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Paper | Regular issue | Vol 91, No. 3, 2015, pp.550-560
Published online, 3rd February, 2015
DOI: 10.3987/COM-14-13159
Intramolecular Methionine Residue and Its Peptide Segments Stabilize Dehydroandrographolide Succinate-Methoxypolyethylene Glycol Conjugates

Senhao Li, Siliang Feng, Lei Qiao, Qingbin Meng, Huajin Dong, Zehui Gong, Dongqin Quan, and Keliang Liu*

*Department of Medicinal Chemistry, Beijing Institute of Pharmacology and Toxicology, No. 27 Taiping Road, Haidian District, Beijing 100850, China

Abstract

The antipyretic, analgesic, and anti-inflammatory activities of dehydroandrographolide succinate (DAS), an andrographolide derivative, are superior to its parent compound. However, its instability and poor water solubility have restricted its clinical use. To solve these problems, a series of DAS conjugates with functional amino acids or peptides coupled to methoxypolyethylene glycol (mPEG) were designed and synthesized. Conjugation of DAS directly to mPEG improved the compound solubility in aqueous solution, but the thermostability of the conjugate was reduced compared with the parent compound. Introduction of methionine (Met) or oligomethionyl peptides, DAS-Metn-mPEG (n = 1, 2, or 3), protected the DAS skeleton from ring opening and double bond oxidation, thus improving the anti-inflammatory properties of these derivatives compared with DAS.