Synthesis of a Novel Esterase-Sensitive Cyclic Prodrug of a Hexapeptide Using an (Acyloxy)alkoxy Promoiety

Gangwar, Sanjeev; Pauletti, Giovanni M.; Siahaan, Teruna J.; Stella, Valentino J.; Borchardt, Ronald T.

doi:10.1021/jo961696a

Cited by 42 publications

(47 citation statements)

References 41 publications

(48 reference statements)

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“…NMR spectra showed that the hydrolysis product can be identified with the desired linear peptide (see Supporting Information), as similarly proposed for cyclic prodrugs of opioid peptides. 14 For predicting the capacity of CP11 to cross the biological barriers, PAMPA assays were performed. To evaluate the GI permeation, the studies were implemented at pH 5.0, 6.5, and 7.4 with an 18 h incubation time; the pH of acceptor and donor compartments was always the same.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Synthesis of a Novel Cyclic Prodrug of S-Allyl-glutathione Able To Attenuate LPS-Induced ROS Production through the Inhibition of MAPK Pathways in U937 Cells

Patruno¹,

Fornasari²,

Stefano³

et al. 2014

Mol. Pharmaceutics

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A novel cyclic prodrug of S-allyl-glutathione (CP11), obtained by using an acyloxy-alkoxy linker, was estimated for its pharmacokinetic and biological properties. The stability of CP11 was evaluated at pH 1.2, 7.4, in simulated fluids with different concentrations of enzymes, and in human plasma. The anti-inflammatory ability of CP11 was assessed in U937 cells, an immortalized human monocyte cell line. Results showed that CP11 is stable at acidic pH showing a possible advantage for oral delivery due to the longer permanence in the stomach. Having a permeability coefficient of 2.49 × 10(-6) cm s(-1), it was classified as discrete BBB-permeable compound. Biological studies revealed that CP11 is able to modulate inflammation mediated by LPS in U937 cells preventing the increase of ROS intracellular levels through interaction with the MAPK pathway.

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Section: ■ Results and Discussionmentioning

confidence: 99%

“…14,15 Two steps are involved in the hydrolysis of CP11: initially a slow enzymatic hydrolysis of the ester bond and then a fast chemical hydrolysis of the carbamate moiety to release S-allyl-GSH, CO 2 , and HCOH (Scheme 1).…”

Section: ■ Introductionmentioning

confidence: 99%

Synthesis of a Novel Cyclic Prodrug of S-Allyl-glutathione Able To Attenuate LPS-Induced ROS Production through the Inhibition of MAPK Pathways in U937 Cells

Patruno¹,

Fornasari²,

Stefano³

et al. 2014

Mol. Pharmaceutics

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“…One approach to improve the oral bioavailability of peptides and peptidomimetics is to modify their physicochemical properties by making cyclic prodrugs. Our laboratory has developed cyclic peptide prodrug methods using chemical linkers such as acyloxyalkoxy, phenylpropionic acid, and coumarinic acid (7–9). The synthetic methodology to make coumarinic acid linker was previously developed by Wang et al .…”

mentioning

confidence: 99%

Synthesis and conformational analysis of a coumarinic acid‐based cyclic prodrug of an opioid peptide with modified sensitivity to esterase‐catalyzed bioconversion

Ouyang

Borchardt

Siahaan

et al. 2002

The Journal of Peptide Research

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The coumarinic acid-based cyclic DADLE (H-Tyr-D-Ala-Gly-Phe-D-Leu-OH) prodrug 1a exhibited more favorable physicochemical properties than did DADLE for permeation across the intestinal mucosa. However, prodrug 1a, whose bioconversion to DADLE was slow, was subject to extensive biliary clearance when administered to rats in vivo. To increase the rate of esterase-catalyzed bioconversion of prodrug 1a, thus decreasing its biliary clearance, the oxymethyl-modified prodrug 1, in which an aldehyde equivalent is inserted between the phenolic group of the promoiety and the carboxylic acid group of the peptide, was synthesized from benzofuran-2-carboxylic acid 16 via a nine-step procedure. Briefly, phenacyl-protected 3-(2-hydroxyphenyl)-propynoic acid 17 was coupled with Boc-d-Leu-OCH(2)I 5 to give the intermediate 18, which was further elaborated and conjugated with tetrapeptide 4 to give linear precursor 2. Precursor 2 was then deprotected and cyclized to obtain compound 1 using a high dilution technique. In an attempt to investigate the effect of the physicochemical properties and the conformation of prodrug 1 on its permeation characteristics, we calculated its physicochemical parameters and determined its solution conformation using spectroscopic techniques (CD and NMR) and molecular dynamics simulations. Prodrug 1 showed a cLogP value and a molecular size similar to that of prodrug 1a. The deconvoluted CD spectra indicated that prodrug 1 has more random component (71%) than prodrug 1a (42%). 2D-NMR studies of prodrug 1 showed no signals for amide-amide hydrogen interactions and few ROE cross-peaks in ROESY spectra. Using distance restraints constructed from ROESY spectra, molecular dynamics simulations of prodrug 1 generated five conformation families. One family satisfied most of the distance restraints and all of the dihedral angles measured by NMR coupling constants. In summary, prodrug 1 showed favorable physicochemical properties for permeation of the intestinal mucosa. Prodrug 1 adopted a more random conformation in solution than prodrug 1a. These differences in solution conformation could affect the permeation of the prodrugs across the intestinal mucosa by passive diffusion and/or their ability to interact with efflux transporter(s) that would limit their transcellular permeation.

