Synthesis and solid-state conformations of 6S,8aR/S-6-alkyl-3,3-dimethyltetrahydrooxazolo[3,4-a]pyrazine-5,8-diones (pseudoproline DKPs).

Anne Beauchard, Helen F Dufton, Kere Odumah, Rhian H Jaggers, Mary F Mahon, Pauline J Wood, Michael Threadgill

Research output: Contribution to journalArticle

Abstract

Peptide-like self-immolative molecular clips are required for release of active drugs from prodrugs by endopeptidases, generating diketopiperazines (DKPs) as by-products. Two diastereomeric series of cyclo-L-aminoacyl-R/S-dimethyloxazolidinecarboxylate DKPs, derived from L-Ala, L-Leu and L Val, were synthesised. The oxazolidines were constructed by acid-catalysed condensation of N-protected L-Aaa-L/D-SerOMe dipeptides with Me2C(OMe)2, providing the protected Dmo dipeptides. Deprotection exposed the primary amines, which cyclised rapidly to give the desired DKPs. The conformations were studied by NMR in CDCl3 solution and, for the L,R series, by X-ray crystallography. The L,S series had the DKP in a boat conformation with the oxazolidine in a half-chair; the L,R series had the DKP in a flattened conformation with the oxazolidine in an alternative half-chair. Early kinetic studies have shown that L,R-Dmo dipeptide amides cyclised more rapidly than L,S-diastereoisomers and that the rate of cyclisation in the L,R series depends inversely on steric bulk at the alpha-carbon. Cyclo-L-Leu-R-Dmo was non-toxic towards human HT29 cells.
LanguageEnglish
JournalIndian Journal of Heterocyclic Chemistry
StatusPublished - 2018

Fingerprint

Diketopiperazines
Pyrazines
S 6
Conformations
Dipeptides
Endopeptidases
HT29 Cells
Ships
X ray crystallography
X Ray Crystallography
Cyclization
Prodrugs
Boats
Surgical Instruments
Amides
Amines
Byproducts
Condensation
Carbon
Nuclear magnetic resonance

Cite this

Synthesis and solid-state conformations of 6S,8aR/S-6-alkyl-3,3-dimethyltetrahydrooxazolo[3,4-a]pyrazine-5,8-diones (pseudoproline DKPs). / Beauchard, Anne; Dufton, Helen F; Odumah, Kere; Jaggers, Rhian H; Mahon, Mary F; Wood, Pauline J; Threadgill, Michael.

In: Indian Journal of Heterocyclic Chemistry, 2018.

Research output: Contribution to journalArticle

@article{1fabb8f8ad024d35b8d7265d31680125,
title = "Synthesis and solid-state conformations of 6S,8aR/S-6-alkyl-3,3-dimethyltetrahydrooxazolo[3,4-a]pyrazine-5,8-diones (pseudoproline DKPs).",
abstract = "Peptide-like self-immolative molecular clips are required for release of active drugs from prodrugs by endopeptidases, generating diketopiperazines (DKPs) as by-products. Two diastereomeric series of cyclo-L-aminoacyl-R/S-dimethyloxazolidinecarboxylate DKPs, derived from L-Ala, L-Leu and L Val, were synthesised. The oxazolidines were constructed by acid-catalysed condensation of N-protected L-Aaa-L/D-SerOMe dipeptides with Me2C(OMe)2, providing the protected Dmo dipeptides. Deprotection exposed the primary amines, which cyclised rapidly to give the desired DKPs. The conformations were studied by NMR in CDCl3 solution and, for the L,R series, by X-ray crystallography. The L,S series had the DKP in a boat conformation with the oxazolidine in a half-chair; the L,R series had the DKP in a flattened conformation with the oxazolidine in an alternative half-chair. Early kinetic studies have shown that L,R-Dmo dipeptide amides cyclised more rapidly than L,S-diastereoisomers and that the rate of cyclisation in the L,R series depends inversely on steric bulk at the alpha-carbon. Cyclo-L-Leu-R-Dmo was non-toxic towards human HT29 cells.",
author = "Anne Beauchard and Dufton, {Helen F} and Kere Odumah and Jaggers, {Rhian H} and Mahon, {Mary F} and Wood, {Pauline J} and Michael Threadgill",
year = "2018",
language = "English",
journal = "Indian Journal of Heterocyclic Chemistry",
issn = "0971-1627",
publisher = "National Academy of Chemistry and Biology",

}

TY - JOUR

T1 - Synthesis and solid-state conformations of 6S,8aR/S-6-alkyl-3,3-dimethyltetrahydrooxazolo[3,4-a]pyrazine-5,8-diones (pseudoproline DKPs).

AU - Beauchard,Anne

AU - Dufton,Helen F

AU - Odumah,Kere

AU - Jaggers,Rhian H

AU - Mahon,Mary F

AU - Wood,Pauline J

AU - Threadgill,Michael

PY - 2018

Y1 - 2018

N2 - Peptide-like self-immolative molecular clips are required for release of active drugs from prodrugs by endopeptidases, generating diketopiperazines (DKPs) as by-products. Two diastereomeric series of cyclo-L-aminoacyl-R/S-dimethyloxazolidinecarboxylate DKPs, derived from L-Ala, L-Leu and L Val, were synthesised. The oxazolidines were constructed by acid-catalysed condensation of N-protected L-Aaa-L/D-SerOMe dipeptides with Me2C(OMe)2, providing the protected Dmo dipeptides. Deprotection exposed the primary amines, which cyclised rapidly to give the desired DKPs. The conformations were studied by NMR in CDCl3 solution and, for the L,R series, by X-ray crystallography. The L,S series had the DKP in a boat conformation with the oxazolidine in a half-chair; the L,R series had the DKP in a flattened conformation with the oxazolidine in an alternative half-chair. Early kinetic studies have shown that L,R-Dmo dipeptide amides cyclised more rapidly than L,S-diastereoisomers and that the rate of cyclisation in the L,R series depends inversely on steric bulk at the alpha-carbon. Cyclo-L-Leu-R-Dmo was non-toxic towards human HT29 cells.

AB - Peptide-like self-immolative molecular clips are required for release of active drugs from prodrugs by endopeptidases, generating diketopiperazines (DKPs) as by-products. Two diastereomeric series of cyclo-L-aminoacyl-R/S-dimethyloxazolidinecarboxylate DKPs, derived from L-Ala, L-Leu and L Val, were synthesised. The oxazolidines were constructed by acid-catalysed condensation of N-protected L-Aaa-L/D-SerOMe dipeptides with Me2C(OMe)2, providing the protected Dmo dipeptides. Deprotection exposed the primary amines, which cyclised rapidly to give the desired DKPs. The conformations were studied by NMR in CDCl3 solution and, for the L,R series, by X-ray crystallography. The L,S series had the DKP in a boat conformation with the oxazolidine in a half-chair; the L,R series had the DKP in a flattened conformation with the oxazolidine in an alternative half-chair. Early kinetic studies have shown that L,R-Dmo dipeptide amides cyclised more rapidly than L,S-diastereoisomers and that the rate of cyclisation in the L,R series depends inversely on steric bulk at the alpha-carbon. Cyclo-L-Leu-R-Dmo was non-toxic towards human HT29 cells.

M3 - Article

JO - Indian Journal of Heterocyclic Chemistry

T2 - Indian Journal of Heterocyclic Chemistry

JF - Indian Journal of Heterocyclic Chemistry

SN - 0971-1627

ER -