10 235-248, 1999. 

Pauletti, G.M., S. Gangwar,T.J. Siahaan, A. Jeffrey, and R.T. Borchardt. 1997. Improvement of oral peptide bioavailability Peptidomimetics and prodrug strategies. Adv. Drug Deliv. Rev. 27 235-256. 

In summary, capecitabine (1), an A -carbamate pyrimidine nucleoside prodrug of cytotoxic antimetabolite 5-fluorouracil, is an FDA-approved anticancer drug that can be administered orally. This compound uses a multilayer of prodrug strategies that not only avoids side effects arising from exposure of toxic metabolites to healthy tissue but is converted to 5-fluorouracil only by enzymes preferentially expressed in many cancer cell types, thus resulting in selective delivery of the drug to tumors. Capecitabine is marketed under the trade name of Xeloda for use in the treatment of metastatic colorectal and breast cancers and metastatic breast cancer that is resistant to paclitaxel or anthracycline therapies. 

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