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

Velázquez, Sonsoles; Castro, Sonia de; Díez-Torrubia, Alberto; Balzarini, Jan; Camarasa, María‐José

doi:10.2174/0929867322666150114163449

Cited by 3 publications

(4 citation statements)

References 80 publications

(142 reference statements)

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“…Therefore, we synthesized prodrugs of TUB091 by conjugation with L-Ser as in AVE-8062 (3) or with an L-Lys-L-Pro dipeptide (12 and 13, Supplementary Methods). The latter was based on our previous results of solubility improvement of antiviral drugs by coupling to di- or oligopeptides and subsequent release by the endogenous enzyme dipeptidyl peptidase IV (DPP-IV/CD26) [26]. …”

Section: Resultsmentioning

confidence: 99%

“…Sodium phosphate salt derivatives of CA-4 (CA-4P) and CA-1 (CA-1P) and the L-serine prodrug of an amino derivative of CA-4 (AVE-8062, rapidly advanced to clinical trials [reviewed in [5]). We have extensively investigated the development of oligopeptide prodrugs that are efficiently release in the presence of dipeptidyl peptidase IV (DPP-IV/CD26) [26]. This enzyme, abundantly found in serum, mainly hydrolyzes peptidic sequences containing an N -terminal penultimate proline.…”

Section: Discussionmentioning

confidence: 99%

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Antivascular and antitumor properties of the tubulin-binding chalcone TUB091

et al. 2016

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We investigated the microtubule-destabilizing, vascular-targeting, anti-tumor and anti-metastatic activities of a new series of chalcones, whose prototype compound is (E)-3-(3’’-amino-4’’-methoxyphenyl)-1-(5’-methoxy-3’,4’-methylendioxyphenyl)-2-methylprop-2-en-1-one (TUB091). X-ray crystallography showed that these chalcones bind to the colchicine site of tubulin and therefore prevent the curved-to-straight structural transition of tubulin, which is required for microtubule formation. Accordingly, TUB091 inhibited cancer and endothelial cell growth, induced G2/M phase arrest and apoptosis at 1-10 nM. In addition, TUB091 displayed vascular disrupting effects in vitro and in the chicken chorioallantoic membrane (CAM) assay at low nanomolar concentrations. A water-soluble L-Lys-L-Pro derivative of TUB091 (i.e. TUB099) showed potent antitumor activity in melanoma and breast cancer xenograft models by causing rapid intratumoral vascular shutdown and massive tumor necrosis. TUB099 also displayed anti-metastatic activity similar to that of combretastatin A4-phosphate. Our data indicate that this novel class of chalcones represents interesting lead molecules for the design of vascular disrupting agents (VDAs). Moreover, we provide evidence that our prodrug approach may be valuable for the development of anti-cancer drugs.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Antivascular and antitumor properties of the tubulin-binding chalcone TUB091

et al. 2016

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“…Phosphate, sulfate, amino acids, sugar moieties, etc. have been attached to low solubility compounds to make successful drug products (88,89). Furthermore, prodrugs can enhance oral availability by decreasing crystal packing, through the solubilization effects of bile salts and lecithin in the human GI tract.…”

Section: Prodrugsmentioning

confidence: 99%

Drug Delivery Approaches in Addressing Clinical Pharmacology-Related Issues: Opportunities and Challenges

Wen¹,

Jung²,

2015

AAPS J

414

189

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Abstract. Various drug delivery approaches can be used to maximize therapeutic efficacy and minimize side effects, by impacting absorption, distribution, metabolism, and elimination (ADME) of a drug compound. For those drugs with poor water solubility or low permeability, techniques such as amorphous solid dispersion, liposomes, and complexations have been used to improve their oral bioavailability. Modified release (MR) formulations have been widely used to improve patient compliance, as well as to reduce side effects, especially for those drugs with short half-lives or narrow therapeutic windows. More than ten drugs using sterile long-acting release (LAR) formulations with clear clinical benefit have been successfully marketed. Furthermore, drug delivery systems have been used in delaying drug clearance processes. Additionally, modifying the in vivo drug distribution using targeted delivery systems has significantly improved oncology treatments. All the drug delivery approaches have their advantages and limitations. For both brand and generic drugs, the achievement of consistent quality and therapeutic performance using drug delivery systems can also pose serious challenges in developing a drug for the market, which requires close collaboration among industry, academia, and regulatory agencies. With the advent of personalized medicines, there will be great opportunities and challenges in utilizing drug delivery systems to provide better products and services for patients.

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“…35 Other groups, including 5'-L-valyl ester, were investigated to increase oral bioavailability. 36 , 37 We decided to investigate a series of compounds with the acetyl group installed on the ribose unit as its 3'- and 5'-ester.…”

Section: Introductionmentioning

confidence: 99%

Extension of furopyrimidine nucleosides with 5-alkynyl substituent: Synthesis, high fluorescence, and antiviral effect in the absence of free ribose hydroxyl groups

Kaczmarek

Twardy

Olson

et al. 2021

European Journal of Medicinal Chemistry

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A novel methodology to access alkynyl nucleoside analogs was elaborated. Highly fluorescent 5-alkynylfuropyrimidines were synthesized (97-46%) and their antiviral properties investigated in vitro . Regiochemistry of the functionalization was achieved with the aid of 5- endo - dig electrophilic halocyclization of acetyl 5- p -tolyl- or 5- p -pentylphenyl-2'-deoxyuridine. Structure of one of the resulting nucleosides, 6- p -tolyl-5-iodo-2'-deoxyribofuranosyl-furo[2,3- d ]pyrimidin-2-one, was confirmed by X-ray crystallography, and its conformation was compared to related nucleosides. Diverse alkynyl substituents were introduced at the heterobicyclic base C-5 position via Sonogashira coupling of 5-iodo-2'-deoxyribofuranosyl-furo[2,3- d ]pyrimidin-2-ones. The resulting compounds had fluorescence emissions of 452 to 481 nm. High quantum yields of 0.53-0.60 were observed for 9-ethynyl-9-fluorenol and propargyl alcohol/methyl ether-modified furopyrimidines. These modified nucleosides, designed in the form of ribose acetyl esters, represent potential tools for fluorescent tagging, studying nucleoside metabolism, 2′-deoxyribonucleoside kinase activity, and antiviral activity. Antiviral assays against a broad spectrum of DNA and RNA viruses showed that in human embryonic lung (HEL) cell cultures some of the compounds showed antiviral activity (EC 50 1.3-13.2 μM) against varicella-zoster virus (VZV). The alkynyl furopyrimidine with two p -pentylphenyl substituents emerged as the best compound with reasonable and selective anti-VZV activity, confirming p -pentylphenyl potency as a pharmacophore.

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

Cited by 3 publications

References 80 publications

Antivascular and antitumor properties of the tubulin-binding chalcone TUB091

Antivascular and antitumor properties of the tubulin-binding chalcone TUB091

Drug Delivery Approaches in Addressing Clinical Pharmacology-Related Issues: Opportunities and Challenges

Extension of furopyrimidine nucleosides with 5-alkynyl substituent: Synthesis, high fluorescence, and antiviral effect in the absence of free ribose hydroxyl groups

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