Synthesis of Diosgenin-Ibuprofen Derivatives and Their Activities against Insulin-Dependent Diabetes Mellitus

Abstract

The synthesis and anti-diabetes activities of diosgenin-ibuprofen derivatives were investigated. Ibuprofen (IBU) was chemically coupled with diosgenin either directly or through amino acid esters linkers. The effects of these compounds on lipopolysaccharide (LPS)-induced nitric oxide (NO) generation were assessed. The results showed spirost-5-en-3β-yl (2-(4-isobutyl-phenyl)-propionate) (4) was of better activity to suppress the production of NO in the supernatant of LPS-stimulated RAW264.7 cells. In vivo investigation on nonobese diabetic (NOD) mice indicated that compound 4 decreased the incidence of insulin-dependent diabetes mellitus (IDDM; type 1 diabetes) of NOD mice which suggested a potential activity of compound 4 against type 1 diabetes.Key words diosgenin-ibuprofen; nitric oxide generation; type 1 diabetes Diabetes mellitus (DM) is a common but complicated metabolic disease characterized by hyperglycemia. Insulin-dependent diabetes mellitus (IDDM; type 1 diabetes) results from the damage of the insulin-secreting β-cells in the pancreas through an autoimmune process, leading to permanent deficiency of endogenous insulin. [1][2][3] Although patients with this form of diabetes could depend on exogenous insulin to sustain life, serious complications such as cardiovascular diseases, blindness, kidney failure and stroke caused by hyperglycemia will lead to a high fatality rate.4-6) Therefore, applying processes or compounds that can strictly control the level of blood glucose or protect islet β-cells against destruction may be an alternative way to treat type 1 diabetes.Proinflammatory cytokines are cytotoxic to β-cells and have been implicated in the pathogenesis of type 1 diabetes. [7][8][9] Insulin which is the primary medication used to treat the diabetes and prevent complications in all DM patients suppresses the inflammatory process of type 1 diabetes through preventing hyperglycemia and modulating key inflammatory molecules.10) On one hand, there were studies suggesting that some non-steroidal anti-inflammatory drugs (NSAIDs) are effective in the treatment of type 1 diabetes, such as lisofylline (LSF), 11) pentoxifylline (PTX) 12) and aspirin. [13][14][15][16][17] Ibuprofen (IBU), also a NSAID, was reported to have the capacity of controlling blood glucose concentration and promoting glucose tolerance.13) It becomes toxic only at very high doses and has a wide therapeutic window.18) The anti-inflammatory activities of IBU were connected with the inhibition of cyclooxygenase enzymes, which reduce the synthesis of prostaglandins. It has also an inhibitory effect on the inducible nitric oxide synthase (iNOS) protein which diminishes the synthesis of the proinflammatory cytokines.19-21) On the other hand, steroidal anti-inflammatory drugs (SAIDS) could induce apoptosis or cell death of inflammatory cells and inhibit the production of inflammatory cytokines which are involved in the regulation of glucose metabolism and β-cell secretion.22) Diosgenin, an aglycone of steroidal saponins, possesses a variety o...

Diosgenin as a Novel Therapeutic Natural Product for Various Diseases: An Overview

“…Hence, n-(phenyl) methyl substitution in DG has strong anti-inflammatory, antioxidant and anti-Aβ activity 69 . Ibuprofen (2-(4-isobutylphenyl)-propionic acid) combined with DG derivatives employing 6-aminohexanoic acid at the 27th position has substantially proven for its anti-inflammatory activity in in-vitro and in-vivo inflammatory models 70 .…”

The crystal structure of (6aR,6bS,8aS,8bR,9S,11aS,12aS,12bS)-10-(4-acetoxy-3-methylbutyl)-6a,8a,9-trimethyl-3,4,5,6,6a,6b,7,8,8a,8b,9,10,11a,12,12a,12b-hexadecahydro-1H-naphtho[2′,1′:4,5]indeno[2,1-b]furan-4-yl acetate, C31H48O5

“…It has been reported that DG shows vasodilatory activity [5], renoprotective effects [6]. DG derivatives are known for the wide spectrum of biological activities, such as to prevent thrombosis effects [7], anti-inflammatory activity [8], anti-cancer activity [9]. Moreover, many steroid sapogenins such as diosgenin, sisalagenin, neo-pentologenin and luvigenin have already been used in many aspects for the treatment of various diseases.…”