Enantiopure Sulforaphane Analogues with Various Substituents at the Sulfinyl Sulfur: Asymmetric Synthesis and Biological Activities

Abstract

A convergent and high-yielding approach for the asymmetric synthesis of sulforaphane 2 and four analogues differently substituted at the sulfinyl sulfur has been developed. The key step of the synthesis is the diastereoselective synthesis of sulfinate ester 23-S(S), using the DAG (diacetone-D-glucofuranose)-methodology. The biological activity of these compounds as inductors of phase II detoxifying enzyme has been studied by determining their ability to activate the cytoprotective transcription factor Nrf2.

Sulforaphane homologues: Enantiodivergent synthesis of both enantiomers, activation of the Nrf2 transcription factor and selective cytotoxic activity

“…Noteworthy, none of these methods is able to give sulforaphane analogues with substituent at the sulfur different from a methyl group. In order to solve this problem we have recently reported that sulfinate ester 10, is an effective sulfinylating agent able to efficiently transfer the linear alkyl sulforaphane side chain in enantiomeric form [39]. In the present work, in order to modulate the different variables of sulforaphane, we need a methodology capable of producing sulforaphane homologues with different substituents at the sulfur, and different chain length between the sulfoxide and the isothiocyanate groups, preferably in both enantiomeric 11 forms.…”

“…A subsequent study on the modulation of glucuronosyl transferase and epoxide hydrolase, two major carcinogen-metabolising enzyme systems, showed that the R-enantiomer enhanced, whereas the S-enantiomer impaired, glucuronosyl transferase activity and that the Rsulforaphane was more effective than the S-enantiomer in up-regulating microsomal epoxide hydrolase [38]. Finally, while the nature of the chain linking the electrophilic isothiocyanate group and the Lewis basic sulfinyl moiety on their anticancer activity has been determined, only few studies have been conducted on the importance of the substituent at the sulfinyl sulfur [31,32,39]. It should be noted that despite the great efforts made, and the hundreds of analogues assayed, no one surpassed yet the biological activity of natural SFN.…”

New Method for the Synthesis of Sulforaphane and Related Isothiocyanates

“…2 The organic isothiocyanates are not produced by the plants as such, but are formed by the enzymatic action of myrosinase (a thioglycosidase) on natural glucosinolates (b-thioglucoside N-hydroxysulfates) such as glucopharin (Scheme 1). 3 When the plants are crushed and chewed, the glucosinolates are hydrolyzed by myrosinase to produce the corresponding isothiocyanates, such as sulforaphane (1; 4-isothiocyanatobutyl methyl sulfoxide). 4 This naturally occurring isothiocyanate was first isolated by scientists at Johns Hopkins University in 1992.…”

“…6 The biological activity of sulforaphane and its derivatives as inducers of phase II detoxifying enzymes has been studied by determining the ability of the isocyanates to activate a cytoprotective transcription factor known as NF-E2-related factor 2 (Nrf2). 3 According to the US National Cancer Institute, sulforaphane (1) is considered to be one of the 40 most promising anticancer agents. 7 This small molecule has attracted considerable attention because of its unique cancer-preventing properties.…”

“…14 Several groups have reported stereoselective syntheses of enantiomerically pure sulforaphane and its derivatives. 3,[15][16] Although the natural form of the substance, (R)-sulforaphane, exists as a single enantiomer, most studies on its biological activities have been conducted by using the racemic form because early studies showed that the chirality of the sulfoxide group in sulforaphane does not affect its potency as an enzyme inducer. 5 As a part of our efforts to investigate structure-activity relationships for sulforaphane (1) and related compounds, we needed to synthesize large quantities of the racemic substance.…”