Solid phase synthesis of fumitremorgin, verruculogen and tryprostatin analogs based on a cyclization/cleavage strategy

Marine Natural Products as Models to Circumvent Multidrug Resistance

“…Fumitremorgins were found to be tremorgenic mycotoxins by interfering the releasing neurotransmitters and also showed inhibitory activity on cell cycle [163]. Compound 74 was reported as a chemosensitizing agent that could reverse a drug-resistant cell lines that do not overexpress P-gp and MRP [163,164].…”

“…Unfortunately, 74 was found to induce tremors or convulsion in mice and other animals [168]. Two derivatives, Ko132 (75) and Ko134 (76), were found to be potent inhibitors of the BCRP-mediated drug efflux in T6400 mouse and T8 human cell lines with low cytotoxicity at an effective concentration of 1 µM [163,169]. In addition, 77 was the most effective inhibitor of BCRP, with very low activity against P-gp or other known drug transporters [168,170].…”

“…This synthetic pathway was based on the formation of the diketopiperazine rings system, followed by simultaneous cleavage of solid support, which acted as a leaving group at the cyclization step. The reaction was performed by the Pictet-Spengler condensation of the hydroxyethyl functionalized polystyrene resin linked L-tryptophan with excess of aldehyde Scheme 15a [163,169]. Another alternative to obtain 78 was achieved by Mg(ClO4)2-catalyzed intramolecular allylic amination with carbamate or sulfonamide as nucleophiles to form substituted piperidine and pyrrolidine (Scheme 15b) [173].…”

Natural Product‐Like Combinatorial Libraries

“…13,21,174 Fumitremorgin C (158) and related analogues constitute a group of alkaloid mycotoxins with an indolyl diketopiperazine core, 176 that are considered lead compounds for cancer chemotherapy. 177 Koomen and co-workers 178 reported a solid-phase synthesis towards fumitremorgin structural analogues, based on a cyclization/cleavage strategy. Starting with resin-bound L-tryptophan (159), a 697 Natural Product-Like Combinatorial Libraries Vol.…”

“…5,2003 42-member combinatorial library (as diastereomeric mixtures) was prepared by parallel synthesis via a PictetSpengler condensation with six aldehydes, subsequent coupling of 160 with seven Fmoc-protected amino-acids and cyclization/cleavage reaction of Fmoc-deprotected 161 with THF/piperidine ( Figure 43). 21,178 A similar solidphase approach has been described for the synthesis of demethoxyfumitremorgin (158a), the most active of this series of alkaloids, allowing the use of a larger variety of aldehydes for the Pictet-Spengler condensation with Nacyliminium species. 179 With the aim to generate libraries of potential activators and/or inhibitors of protein kinase C (PKC), 180,181 Waldmann and co-workers 182 established a methodology for the solidphase synthesis of analogues of (-)-indolactam V (163), a metabolite that possess the core structure of the tumor promoting teleocidins and has been recognised as a PKC activator.…”