ChemInform Abstract: AMINO ACIDS AND PEPTIDES. PART 36. DEHYDROAMINO ACIDS. PART 16. SIMPLE PREPARATION OF N‐ACYL‐2‐(DIETHOXYPHOSPHORYL)GLYCINE ESTERS AND THEIR APPLICATION IN THE SYNTHESIS OF DEHYDROAMINO ACID ESTERS

A series of N-(2-aminoethyl)-alpha-amino acid thymine peptide nucleic acid (PNA) monomers bearing glycosylated side chains in the alpha-amino acid position have been synthesized. These include PNA monomers where glycine has been replaced by serine and threonine (O-glycosylated), derivatives of lysine and nor-alanine (C-glycosylated), and amide derivatives of aspartic acid (N-glycosylated). The Boc and Fmoc derivatives of these monomers were used for incorporation in PNA oligomers. Twelve PNA decamers containing the glycosylated units in one, two, or three positions were prepared, and the thermal stability (T(m)) of their complexes with a complementary RNA was determined. Incorporation of the glycosyl monomers reduced the duplex stability by 0-6 degrees C per substitution. A cysteine was attached to the amino terminus of eight of the PNA decamers (Cys-CTCATACTCT-NH(2)) for easy conjugation to a [(18)F]radiolabeled N-(4-fluorobenzyl)-2-bromoacetamide. The in vivo biodistribution of these PNA oligomers was determined in rat 2 h after intravenous administration. Most of the radioactivity was recovered in the kidneys and in the urine. However, N-acetylgalactosamine (and to a lesser extent galactose and mannose)-modified PNAs were effectively targeting the liver (40-fold over unmodified PNA). Thus, the pharmacodistribution in rats of PNA oligomers can be profoundly changed by glycosylation. These results could be of great significance for PNA drug development, as they should allow modulation and fine-tuning of the pharmacokinetic profile of a drug lead.

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Modulation of the Pharmacokinetic Properties of PNA: Preparation of Galactosyl, Mannosyl, Fucosyl, N-Acetylgalactosaminyl, and N-Acetylglucosaminyl Derivatives of Aminoethylglycine Peptide Nucleic Acid Monomers and Their Incorporation into PNA Oligomers

Hamzavi

Dollé

Tavitian

et al. 2003

Bioconjugate Chem.

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ChemInform Abstract: AMINO ACIDS AND PEPTIDES. PART 36. DEHYDROAMINO ACIDS. PART 16. SIMPLE PREPARATION OF N‐ACYL‐2‐(DIETHOXYPHOSPHORYL)GLYCINE ESTERS AND THEIR APPLICATION IN THE SYNTHESIS OF DEHYDROAMINO ACID ESTERS

Abstract: Das geschützte Hydroxy‐glycin (Ia) wird in den Phosphonsäureester (II) übergeführt, der mit den Aldehyden (III) zu den Dehydroaminosäureestern (IV) kondensiert wird.

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Modulation of the Pharmacokinetic Properties of PNA: Preparation of Galactosyl, Mannosyl, Fucosyl, N-Acetylgalactosaminyl, and N-Acetylglucosaminyl Derivatives of Aminoethylglycine Peptide Nucleic Acid Monomers and Their Incorporation into PNA Oligomers

Modulation of the Pharmacokinetic Properties of PNA: Preparation of Galactosyl, Mannosyl, Fucosyl, N-Acetylgalactosaminyl, and N-Acetylglucosaminyl Derivatives of Aminoethylglycine Peptide Nucleic Acid Monomers and Their Incorporation into PNA Oligomers

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