Dipeptidyl Peptidase IV Dependent Water-Soluble Prodrugs of Highly Lipophilic Bicyclic Nucleoside Analogues

Díez-Torrubia, Alberto; Balzarini, Jan; Andrei, Gracíela; Snoeck, Robert; Meester, Ingrid De; Camarasa, Marı́a-José; Velázquez, Sonsoles

doi:10.1021/jm101624e

Cited by 17 publications

(16 citation statements)

References 39 publications

(78 reference statements)

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“…Fortunately, various approaches may be applied to increase the solubility of highly lipophilic compounds. In particular, we managed to increase the water solubility (and oral bioavailability) of poorly soluble amine-containing parent drugs up to 1,000-fold by using a dipeptidyl peptidase IV (DPPIV/CD26)-based prodrug approach (51,52). A similar approach is in progress in our laboratory to generate more soluble KIN59 prodrugs.…”

Section: Discussionmentioning

confidence: 99%

The Thymidine Phosphorylase Inhibitor 5′-O-Tritylinosine (KIN59) Is an Antiangiogenic Multitarget Fibroblast Growth Factor-2 Antagonist

Liekens

Bronckaers

Belleri

et al. 2012

Molecular Cancer Therapeutics

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is an allosteric inhibitor of the angiogenic enzyme thymidine phosphorylase.Previous observations showed the capacity of KIN59 to abrogate thymidine phosphorylase-induced as well as developmental angiogenesis in the chicken chorioallantoic membrane (CAM) assay. Here, we show that KIN59 also inhibits the angiogenic response triggered by fibroblast growth factor-2 (FGF2) but not by VEGF in the CAM assay. Immunohistochemical and reverse transcriptase PCR analyses revealed that the expression of laminin, the major proteoglycan of the basement membrane of blood vessels, is downregulated by KIN59 administration in control as well as in thymidine phosphorylase-or FGF2-treated CAMs, but not in CAMs treated with VEGF. Also, KIN59 abrogated FGF2-induced endothelial cell proliferation, FGF receptor activation, and Akt signaling in vitro with no effect on VEGF-stimulated biologic responses. Accordingly, KIN59 inhibited the binding of FGF2 to FGF receptor-1 (FGFR1), thus preventing the formation of productive heparan sulphate proteoglycan/FGF2/FGFR1 ternary complexes, without affecting heparin interaction. In keeping with these observations, systemic administration of KIN59 inhibited the growth and neovascularization of subcutaneous tumors induced by FGF2-transformed endothelial cells injected in immunodeficient nude mice. Taken together, the data indicate that the thymidine phosphorylase inhibitor KIN59 is endowed with a significant FGF2 antagonist activity, thus representing a promising lead compound for the design of multitargeted antiangiogenic cancer drugs.

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Section: Discussionmentioning

confidence: 99%

The Thymidine Phosphorylase Inhibitor 5′-O-Tritylinosine (KIN59) Is an Antiangiogenic Multitarget Fibroblast Growth Factor-2 Antagonist

Liekens

Bronckaers

Belleri

et al. 2012

Molecular Cancer Therapeutics

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“…Thus, the tripeptide prodrug derivative may not only have the advantage of increased solubility and better formulation but may also result in an increased oral bioavailability, as previously demonstrated for the tripeptidyl (Val-Pro-Val) derivatives of bicyclic nucleoside analogue Cf1743. [20]…”

Section: Analysis Of the Conversion Of The [Val-pro]-[val]-[propranolol]mentioning

confidence: 99%

“…[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. Thus, tripartite conjugates [Xaa-Pro]-[connector]-[drug] ( Figure 2) were prepared and evaluated.…”

Section: Introductionmentioning

confidence: 99%

“…We also demonstrated a markedly enhanced oral bioavailability of the prodrugs versus the parent drug in mice. [20] With these promising results in hand, we considered extending the applicability of our prodrug strategy to a variety of hydroxy-containing drugs targeting various types of hydroxy groups as proof of concept of the methodology (Figure 3). For drugs containing primary hydroxy groups, the anti-HIV drug didanosine [21] was chosen as an example of a polar purine nucleoside.…”

