TY - JOUR
T1 - Synthesis of new arylsulfonylspiroimidazolidine-2 ',4 '-diones and study of their effect on stimulation of insulin release from MIN6 cell line, inhibition of human aldose reductase, sorbitol accumulations in various tissues and oxidative stress
AU - Iqbal, Zafar
AU - Morahan, Grant
AU - Arooj, Mahreen
AU - Sobolev, Alexandre N.
AU - Hameed, Shahid
PY - 2019/4/15
Y1 - 2019/4/15
N2 - A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293). (C) 2019 Published by Elsevier Masson SAS.
AB - A novel class of spiroimidazolidine-2',4'-diones substituted with aryl sulfonyl group at different positions was designed and synthesized. The target compounds were evaluated for their potential to release insulin from MIN6 cell line derived from in-vivo immortalized insulin-secreting pancreatic cells. The MIN6 cells represent an important model of beta cells, which as passage numbers increases, lose the first phase but retain partial second phase glucose stimulated insulin secretion (GSIS), similar to patients in early type 2 diabetes onset. Some of the compounds exhibited high potency. Compound 2d and 3f exhibited excellent insulin release activity from MIN6 cells when compared with standard drug, tolbutamide. Some of these compounds had a potent inhibitory activity for human recombinant aldose reductase (ALR2), an enzyme which converts glucose into sorbitol and plays a key role in development of complications arising from diabetes, such as retinopathy, nephropathy, neuropathy and cataract formation. Against human recombinant ALR2, compounds 2a, 3a-d, and 3f-h displayed effective inhibition activities. The results were augmented by the ability of the compounds to prevent sorbitol accumulation in the isolated rat lenses, sciatic nerves and erythrocytes. Some of the compounds were found to possess excellent dual activity, hence they may be promising candidates to modify and evaluate their dual action, i.e., insulin release to combat diabetes and ALR2 inhibition to prevent/treat diabetic complications. The compounds were also found to possess good antioxidant efficacy. Furthermore, most of the compounds lack toxicity as determined on human embryonic kidney cell lines 293 (HEK293). (C) 2019 Published by Elsevier Masson SAS.
KW - Insulin secretion
KW - Aldose reductase
KW - Aldehyde reductase
KW - Sorbitol accumulation
KW - Oxidative stress
KW - Sulfonylureas
KW - Spiroimdazolidinediones
KW - RESOLUTION DRUG DESIGN
KW - IN-VITRO
KW - HYPOGLYCEMIC ACTIVITY
KW - DIABETIC-NEUROPATHY
KW - POTENT
KW - FIDARESTAT
KW - GLUCOSE
KW - SECRETION
KW - BINDING
KW - COMPLICATIONS
U2 - 10.1016/j.ejmech.2019.02.036
DO - 10.1016/j.ejmech.2019.02.036
M3 - Article
C2 - 30818176
SN - 0223-5234
VL - 168
SP - 154
EP - 175
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -