Synthesis of chemoreversible prodrugs of ara-C with variable time-release profiles. Biological evaluation of their apoptotic activity

Wipf, Peter; Li, Wenjie; Adeyeye, Christianah Moji; Rusnak, James M.; Lazo, John S.

doi:10.1016/0968-0896(96)00153-8

Cited by 31 publications

(26 citation statements)

References 21 publications

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“…246,247 Studies have demonstrated azapeptide resistance to amino-and carboxy-peptidases and they have also been used as prodrugs. 248 It has been recently shown that that the azapeptide conformational bias is neither disruptive to binding the MHC II protein nor to T-cell activation. 249 Peptides with single and double aza-amino acid substitutions bind to MHC II proteins with af®nities that range from 20±100% of the native peptide.…”

Section: D E S I G N O F P E P T I D E -M I M E T I C S T H a T Bmentioning

confidence: 99%

Binding interactions between peptides and proteins of the class II Major Histocompatibility Complex

McFarland

Beeson

2002

Medicinal Research Reviews

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The activation of helper T cells by peptides bound to proteins of the class II Major Histocompatibility Complex (MHC II) is pivotal to the initiation of an immune response. The primary functional requirement imposed on MHC II proteins is the ability to efficiently bind thousands of different peptides. Structurally, this is reflected in a unique architecture of binding interactions. The peptide is bound in an extended conformation within a groove on the membrane distal surface of the protein that is lined with several pockets that can accommodate peptide side-chains. Conserved MHC II protein residues also form hydrogen bonds along the length of the peptide main-chain. Here we review recent advances in the study of peptide-MHC II protein reactions that have led to an enhanced understanding of binding energetics. These results demonstrate that peptide-MHC II protein complexes achieve high affinity binding from the array of hydrogen bonds that are energetically segregated from the pocket interactions, which can then add to an intrinsic hydrogen bond-mediated affinity. Thus, MHC II proteins are unlike antibodies, which utilize cooperativity among binding interactions to achieve high affinity and specificity. The significance of these observations is discussed within the context of possible mechanisms for the HLA-DM protein that regulates peptide presentation in vivo and the design of non-peptide molecules that can bind MHC II proteins and act as vaccines or immune modulators.

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Section: D E S I G N O F P E P T I D E -M I M E T I C S T H a T Bmentioning

confidence: 99%

Binding interactions between peptides and proteins of the class II Major Histocompatibility Complex

McFarland

Beeson

2002

Medicinal Research Reviews

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“…Consequently, ara-C has a very short plasma half-life as well as low systemic exposure and must be administered in continuous infusion or on a complex schedule to provide maximum therapeutic efficacy (Ho and Frei 1971;Rustum and Raymakers 1992). In an attempt to avoid the deamination and also to enhance the cellular uptake of ara-C, many prodrug strategies have been explored with varied degrees of success but few have led to an approved product (Hadfield & Sartorelli 1984;Wipf & Li 1994;Wipf et al 1996;Greenwald et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Enhanced cellular uptake of Ara-C via a peptidomimetic prodrug, L-valyl-ara-C in Caco-2 cells

Cheon

Hong

Han

2006

Journal of Pharmacy and Pharmacology

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This study aimed to investigate the gastrointestinal stability and the cellular uptake characteristics of L-valyl-ara-C, a peptidomimetic prodrug of ara-C (cytarabine). After the synthesis of Lvalyl-ara-C via the incorporation of L-valine into the N4-amino group of the cytosine ring in ara-C, the gastrointestinal stability of L-valyl-ara-C was examined using artificial gastric juice and artificial intestinal fluids. The cellular uptake characteristics of L-valyl-ara-C were also examined in Caco-2 cells. The disappearance half-life of L-valyl-ara-C was 2.2 h in artificial gastric juice, while the degradation of L-valyl-ara-C was negligible in artificial intestinal fluid and also in the supernatant above the Caco-2 cell monolayer during the 2-h incubation. The cellular accumulation of L-valyl-ara-C was 5-fold higher than that of ara-C in Caco-2 cells. Furthermore, the cellular uptake of L-valyl-ara-C did not increase proportionally to the increase in drug concentration. The cellular accumulation of L-valyl-ara-C was significantly reduced in the presence of uridine, p-aminohippurate, tetraethylammonium and small dipeptides, while it was not changed in the presence of L-valine and benzoic acid, suggesting that L-valyl-ara-C could interact with multiple uptake transporters, including peptide transporters, organic anion and cation transporters and nucleoside transporters, but might not interact with amino acid transporters. In conclusion, L-valyl-ara-C could be effective to improve the oral absorption of ara-C via the carrier-mediated transport pathway.

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“…Consequently, ara-C has a very short plasma half-life as well as low systemic exposure, and must be administered in continuous infusion or on a complex schedule to provide maximum therapeutic efficacy [3,4] . Therefore, considerable efforts have been directed at an enhancement of the therapeutic efficacy of ara-C, and many prodrug strategies have been explored for the oral delivery of ara-C with varied degrees of success [5][6][7][8] . However, few have led to an approved product and thus, there continues to be a great need for improved methods to deliver pharmacologically active ara-C.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic characteristics of L-valyl-ara-C and its implication on the oral delivery of ara-C

Cheon

Han

2007

Acta Pharmacologica Sinica

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Aim: To evaluate the pharmacokinetic characteristics of L‐valyl‐ara‐C, a peptidomimetic prodrug of ara‐C. Methods: After the synthesis of L‐valyl‐ara‐C, the in vitro stability of L‐valyl‐ara‐C was examined in various biological media. Plasma pharmacokinetic profiles of ara‐C and L‐valyl‐ara‐C were also evaluated in rats. Results: The degradation of L‐valyl‐ara‐C was negligible in fresh plasma and also in the presence of plasmin over a 2 h incubation period. Furthermore, L‐valyl‐ara‐C appeared to be stable in the leukemia cell homogenates, and subsequently, it was far less cytotoxic than the parent, ara‐C in AML2 and L1210 cells. The chemical hydrolysis of L‐valyl‐ara‐C was rather accelerated in acidic pH. Following an oral administration of L‐valyl‐ara‐C, the appearance of ara‐C was observed in plasma although the systemic exposure of the prodrug was much higher than that of ara‐C. The bioavailability of ara‐C was about 4% via prodrug administration. Conclusion: The amide bond of L‐valyl‐ara‐C was stable against the enzymatic hydrolysis, and the utility of L‐valyl‐ara‐C as an oral delivery system of ara‐C appeared to be limited by its low metabolic conversion to ara‐C in rats.

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Synthesis of chemoreversible prodrugs of ara-C with variable time-release profiles. Biological evaluation of their apoptotic activity

Cited by 31 publications

References 21 publications

Binding interactions between peptides and proteins of the class II Major Histocompatibility Complex

Binding interactions between peptides and proteins of the class II Major Histocompatibility Complex

Enhanced cellular uptake of Ara-C via a peptidomimetic prodrug, L-valyl-ara-C in Caco-2 cells

Pharmacokinetic characteristics of L-valyl-ara-C and its implication on the oral delivery of ara-C

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