Section: Introductionmentioning

confidence: 99%

“…For the peptide pro-moiety, we used the Val-Pro dipep-tide prodrug sequence efficiently recognized by the DPPIV/ CD26 enzyme with the valine as a connector, based on the promising results obtained for the Cf1743 prodrugs. [20] The synthesis, stability, and water solubility studies of target tripartite prodrugs of the general formula I (Figure 3), their ability to act as efficient substrates for DPPIV/CD26, and their human and bovine serum hydrolysis profiles is described herein.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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We previously described a novel prodrug approach in which a di- or tetrapeptide moiety is linked to a wide variety of amine-containing drugs through an amide bond, which is specifically cleaved by dipeptidyl peptidase IV (DPPIV/CD26) activity. Herein we report the application of this prodrug approach to a variety of hydroxy-containing drugs (primary, secondary, tertiary, or aromatic hydroxy groups). We designed and studied tripartite prodrugs containing a dipeptide moiety (cleavable by DPPIV/CD26) and a valine as a hetero-bifunctional connector to link the dipeptide to the hydroxy group of the drug through a metabolically labile ester bond. The hydroxy-containing prodrugs showed various susceptibilities to hydrolysis by DPPIV/CD26 and serum, depending on the nature of the compound. Prodrugs of compounds containing a primary hydroxy group (as in didanosine) or a hydroxy moiety on an aromatic entity (as in acetaminophen) were most efficiently converted. In contrast, a tertiary hydroxy group was much less susceptible to conversion into its parent drug by DPPIV/CD26 or serum. A number of the prodrugs showed remarkable increases in water solubility relative to their parent drugs.

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Comparison of Free‐Hydroxy With 3′,5′‐Di‐O‐Acetyl Ribose of 5‐Alkynyl Dicobalt Hexacarbonyl 2′‐Deoxy‐Furopyrimidines Hybrids: Synthesis, Antiproliferative Activity, and ROS Determination

Kaczmarek,

Radzikowska‐Cieciura,

Królewska‐Golińska

et al. 2024

Applied Organom Chemis

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Synthesis of 5‐alkynyl furopyrimidine nucleoside analogs, with free‐ribose groups, was carried out, and their biological activity was evaluated. The substituents introduced at the C‐5 included propargyl and homopropargyl alcohols, 4‐methylphenyl (p‐tolyl), and 4‐pentylphenyl substituted alkynyl groups (56%–88%). Subsequently, alkyne function was coordinated to dicobalt hexacarbonyl unit, yielding the corresponding dicobalt hexacarbonyl 5‐alkynyl furopyrimidine nucleosides (51%–75%). All compounds contained 4‐pentylphenyl group attached at the C‐6 position of the bicyclic base, in line with most active antiviral structures. The antiproliferative effect of these modified nucleosides on cancer cells of different phenotypes was determined using in vitro studies. The tested compounds show antiproliferative effects with median inhibitory concentration (IC50) values of 16–23 and 9–15 μM for HeLa and K562 cells, respectively. The determination of reactive oxygen species (ROS) formation in K562 cells in the presence of modified nucleosides may suggest that the mode of action of the examined compounds may be attributed to the induction of oxidative stress.

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Dipeptidyl Peptidase IV Dependent Water-Soluble Prodrugs of Highly Lipophilic Bicyclic Nucleoside Analogues

Cited by 17 publications

References 39 publications

The Thymidine Phosphorylase Inhibitor 5′-O-Tritylinosine (KIN59) Is an Antiangiogenic Multitarget Fibroblast Growth Factor-2 Antagonist

The Thymidine Phosphorylase Inhibitor 5′-O-Tritylinosine (KIN59) Is an Antiangiogenic Multitarget Fibroblast Growth Factor-2 Antagonist

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

Comparison of Free‐Hydroxy With 3′,5′‐Di‐O‐Acetyl Ribose of 5‐Alkynyl Dicobalt Hexacarbonyl 2′‐Deoxy‐Furopyrimidines Hybrids: Synthesis, Antiproliferative Activity, and ROS Determination

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