Effects of steric bulk and stereochemistry on the rates of diketopiperazine formation from N-aminoacyl-2,2-dimethylthiazolidine-4-carboxamides (Dmt dipeptide amides)—a model for a new prodrug linker system

Suaifan, Ghadeer A. R. Y.; Mahon, Mary F.; Arafat, Tawfiq; Threadgill, Michael D.

doi:10.1016/j.tet.2006.09.009

Cited by 15 publications

(5 citation statements)

References 39 publications

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“…Overall, these results suggest that steric hindrance at the C-terminus of the dipeptide backbone is the major factor affecting the rate of cyclization. [37] Hydrolysis in human plasma Dipeptide esters 2 were incubated at 37 8C in 80 % human plasma and their degradation monitored by HPLC. The degradation of the esters displayed first-order kinetics for three to four substrate half-lives.…”

Section: Chemical Stabilitymentioning

confidence: 99%

Dipeptide Derivatives of AZT: Synthesis, Chemical Stability, Activation in Human Plasma, hPEPT1 Affinity, and Antiviral Activity

et al. 2008

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5′‐O‐Dipeptide ester prodrugs of antiviral zidovudine (AZT) were designed to target the human intestinal oligopeptide transporter, hPEPT1, and were evaluated for their stability at pH 7.4 in buffer and in human plasma, affinity toward hPEPT1, cytotoxicity, and antiretroviral activity. The dipeptide esters of AZT undergo cyclization in buffer at pH 7.4 to release the parent drug at a rate that depends on the size of the side chains of the peptide carrier; the prodrug is considerably more stable if bulky β‐branched amino acids such as Ile and Val are present, particularly as C‐terminal residues. Incubation in human plasma showed that most of the dipeptide esters of AZT release the parent drug through two aminopeptidase‐mediated pathways: 1) stepwise cleavage of each of the amino acids and 2) direct cleavage of the dipeptide–drug ester bond. However, the plasma hydrolysis of Gly‐Gly‐AZT and Phe‐Gly‐AZT showed only direct cleavage of the dipeptide–drug ester bond. Substrate half‐lives in plasma were again remarkably high when hydrophobic β‐branched amino acids (Val, Ile) were present. The esters were also good substrates for the intestinal oligopeptide transporter hPEPT1 in vitro, with Val‐Gly‐AZT and Val‐Ala‐AZT presenting the highest affinity toward the transporter (IC50: 0.20 and 0.15 mM, respectively). The AZT dipeptide esters were assayed against the IIIB and ROD strains of HIV, and their cytotoxicity was evaluated in MT‐4 cells. The selectivity index of the prodrugs was two‐ to threefold higher than that of AZT for all compounds analyzed. These results point to the potential of dipeptide‐based carriers for the development of effective antiviral drug‐delivery systems. Val‐Ala‐AZT appears to combine chemical stability with good affinity for the hPEPT1 transporter and an improved cytotoxicity/antiretroviral index relative to AZT.

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Section: Chemical Stabilitymentioning

confidence: 99%

Dipeptide Derivatives of AZT: Synthesis, Chemical Stability, Activation in Human Plasma, hPEPT1 Affinity, and Antiviral Activity

et al. 2008

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“…Plasmin, a serine protease, plays an important role in tumor invasion and metastasis. 24,25 The proteolytically active form of plasmin may be localized around the tumor tissue because it is formed from the inactive proenzyme plasminogen by the urokinase-type plasminogen activator produced by cancer and/or stroma cells. 7,[26][27][28][29][30] Plasmin activity is very rapidly inhibited by inhibitors, such as a 2 -anti-plasmin, present within the blood circulation.…”

Section: Introductionmentioning

confidence: 99%

Development of a diketopiperazine-forming dipeptidyl Gly-Pro spacer for preparation of an antibody–drug conjugate

et al. 2013

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“…In the search for suitable R 3 and R 4 groups to enable the formation of DKP (Scheme B), the first sequence evaluated was FLQLYGLPET 0 G 1 Sar 2 H 3 G-NH 2 ( 2 , the positions of selected residues are labeled as the superscripted numbers, Table ). To achieve accelerated DKP formation, two hypotheses were pursued: (1) Sar 2 was incorporated into substrate peptide 2 to potentially increase the cis -amide bond population, and (2) His 3 was incorporated to potentially activate the Sar-His amide bond (Scheme A). − However, it was found that the ligation did not proceed, as no conversion was detected by HPLC (high-performance liquid chromatography) and MS (mass spectrometry) after 24 h incubation at 37 °C with 5% (mol/mol) SrtA. It is likely that SrtA did not recognize substrate peptide 2 , possibly a result of the N -methylamino acid at the 2 position.…”

Section: Resultsmentioning

confidence: 99%

Irreversible Sortase A-Mediated Ligation Driven by Diketopiperazine Formation

et al. 2014

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Sortase A (SrtA)-mediated ligation has emerged as an attractive tool in bioorganic chemistry attributing to the remarkable specificity of the ligation reaction and the physiological reaction conditions. However, the reversible nature of this reaction limits the efficiency of the ligation reaction and has become a significant constraint to its more widespread use. We report herein a novel set of SrtA substrates (LPETGG-isoacyl-Ser and LPETGG-isoacyl-Hse) that can be irreversibly ligated to N-terminal Gly-containing moieties via the deactivation of the SrtA-excised peptide fragment through diketopiperazine (DKP) formation. The convenience of the synthetic procedure and the stability of the substrates in the ligation buffer suggest that both LPETGG-isoacyl-Ser and LPETGG-isoacyl-Hse are valuable alternatives to existing irreversible SrtA substrate sequences.

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Effects of steric bulk and stereochemistry on the rates of diketopiperazine formation from N-aminoacyl-2,2-dimethylthiazolidine-4-carboxamides (Dmt dipeptide amides)—a model for a new prodrug linker system

Cited by 15 publications

References 39 publications

Dipeptide Derivatives of AZT: Synthesis, Chemical Stability, Activation in Human Plasma, hPEPT1 Affinity, and Antiviral Activity

Dipeptide Derivatives of AZT: Synthesis, Chemical Stability, Activation in Human Plasma, hPEPT1 Affinity, and Antiviral Activity

Development of a diketopiperazine-forming dipeptidyl Gly-Pro spacer for preparation of an antibody–drug conjugate

Irreversible Sortase A-Mediated Ligation Driven by Diketopiperazine Formation

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