title: Synthesis and biological activities of d-chiro-inositol analogues with insulin-like actions.
abstract: 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.
authors.affiliation: Ferrier Research Institute, Victoria University of Wellington, Lower Hutt, New Zealand.
authors.forename: P M
authors.initials: PM
authors.lastname: Rendle
authors.affiliation: School of Biological Sciences, University of Auckland, New Zealand.
authors.forename: F
authors.initials: F
authors.lastname: Kassibawi
authors.affiliation: Ferrier Research Institute, Victoria University of Wellington, Lower Hutt, New Zealand.
authors.forename: K A
authors.initials: KA
authors.lastname: Johnston
authors.affiliation: Ferrier Research Institute, Victoria University of Wellington, Lower Hutt, New Zealand.
authors.forename: J B
authors.initials: JB
authors.lastname: Hart
authors.affiliation: Ferrier Research Institute, Victoria University of Wellington, Lower Hutt, New Zealand.
authors.forename: S A
authors.initials: SA
authors.lastname: Cameron
authors.affiliation: Ferrier Research Institute, Victoria University of Wellington, Lower Hutt, New Zealand.
authors.forename: A
authors.initials: A
authors.lastname: Falshaw
authors.affiliation: Ferrier Research Institute, Victoria University of Wellington, Lower Hutt, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, New Zealand. Electronic address: gavin.painter@vuw.ac.nz.
authors.forename: G F
authors.initials: GF
authors.lastname: Painter
authors.affiliation: School of Biological Sciences, University of Auckland, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, New Zealand. Electronic address: k.loomes@auckland.ac.nz.
authors.forename: K M
authors.initials: KM
authors.lastname: Loomes
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000478:Alkylation; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D005947:Glucose / Q000378:metabolism; D007294:Inositol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D007328:Insulin; D007294:Inositol; D005947:Glucose
keywords: Diabetes mellitus; Insulin mimetics; Metabolic disease; Polycystic ovarian syndrome; d-chiro-inositol