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“…The syntheses of cyclic prodrugs 1a–d were achieved by converging two key intermediates 5 and 8a–d to give linear precursors 9a–d . The synthesis of intermediate 5 was performed using a previously described method (23).…”

Section: Synthetic Chemistrymentioning

confidence: 99%

“…The physical characterizations of each type of intermediates (i.e. 8a, 8b, 8c, and 1-Iodomethyl-p-nitrophenyl carbonate (3), Boc-PheO ) Cs + (4), Boc-[(phenylalaninyloxyl)methyl]-p-nitrophenyl carbonate (5), and TFAAEH-Asp(OBzl)-OTce were prepared according to previous literature reports (23). Due to the side reaction, the best yield obtained for compound 5 was 37%.…”

Section: Synthetic Proceduresmentioning

confidence: 99%

Syntheses of cyclic prodrugs of RGD peptidomimetics with various macrocyclic ring sizes: evaluation of physicochemical, transport and antithrombic properties

Song

et al. 2003

The Journal of Peptide Research

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The objective of this work was to synthesize cyclic prodrugs 1a-d of RGD peptidomimetics 2a-d with various ring sizes (n[CH2] = 1, 3, 5 and 7) and to evaluate the effect of ring size on their transport, physicochemical, enzymatic stability, and antithrombic properties. The syntheses of cyclic prodrugs 1a-d were achieved by converging two key intermediates, Boc-Phe-O-CH2-OCO-OpNP (5) and H2N-(CH2)n-CO-Asp(OBzl)-OTce (8a-d), to give linear precursors Boc-Phe-O-CH2-OCO-HN-(CH2)n-CO-Asp(OBzl)-OTce (9a-d). The N- and C-terminus protecting groups were removed from 9a-d to give 10a-d. Linear precursors 10a-d were cyclized, and the remaining Bzl-protecting group was removed to produce cyclic prodrugs 1a-d in around 20% overall yield. The linear RGD peptidomimetics (2a-d) were synthesized using standard Boc-amino acid chemistry by solution-phase method. Increasing the ring size by adding methylene groups also increases the hydrophobicity of the cyclic prodrugs and parent RGD peptidomimetics. The transport properties of cyclic prodrugs 1c and 1d were 2.6- and 4.4-fold better than those of parent compounds 2c and 2d, respectively. These results suggest that increasing the hydrophobicity of the cyclic prodrugs and parent RGD peptidomimetics enhanced their transport properties. The hydrodynamic radii of the cyclic prodrugs were also smaller than those of their respective parent compounds, suggesting that the change in size may contribute to their transport properties. The chemical stability of the cyclic prodrugs was affected by the ring size, and the cyclic prodrug with the larger ring size (i.e. 1d) was more stable than the smaller one (i.e. 1a). All the cyclic prodrugs were more stable at pH 4 than at pH 7 and 10. Prodrug-to-drug conversion could be induced by isolated esterase as well as esterase found in human plasma. An increase in the length of methylene group (n[CH2] = 1, 3, 5, 7) enhanced the antithrombic activity of the prodrugs and the parent compounds. In summary, the ring size of cyclic prodrugs affected their transport, physicochemical, and antithrombic properties.

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Synthesis of a Novel Esterase-Sensitive Cyclic Prodrug of a Hexapeptide Using an (Acyloxy)alkoxy Promoiety

Cited by 42 publications

References 41 publications

Synthesis of a Novel Cyclic Prodrug of S-Allyl-glutathione Able To Attenuate LPS-Induced ROS Production through the Inhibition of MAPK Pathways in U937 Cells

Synthesis of a Novel Cyclic Prodrug of S-Allyl-glutathione Able To Attenuate LPS-Induced ROS Production through the Inhibition of MAPK Pathways in U937 Cells

Synthesis and conformational analysis of a coumarinic acid‐based cyclic prodrug of an opioid peptide with modified sensitivity to esterase‐catalyzed bioconversion

Syntheses of cyclic prodrugs of RGD peptidomimetics with various macrocyclic ring sizes: evaluation of physicochemical, transport and antithrombic properties

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