Regioselective solid-phase synthesis of N-mono-hydroxylated and N-mono-methylated acylpolyamine spider toxins using an 2-(ortho-nitrophenyl)ethanal-modified resin

Abstract

A recently introduced new SPS resin, possessing a 2-(ortho-nitrophenyl)ethanal linker, was used for the regioselective on-resin synthesis of N-mono-hydroxylated and N-mono-methylated polyamine spider toxins of Agelenopsis aperta and Larinioides folium. The polyamine backbones of the target compounds were efficiently constructed from the center by reductive amination of the aldehyde linker, followed by stepwise alkylation and acylation on solid support. Depending on the cleavage conditions, employing either oxidation/Cope elimination or methylation/Hofmann elimination, regioselectively the respective N-hydroxyl or N-methyl products were obtained. Employing this methodology, a number of acylpolyamine spider toxins were synthesized and identified as venom components by UHPLC and ESI-MS/MS.

Spider and Wasp Acylpolyamines: Venom Components and Versatile Pharmacological Leads, Probes, and Insecticidal Agents

“…Philanthotoxins comprise the unique and well-studied native venom acylpolyamine of wasp and their analogs (see below). Researchers have synthesized many analogs from their original structures with variable potency and selectivity for their targets, especially nAchRs and iGluRs [ 54 , 55 , 56 ].…”

“…Argi-opine and pseudoargiopines are naturally N-methylated acylpolyamines. The N-mono-methylated and N-mono-hydroxylated acylpolyamine spider toxins were also identi-fied as venom components of Agelenopsis aperta and Larinioides folium, as they were synthesized using SPS resin and a regioselective reaction [ 55 ]. Interestingly, the syn-thesis of N-mono-hydroxylated and N-mono-methylated argiopine and analogs pro-duced highly potent and selective antagonists of NMDA and AMPA iGluRs recombi-nantly expressed in Xenopus laevis oocytes [ 60 ], increasing the repertoire of acylpoly-amine structures.…”

VenoMS—A Website for the Low Molecular Mass Compounds in Spider Venoms

“…Our group started with the structure elucidation of acylpolyamines in spider venoms by HPLC-MS and MS/MS [7,8], improved the analytical methods in order to obtain better selectivities and sensitivities [9,10], synthesized acylpolyamines as reference material [11][12][13], and studied their MS/MS fragmentation behavior [14]. The key revelation of these studies was that polyamine derivatives undergo mainly intramolecular nucleophilic substitution reactions at protonated amino groups under MS/MS conditions.…”