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

Zafar Iqbal, Grant Morahan, Mahreen Arooj, Alexandre N. Sobolev, Shahid Hameed

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Abstract

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.

Original languageEnglish
Pages (from-to)154-175
Number of pages22
JournalEuropean Journal of Medicinal Chemistry
Volume168
DOIs
Publication statusPublished - 15 Apr 2019

Cite this

@article{7a3ca92de92c47f89fd2f2c42021fbfc,
title = "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",
abstract = "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.",
keywords = "Insulin secretion, Aldose reductase, Aldehyde reductase, Sorbitol accumulation, Oxidative stress, Sulfonylureas, Spiroimdazolidinediones, RESOLUTION DRUG DESIGN, IN-VITRO, HYPOGLYCEMIC ACTIVITY, DIABETIC-NEUROPATHY, POTENT, FIDARESTAT, GLUCOSE, SECRETION, BINDING, COMPLICATIONS",
author = "Zafar Iqbal and Grant Morahan and Mahreen Arooj and Sobolev, {Alexandre N.} and Shahid Hameed",
year = "2019",
month = "4",
day = "15",
doi = "10.1016/j.ejmech.2019.02.036",
language = "English",
volume = "168",
pages = "154--175",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier",

}

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

VL - 168

SP - 154

EP - 175

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -