Novel water-soluble prodrugs of acyclovir cleavable by the dipeptidyl-peptidase IV (DPP IV/CD26) enzyme

Díez-Torrubia, Alberto; Cabrera, Silvia; Castro, Sonia de; Garcı́a-Aparicio, Carlos; Mulder, Gwenn E.; Meester, Ingrid De; Camarasa, Marı́a-José; Balzarini, Jan; Velázquez, Sonsoles

doi:10.1016/j.ejmech.2013.10.001

Cited by 19 publications

(18 citation statements)

References 40 publications

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“…The ValPro dipeptide and the ValProValPro tetrapeptide (efficient substrates of the DPPIV/CD26 enzyme) were selected as peptide promoieties for the target peptidyl amide prodrugs 21 and 22 (Fig. (9)) [96]. The Val-Pro dipeptide and the valine as connector were chosen as tripeptide promoiety for the peptidyl ester prodrug 23 based on prior findings [83].…”

Section: Peptidyl Amideversus Peptidyl Ester Prodrugs Of Acyclovirmentioning

confidence: 99%

“…For the preparation of the challenging peptidyl amide prodrugs of acyclovir 21 and 22 both solution-phase and solid-phase synthetic approaches employing a variety of different coupling reagents and resins were examined. The use of acid fluorides as coupling reagents in solution-phase methods and the selection of Ellman's dihydropyran resin in the solid-phase strategy were key issues for the successful synthesis of the target molecules [96]. As in the case of cytidine and adenosine dipeptide prodrugs [74], the Ndeprotected dipeptide amide conjugate of ACV 21 was chemically unstable and could not be isolated due to diketopiperazine formation during the N-deprotection step while the corresponding tetrapeptide amide conjugate 22 was stable.…”

Section: Peptidyl Amideversus Peptidyl Ester Prodrugs Of Acyclovirmentioning

confidence: 99%

“…As in the case of cytidine and adenosine dipeptide prodrugs [74], the Ndeprotected dipeptide amide conjugate of ACV 21 was chemically unstable and could not be isolated due to diketopiperazine formation during the N-deprotection step while the corresponding tetrapeptide amide conjugate 22 was stable. Chemical stability studies also revealed that in contrast to the valyl ester prodrug VACV, with almost 50% spontaneous conversion to free ACV, both the tetrapeptide amide prodrug 22 and the tripeptide ester prodrug 23 were completely stable in PBS after 24 h [96].…”

Section: Peptidyl Amideversus Peptidyl Ester Prodrugs Of Acyclovirmentioning

confidence: 99%

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Dipeptidyl-Peptidase IV (DPP IV/CD26)-Activated Prodrugs: A Successful Strategy for Improving Water Solubility and Oral Bioavailability

Velázquez

Castro²,

Díez-Torrubia³

et al. 2015

CMC

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In the search of novel enzyme-based prodrug approaches to improve pharmacological properties of therapeutic drugs such as solubility and bioavailability, dipeptidyl-peptidase IV (DPP IV, also termed as CD26) enzyme activity provides a previously unexplored successful prodrug strategy. This review covers key aspects of the enzyme useful for the design of CD26-directed prodrugs. The proof-of-concept of this prodrug technology is provided for amine-containing agents by directly linking appropriate di- (or oligo)peptide moieties to a free amino group of a non-peptidic drug through an amide bond which is specifically hydrolized by DPP IV/CD26. Special emphasis is also made in discussing the design and synthesis of more elaborated tripartite prodrug systems, for further extension of the strategy to hydroxy-containing drugs. The application of this technology to improve water solubility and oral bioavailability of prominent examples of antiviral nucleosides is highlighted.

