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Synthesis of Cholic Acid-Peptide Conjugates With A Negatively Charged Ester Linkage for Oral Delivery | OMICS International | Abstract
ISSN: 2161-0444

Medicinal Chemistry
Open Access

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Research Article

Synthesis of Cholic Acid-Peptide Conjugates With A Negatively Charged Ester Linkage for Oral Delivery

Hengguang Li1*, Haijing Song2, Svein Oie2 and D’Robert Lu3

1Department of Chemistry and Physics, Fayetteville State University, Fayetteville, NC, USA

2Metabolic Center, Duke University, Durham, NC, USA

3College of Pharmacy, University of Georgia, Athens, GA, USA

*Corresponding Author:
Hengguang Li
Department of Chemistry and Physics
Fayetteville State University, Fayetteville
NC 28301, USA
Tel: 410-900-3013 (or) 910-672-2651
E-mail: [email protected]

Received Date: January 22, 2017; Accepted Date: February 02, 2017; Published Date: February 06, 2017

Citation: Li H, Song H, Oie S, Lu RD (2017) Synthesis of Cholic Acid-Peptide Conjugates With A Negatively Charged Ester Linkage for Oral Delivery. Med Chem (Los Angeles) 7:031-038. doi: 10.4172/2161-0444.1000428

Copyright: © 2017 Hengguang Li, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

The progress in oral absorption of protein and peptide drugs has been hampered by the difficulty in transporting larger molecules across the gastrointestinal membrane. We are reporting here a study of the design and synthesis of cholic acid-peptide conjugates for peptide drug delivery through gastrointestinal track mediated by bile acid transporter. As principal samples, three small cholic acid-peptide conjugates containing a biodegradable ester bond via threonine linker have been synthesized. In order to introduce ester bond between cholic acid and peptides, conventional solid phase synthesis is not practicable, thus solution phase was employed. The threonine moiety was chosen to introduce a hydroxyl group, on which an ester bond can be formed with different peptides. The threonine moiety also provides the necessary negative charge adjacent to the C24 position as required for transport recognizing by the bile acid transporter in the ilue epicell. The synthetic process was based on DCC chemistry. By using catalytic amounts of N-hydroxysuccinimide the procedure for amide coupling was simplified and shortened while maintaining high efficiency. Esterification using ethyl acetate in the presence of triethylamine selectively introduced an ester bond at the C27 position giving higher yield with no protection on other three hydroxyls. The work also demonstrated that in solution phase synthesis of these peptide conjugates fluoride ion (F-) was more efficient than piperidine to cleave Fmoc from the amino group.

Cell culture experiment showed the efficiencies of transporting of the conjugates and the dissociation of the conjugates detected by HPLC, suggesting that the cholic acid conjugates linked by degradable ester bond can be used as bigger molecule drugs delivering template. Further study would be designed by using more different linkers that would be also biodegradable bonds, such as thioester and so forth.

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