Stereoselective Synthesis and Biological Evaluation of Anisomycin and 2-Substituted Analogues

Abstract

The naturally occurring pyrrolidine anisomycin 1, its deacetyl derivative 9k, and some previously unknown analogues were prepared from 2-O-benzyl-3,4-O-isopropylidene-L-threose 2, via the N-benzylimine 3, using highly threo-selective additions of organolithium and Grignard compounds and subsequent cyclization as key steps. Anisomycin 1 was obtained in 8 steps/44% total yield from L-threose 2 (12 steps/23% from diethyl L-tartrate). The overall yields for deacetylanisomycin 9k were 54% (5 steps from L-threose 2) and 28% (9 steps from diethyl L-tartrate), respectively. The compounds 1, 8i, 8k, 9k, 18, 20, and 23 showed good to high cytotoxic activity towards three tumour and non-tumour cell lines.

Inhibition of Cyclin-Dependent Kinase Activity and Induction of Apoptosis by Preussin in Human Tumor Cells

“…At the molecular level, preussin strongly inhibits cyclin E-CDK2 activity in vitro, which is mirrored in vivo by a delay or blockage of progression through G 1 into S phase. Since its effect on protein biosynthesis is rather modest and clearly below the level required for the induction of cell death by other translational inhibitors, such as anisomycin (26,37), we attribute preussin's growth-inhibitory potential to the inhibition of CDK activity rather than to a generalized effect on translation. This conclusion is also in agreement with the fact that preussin induced distinct changes in the steady-state levels of specific proteins: up-regulation of p27…”

A Concise Stereoselective Synthesis of Preussin, 3-epi-Preussin, and Analogues

“…Due to the limitations of existing synthetic routes, very little work has been conducted on the synthesis and study of preussin analogues . However, limited studies on the effect of arene substitution on the activity of the related alkaloid anisomycin ( 2 ) have been performed that demonstrate the nature of the C1‘−aryl group has a profound effect on biological activity. , For example, an anisomycin analogue bearing a phenyl group in place of the p -methoxyphenyl moiety showed 40-fold less cytotoxic potency than 2 against a human KB cell line . Thus, a synthetic route to preussin that allows facile modification of the arene moiety may be of significant biological interest.…”

Synthesis of a New Stable Conformationally Constrained 2,7-Anhydrosialic Acid Derivative

“…The N -benzylimine 8 was treated with 3 equiv of allylmagnesium bromide in ether at room temperature to afford the syn adduct 9 (two steps in 56% yield) and minor anti adduct (syn/anti > 10:1 as measured by the 1 H NMR of crude product). The syn selectivity was finally confirmed by an X-ray study of a related derivative after five-step transformation from the major adduct 9 (unpublished results; see the Supporting Information), and the stereochemistry of addition could be explained well by Cram's rule. − The amine 9 was directly treated with Ac 2 O and triethylamine in CH 2 Cl 2 using DMAP as catalyst to give acetamide 10 in 88% yield. Dihydroxylation of alkene 10 with NMO and catalytic OsO 4 (2.5 wt % in n BuOH) in acetone and H 2 O afforded diol 11 in 76% yield (as a mixture of two diastereomers).…”