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Section: Peptidyl Amideversus Peptidyl Ester Prodrugs Of Acyclovirmentioning

confidence: 99%

Section: Peptidyl Amideversus Peptidyl Ester Prodrugs Of Acyclovirmentioning

confidence: 99%

Section: Peptidyl Amideversus Peptidyl Ester Prodrugs Of Acyclovirmentioning

confidence: 99%

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Dipeptidyl-Peptidase IV (DPP IV/CD26)-Activated Prodrugs: A Successful Strategy for Improving Water Solubility and Oral Bioavailability

Velázquez

Castro²,

Díez-Torrubia³

et al. 2015

CMC

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“…A prodrug refers to a pharmacologically inactive compound which is transformed into an active substance by either chemical or metabolic processes. Nowadays approximately 10% of drugs used in therapy are administered as prodrugs, and about half of these are hydrolyzed to the active form, in particular by hydrolysis of esters (figure 1) [1][2][3][4][5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Prodrug Strategy in Drug Development

Kelemen

Hancu

Rusu

et al. 2016

Acta Medica Marisiensis

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Prodrugs are chemically modified derivatives introduced in therapy due to their advantageous physico-chemical properties (greater stability, improved solubility, increased permeability), used in inactive form. Biological effect is exerted by the active derivatives formed in organism through chemical transformation (biotransformation). Currently, 10% of pharmaceutical products are used as prodrugs, nearly half of them being converted to active form by hydrolysis, mainly by ester hydrolysis. The use of prodrugs aims to improve the bioavailability of compounds in order to resolve some unfavorable characteristics and to reduce first-pass metabolism. Other objectives are to increase drug absorption, to extend duration of action or to achieve a better tissue/organ selective transport in case of non-oral drug delivery forms. Prodrugs can be characterized by chemical structure, activation mechanism or through the presence of certain functional groups suitable for their preparation. Currently we distinguish in therapy traditional prodrugs prepared by chemical derivatisation, bioprecursors and targeted delivery systems. The present article is a review regarding the introduction and applications of prodrug design in various areas of drug development.

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“… 11 , 13 , 26 , 27 Thus, a DPPIV-cleavable prodrug containing a proline dipeptide conjugated to a cytotoxic chemotherapeutic agent may limit nonspecific activation. 28 − 31 …”

Section: Introductionmentioning

confidence: 99%

Dipeptidyl Peptidase IV as a Potential Target for Selective Prodrug Activation and Chemotherapeutic Action in Cancers

et al. 2014

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The efficacy of chemotherapeutic drugs is often offset by severe side effects attributable to poor selectivity and toxicity to normal cells. Recently, the enzyme dipeptidyl peptidase IV (DPPIV) was considered as a potential target for the delivery of chemotherapeutic drugs. The purpose of this study was to investigate the feasibility of targeting chemotherapeutic drugs to DPPIV as a strategy to enhance their specificity. The expression profile of DPPIV was obtained for seven cancer cell lines using DNA microarray data from the DTP database, and was validated by RT-PCR. A prodrug was then synthesized by linking the cytotoxic drug melphalan to a proline-glycine dipeptide moiety, followed by hydrolysis studies in the seven cell lines with a standard substrate, as well as the glycyl-prolyl-melphalan (GP-Mel). Lastly, cell proliferation studies were carried out to demonstrate enzyme-dependent activation of the candidate prodrug. The relative RT-PCR expression levels of DPPIV in the cancer cell lines exhibited linear correlation with U95Av2 Affymetrix data (r2 = 0.94), and with specific activity of a standard substrate, glycine-proline-p-nitroanilide (r2 = 0.96). The significantly higher antiproliferative activity of GP-Mel in Caco-2 cells (GI50 = 261 μM) compared to that in SK-MEL-5 cells (GI50 = 807 μM) was consistent with the 9-fold higher specific activity of the prodrug in Caco-2 cells (5.14 pmol/min/μg protein) compared to SK-MEL-5 cells (0.68 pmol/min/μg protein) and with DPPIV expression levels in these cells. Our results demonstrate the great potential to exploit DPPIV as a prodrug activating enzyme for efficient chemotherapeutic drug targeting.

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Novel water-soluble prodrugs of acyclovir cleavable by the dipeptidyl-peptidase IV (DPP IV/CD26) enzyme

Cited by 19 publications

References 40 publications

Dipeptidyl-Peptidase IV (DPP IV/CD26)-Activated Prodrugs: A Successful Strategy for Improving Water Solubility and Oral Bioavailability

Dipeptidyl-Peptidase IV (DPP IV/CD26)-Activated Prodrugs: A Successful Strategy for Improving Water Solubility and Oral Bioavailability

Prodrug Strategy in Drug Development

Dipeptidyl Peptidase IV as a Potential Target for Selective Prodrug Activation and Chemotherapeutic Action in Cancers

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