Nitrosopurines En Route to Potently Cytotoxic Asmarines

Abstract

A nitrosopurine-ene reaction easily assembles the asmarine pharmacophore and transmits remote stereochemistry to the diazepine-purine hetereocycle. This reaction generates potent cytotoxins that exceed the potency of asmarine A (1.2 μM IC 50 ) and supersede the metabolites as useful leads for biological discovery. Keywordsalkaloids; terpenoids; nitroso; purine; ene reaction Asmarines A and B (1&2, Figure 1) were identified in 1998 by Kashman and co-workers as the bioactive constituents of a Red Sea sponge (Raspailia sp.) extract, exhibiting cytotoxicity against several cancer cell lines with a minimum EC 50 of 1.2 μM and 120 nM, respectively. [1] The asmarines are unique among alkaloids by virtue of the embedded Nhydroxypurine diazepine (primary pharmacophore) [2] connected by an ethyl bridge to a

Marine Alkylpurines: A Promising Group of Bioactive Marine Natural Products

“…Recently, Shenvi and co-workers [ 77 , 142 ] have obtained a very close analogue of asmarine A, 97 , by the cyclization through a nitrosopurine ene reaction as shown in Scheme 8 . The starting formylpyrimidine was made to react with an alkyl iodide in basic conditions giving the alkylation and cyclization product, 147 , that was transformed into the corresponding bromide 148 .…”

Tetrahedron Young Investigator Awards: R. A. Shenvi and R. Rodriguez / Max Bergmann Medal: O. Seitz

“…They are also interested in how different functional endpoints can alter retrosynthetic analysis. Shenvi has reported in Angewandte Chemie on a nitrosopurine ene reaction in the synthesis of asmarines …”

Unexpected Racemization in the Course of the Acetalization of (+)-(S)-5-Methyl-Wieland–Miescher Ketone with 1,2-Ethanediol and TsOH under Classical Experimental Conditions

“…In the course of our work on bioactive natural products and bioactive materials [117][118][119][120][121][122][123][124], it occurred to us to observe the partial racemization of (+)-5 during the acetalization of (+)-1 with 1,2-ethanediol and TsOH in the presence of a Dean-Stark apparatus. According to our best knowledge, obtaining partially racemized (+)-5 or (−)-5 when the acetalization reaction is carried out by this procedure on (+)-1 or (-)-1 [33,35,39,40,44,48,49,72,77,81,84,[87][88][89][90][91]116], respectively, has not been previously reported in the literature, which was the reason behind investigating this reaction.…”