Synthesis and Sulfur Electrophilicity of the Nuphar Thiaspirane Pharmacophore

Abstract

We describe a general method to synthesize the iminium tetrahydrothiophene embedded in the dimeric Nuphar alkaloids. In contrast to prior studies, the sulfur atom of the thiaspirane pharmacophore is shown to be electrophilic. This α-thioether reacts with thiophenol or glutathione at ambient temperature to cleave the C–S bond and form a disulfide. Rates of conversion are proportional to the corresponding ammonium ion pKa and exhibit half-lives less than 5 h at a 5 mM concentration of thiol. A simple thiophane analogue of the Nuphar dimers causes apoptosis at single-digit micromolar concentration and labels reactive cysteines at similar levels as the unsaturated iminium “warhead”. Our experiments combined with prior observations suggest the sulfur of the Nuphar dimers can react as an electrophile in cellular environments and that sulfur-triggered retrodimerization can occur in the cell.

Nuphar lutea Extracts Exhibit Anti-Viral Activity against the Measles Virus

“…We hypothesize that the mechanism of action of nupharidines goes via the electrophilic thiaspirane warhead of nupharidine(s), which targets a nucleophilic cysteine at the active site of cysteine proteases and potentially other enzymes. This mechanism may explain the pleiotropic effect of this family of compounds [31]. The potential medicinal properties of N. lutea require specific defined therapeutic windows for each system to be effective.…”

Получение Нуфлеина — Алкалоида Кубышки Желтой — И Его Цитотоксическое Действие На Культуры Нормальных И Опухолевых Клеток Человека

“…Ïðåäïîëàãàåòñÿ, ÷òî öèòîòîêñè÷íîå äåéñòâèå íóôëåèíà îïðåäåëÿåòñÿ ñâîéñòâàìè àòîìà ñåðû, íàõîäÿùåãîñÿ â òèîýôèðíîé ñâÿçè â ìîëåêóëå ôàðìàêîôîðà.  ðàáîòå [14] ïîêàçàíî, ÷òî ýëåêòðîôèëüíûé àòîì ñåðû ðåàãèðóåò c òèîëàìè îêðóaeàþùåé ñðåäû, ïðåèìóùåñòâåííî ñî ñâîáîäíûìè òèîëàìè, òàêèìè êàê ãëóòàòèîí, ñ îáðàçîâàíèåì äèñóëüôèäîâ. Êîíöåíòðàöèè íóôëåèíà è åãî ñèíòåçèðîâàííûõ ñòðóêòóðíûõ àíàëîãîâ (ñòåðåîèçîìåðîâ è äèìåðîâ), èíäóöèðóþùèå áûñòðûé àïîïòîç êëåòîê Jurkat and HT29, âàðüèðîâàëè îò 1 äî 25 ìêÌ.…”

6,6′-Dihydroxythiobinupharidine (DTBN) Purified from Nuphar lutea Leaves Is an Inhibitor of Protein Kinase C Catalytic Activity

“…We hypothesize that the mechanism of action of nupharidines goes via the electrophilic thiaspirane warhead of nupharidine(s), which targets a nucleophilic cysteine at the active site of cysteine proteases, and potentially other enzymes. This mechanism may explain the pleiotropic effect of this family of compounds [ 15 ]. Being pleiotropic and not limited to a single molecular target may be advantageous.…”