Invited Speaker

Programmable Pro-Prodrug Systems
Rafik Karaman

Recently we have been engaged in (a) developing a pro-drug entity to be exploited as a host for different classes of amine drugs that upon their penetration to the human body can release the active drug in programmable manner (Chart 1). (b) Developing candidates for potent anti-Parkinson pro-prodrugs that might possess a relatively high bioavailability and can enter the blood brain barrier upon administration to the human body by a variety of different dosage forms (Chart 2).

For achieving the goal in (a) we have chosen to exploit the trimethyl lock system (Cohen’s model).1 Our interest in examining this model stems from the need to make a chemical device that is composed of a drug and an entity that binds to the drug and can undergo a rapid reaction upon administration to the human body to furnish the drug and the pharmacologically inactive moiety. This device is known as a chemically driven pro-prodrug (Chart 1a). There is a pressing need for such devices since a significant number of drugs have low solubility in water so that their use in intravenous injection (I.V.) dosage forms is not feasible. Linking these drugs to an entity such as hydroxyhydrocinnamic acid system enables them to be used intravenously due to the higher water solubility of the drug-hydroxyhydrocinnamic acid complex (pro-prodrug). Furthermore, this system can be utilized as a programmable chemical device that can release the active drug in a rate that is controlled by the nature of the groups on the phenyl ring.

In the past ten years some prodrugs based on hydroxyhydrocinnamic acid derivatives have been introduced. 2 For example, Borchardt et al reported the use of the 3-(2’-acetoxy-4’, 6’-dimethyl)-phenyl-3, 3-dimethylpropionamide derivative (pro-prodrug) that is capable of releasing the biologically active amine (drug) upon acetate hydrolysis by enzyme triggering (Chart 1b). Another successful example of the pharmaceutical applications for examining Cohen’s model is the prodrug Taxol which enables the drug to be water soluble and thus to be administered to the human body via intra-venous (I.V.) injection. Taxol is the brand name for paclitaxel, a natural diterpene, approved in the U.S.A for use as anti-cancer agent.

For fulfilling the goal in (b), Menger’s tri-carboxylic acid shown in Chart 2 was chosen as a host for dopamine.3 This chemical device is capable of being a new pro-prodrug for the treatment of Parkinson’s disease that posses the following characteristics: (1) a relatively, high bioavailability due to the capability of the pro-drug to penetrate the blood brain barrier, (2) a moderate Hydrophilic Lipophylic Balance (HLB) for achieving two goals: (i) maximum absorption once the pro-prodrug enters the body tissues, and (ii) to enable the use of the drug in different dosage forms; (3) a controlled cleavage of the pro-drug moiety to dopamine and to a non-toxic inactive host. Controlling the pro-prodrug cleavage rate provides a chemically driven controlled release system that librates dopamine once the pro-drug reaches the human brain system.


For fulfilling the two goals in (a) and (b) we sought to theoretically investigate the driving force(s) for the significant enhancements in rate of some intramolecular processes that have been utilized as enzyme models and pro prodrug hosts. Using molecular mechanics, DFT and ab initio levels of theory, we investigated the thermodynamic and kinetic properties of a) acid-catalyzed lactonization of hydroxy-acids as studied by Cohen 1 and Menger 3 and b) intramolecular proton-transfer in rigid systems as studied by Menger.3 The conclusions emerged from these studies are as follows: (1) both factors, ground state strain and proximity orientation of the two reactive centers are important in accelerating the rate of an intramolecular process, depending on the nature of the system. (2) The distance between the two reactive centers in an intramolecular reaction is a crucial factor in determining whether the reaction is inter- or intramolecular. (3) Enthalpic as well as entropic effects are both important factors in enhancing the rate of intramolecular process.⁴

References

1. S. Milstein, L. A. Cohen, Proc. Natl. Acad. Sci. U. S. A. 67 (1970), 1143. S. Milstein, L. A. Cohen, J. Am. Chem. Soc. 94 (1972), 9158.

2. For recent reviews, see: (a) D. Shan, M. G. Nicholaou, R. D Borchardt, B. J. Wang, J. Pharm. Sci. 86 (1997) 765. (b) B. Testa, J. M. Mayer, Drug Metab. Rev. 30 (1998) 787. (c) W. Wang, J. Jiang, C. E. Ballard, B. Wang, Curr. Pharm. Des. 5 (1999) 265.

3. F. M. Menger, M. Ladika, J. Am Chem. Soc. 110 (1988), 6794. F. M. Menger, Acc. Chem. Res. 18 (1985), 128. F. M. Menger, Tetrahedron 39 (1983), 1013. F. M. Menger, Pure Appl. Chem. 77 (2005), 1873 and references therein.

4. R. Karaman, Tet. Lett. 49 (2008), 5998. R. Karaman, Bioorg. Chem. 37 (2009), 11. R. Karaman, Tet. Lett. 50 (2009), 452. R. Karaman, Res. Lett. Org. Chem. doi: 10.1155/2009/240253. R. Karaman, Bioorg. Chem. 37 (2009), 106. R. Karaman, J. Mol. Struct. 910 (2009), 27. R. Karaman, Tet. Lett. 50 (2009), 6083. R. Karaman, J. Mol. Struct. (Theochem), accepted. R. Karaman, Tet. Lett., accepted.