RESUMEN
Trihydroxypiperidines are a therapeutically valuable class of iminosugar. We applied a one-pot amination-cyclisation cascade reaction to synthesise 3,4,5-trihydroxypiperidine stereoisomers in three steps from commercially available pentoses and in excellent overall yields. Using our methodology, the yields of the syntheses of meso-1, meso-2 and 3L are the highest reported to date. The synthetic methodology was readily extended to the three-step synthesis of N-alkyl derivatives by replacing the ammonia nitrogen source with a primary amine. The trihydroxypiperidines and N-alkyl analogues were screened for enzyme inhibitory activity using Fabrazyme (Fabry disease), GCase (Gaucher's disease), Agrobacterium sp. ß-glucosidase, and Escherichia coli ß-galactosidase. N-Phenylethyl 3,4,5-trihydroxypiperidine (N-phenylethyl-1-(3R,4R,5S)-piperidine-3,4,5-triol) showed good inhibitory activity of Fabrazyme (Ki = 46 µM). This activity was abolished when the N-phenylethyl group was removed or replaced with a non-aromatic alkyl chain.
Asunto(s)
Inhibidores Enzimáticos , Piperidinas , Piperidinas/química , Piperidinas/farmacología , Piperidinas/síntesis química , Aminación , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/química , Ciclización , Glicósido Hidrolasas/antagonistas & inhibidores , Glicósido Hidrolasas/metabolismo , Escherichia coli/efectos de los fármacos , Escherichia coli/enzimología , Estructura MolecularRESUMEN
The development of a one-step amination-cyclization cascade reaction for the synthesis of N-substituted iminosugars from iodo-pentoses and hexoses is reported. This novel methodology allows for the stereoselective conversion of easily accessible iodo-aldoses and iodo-ketoses into iminosugars in a single step, in highly efficient yields (63-95%), and in aqueous media. Furthermore, the use of functionalized amines allows for the synthesis of N-functionalized iminosugars without additional steps. To illustrate this methodology, a number of biologically important iminosugars were prepared, including 1-deoxynojirimycin, (3S,4R,5S,6R)-azepane-3,4,5,6-tetraol, and N-functionalized 1-deoxymannojirimycins.
RESUMEN
A series of N,N-bis(glycityl)amines with promising anti-cancer activity were prepared via the reductive amination of pentoses and hexoses, and subsequently screened for their ability to selectively inhibit the growth of cancerous versus non-cancerous cells. For the first time, we show that this class of compounds possesses anti-proliferative activity, and, while the selective killing of brain cancer (LN18) cells versus matched (SVG-P12) cells was modest, several of the amines, including d-arabinitylamine 1a and d-fucitylamine 1g, exhibited low micromolar IC50 values for HL60 cells. Moreover, these two amines showed good selectivity towards HL60 cells when compared to non-cancerous HEK-293 cells. The compounds also showed low micromolar inhibition of the leukaemic cell line, THP-1. The modes of action of amines 1a and 1g were then determined using yeast chemical genetics, whereby it was established that both compounds affect similar but distinct sets of biochemical pathways. Notably purine nucleoside monophosphate biosynthesis was identified as an enriched mechanism. The rapid synthesis of the amines and their unique mode of action thus make them attractive targets for further development as anti-cancer drugs.