Application of the Dipeptidyl Peptidase IV (DPPIV/CD26) Based Prodrug Approach to Different Amine-Containing Drugs

Abstract

Here we explore the applicability of the dipeptidyl peptidase IV (DPPIV/CD26) based prodrug approach to a variety of amine-containing drugs. Efficient procedures have been developed for the synthesis of dipeptide and tetrapeptide amide prodrugs including N-acylation protocols of the exocyclic amino function of cytidine and adenosine nucleosides. Our studies demonstrated that XaaPro dipeptides linked to a free amino group present on an aromatic ring or on a sugar entity are prodrugs that efficiently release the parent drug upon conversion by purified DPPIV/CD26 as well as soluble DPPIV/CD26 in bovine and human serum. Vildagliptin, a specific inhibitor of DPPIV/CD26, was able to completely block the hydrolysis of the prodrugs in the presence of purified CD26 but also in human and bovine serum. When the amino group is present on a pyrimidine or purine ring, the dipeptide derivatives are chemically unstable, whereas the tetrapeptide derivatives (i.e., ValProValPro or ValAlaValPro) were much more stable in solution and efficiently converted to the parent drug by the action of DPPIV/CD26. This DPPIV/CD26-directed prodrug technology can be useful to increase solubility of the parent drug molecules and/or to allow better formulation properties.

Addition of amino acid moieties to lapatinib increases the anti‐cancer effect via amino acid transporters

“…As mentioned, Val-SN-38 was readily hydrolysed and did not possess adequate metabolic stability to act as a substrate of amino acid transporters [9]. Likewise, Diez-Torrubia et al [21] reported that dipeptide and tetrapeptide addition to anti-cancer agents, including 6-aminoquinoline, doxorubicin, cytarabine and vidarabine, were metabolically unstable, resulting in the rapid release of the active drug by dipeptidyl peptidase IV, in bovine and human serum. In this regard, the present amide linkage approach seems a promising method of modifying the chemical structure of an agent without causing stability issues.…”

α‐N‐Protected dipeptide acids: a simple and efficient synthesis via the easily accessible mixed anhydride method using free amino acids in DMSO and tetrabutylammonium hydroxide

“…Dipeptides and small peptides have wide applications both in medicinal and synthetic chemistry. For example, they are enzyme inhibitors [1][2][3], prodrugs [4][5][6][7][8][9][10][11][12], peroxisome proliferator-activated receptor gamma antagonist [13], anti-HIV-1 [14], and chemotherapeutic metallopharmaceuticals [15][16][17][18][19][20][21]. Dipeptides are also used as additional supplementation of single important amino acid nutrients like glutamine [22][23][24][25][26][27][28][29], tyrosine [25,30,31], and cysteine [25].…”

“…There are many reports on the coupling reaction between free and a-N-protected amino acids with different a-carboxyl activating agents. The active ester has been by far the most used: both phenols and N-hydroxy compounds such as 4-nitro- [13,48], 2,3,4,5,6-pentafluorophenol [49][50][51], 1-hydroxybenzotriazole [52][53][54][55][56], benzisoxazolium salts [57,58], N-hydroxysuccinimide [59,60], and N-hydroxy-3-azaspiro [5,5]undecane-2,4-dione [61] have been employed to this purpose. These intermediates are stable and the coupling reaction can be carried out under the experimental conditions suitable to dissolve the free amino acids (water with or without an organic cosolvent, presence of an inorganic or organic base).…”

Dipeptidyl Peptidase IV (DPPIV/CD26)‐Based Prodrugs of Hydroxy‐Containing Drugs

“…[13] Based on this study, we have reported a novel type of prodrug approach that could be applied to mediate the solubility, formulation, and bioavailability of therapeutic agents. [14][15][16] In our approach, a di-or oligopeptide moiety (Xaa-Pro) n was linked to the free amino group of a nonpeptidic drug through an amide bond which is specifically cleaved by the endogenous DPPIV/CD26 enzyme ( Figure 1).…”

“…[17] This prodrug approach was successfully applied to a broad variety of compounds/drugs with a free amino group on an alkyl chain (e.g., the N-3 aminopropyl derivative of the anti-HIV TSAO compounds) [18,19] or on heteroaromatic (6-aminoquinoline), carbohydrate (doxorubicin), heterocyclic pyrimidine (cytarabine), or purine rings (vidarabine). [14][15][16] We recently applied this prodrug technology to the highly lipophilic antiviral drug family of bicyclic furanopyrimidine nucleoside analogues, specifically the Cf1743 analogue ( Figure 2), to improve its physicochemical and pharmacokinetic properties. [20] In this hydroxy-containing drug, the peptidic sequence cannot be linked directly to the hydroxy group through an ester bond as the DPPIV/CD26 enzyme specifically recognizes free amide bonds.…”