Synthesis of hydantoin analogues of (2S,3R,4S)-4-hydroxyisoleucine with insulinotropic properties

Bioorganic and Medicinal Chemistry Letters

Volumn 18, Issue 15, 2008, Pages 4332-4335

  Sergent, Didier ^a   Wang, Qian ^a   Sasaki, N André ^a   Ouazzani, Jamal ^a  

^a CNRS   (France)

Author keywords

4 Hydroxyisoleucine; Fenugreek; Hydantoin; Insulin secretion; Type 2 diabetes

Indexed keywords

4 HYDROXYISOLEUCINE; ALDEHYDE; HYDANTOIN DERIVATIVE; REPAGLINIDE;

ANIMAL CELL; ARTICLE; BIOLOGICAL ACTIVITY; CONTROLLED STUDY; DRUG STABILITY; DRUG SYNTHESIS; INSULIN LIKE ACTIVITY; INSULIN RELEASE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PH; RAT;

ANIMALS; DIABETES MELLITUS, TYPE 2; HYDANTOINS; INSULIN; ISOLEUCINE; MOLECULAR STRUCTURE; RATS; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP;

TRIGONELLA FOENUM-GRAECUM;

EID: 47749083456     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.06.081     Document Type: Article

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15. 1H NMR spectra of the lactones obtained from the minor hydantoin and authentic (2S,3R,4S)-4-hydroxyisoleucine match perfectly. In order to avoid epimerization, transformations of both isomers of 3 to lactones were carried out under acidic conditions (6 N HCl, 2 h, 70 °C).
16. 3 (172,18): Calcd C, 48.83; H, 7.02; N, 16.27; O, 27.88. Found: C, 48.77; H, 6.88; N, 16.06; O, 27.45.
17. 9 The same procedure gives (2S,3R,4S)-hydroxyisoleucine from (2S,3R,4S)-hydantoin.
18. Stability of (2S,3R,4S)-4-hydroxyisoleucine and (2R,3R,4S)-hydantoin under acidic conditions (Fig. 3). The two doublet peaks at δ1.15 and 0.87 are attributed to the methyl groups of C-3 and C-4 position of (2S,3R,4S)-4-hydroxyisoleucine, respectively. When incubated at 37 °C and at pH 1 for 1 h, two new doublet peaks appear at δ 1.35 and 1.06 due to the two methyl groups of newly formed lactone that is about 10% with respect to 4-hydroxyisoleucine. After 4 h, the lactone represents 32%. After 20 h at the same conditions, the two doublets of the methyl groups of lactone become predominant. On the contrary, the hydantoins of (2R,3R,4S)-4-hydroxyisoleucine 1 are relatively stable under acidic conditions. The two doublet peaks at δ 1.25 and 0.82 attributed to the two methyl groups of compound 1 are still the major peaks (73%) after 20 h of incubation at 37 °C and at pH 1.
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