Synthesis and biological activities of d-chiro-inositol analogues with insulin-like actions

• d-chiro-inositol evokes therapeutic actions in diabetes and insulin resistance.
• The 1/6-hydroxyl group is not essential for activity and can be modified.
• Removal of the 3/4-hydroxyl group removal has little effect on activity.
• The hydroxyl at position 2 is crucial to activity but can withstand modification.
• Chemical modifications offer scope for the development of DCI analogues.

d-chiro-inositol (DCI, 1) evokes therapeutic actions in diabetes and insulin resistance but has sub-optimal pharmacokinetic profiles. To investigate what positions on the DCI cyclohexanol ring may be amenable to modification to improve pharmaceutical formulations, a series of analogues based on DCI were synthesised. These compounds were then evaluated for their ability to stimulate glucose transport using 3T3-L1 adipocytes as a model system. Positional analyses indicate that the hydroxyl group at position 1 is not essential for activity and can be modified without affecting glucose uptake. Removal of the hydroxyl at position 3 also had minimal effect on activity but this group is sensitive to modification. By comparison, the oxygen at position 2 is crucial to the potency of DCI, although this group can withstand modification without fundamentally affecting activity. These data reveal that positions 1 and 2 on the cyclohexanol ring of DCI offer further scope for modification to develop DCI analogues with desirable pharmacokinetic profiles for the potential treatment of metabolic disease.

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