122(P66) Proteasomeの特異的阻害剤lactacystinの全合成と構造活性相関研究(ポスター発表の部)

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Lactacystin (1), a microbial product, first isolated by Omura et al., was originally obtained from a screening effort based on a nerve growth factor (NGF)-like capacity to induce neurite sprouting in a mouse neuroblastoma cell line (Neuro-2A) and considered to be a mimic of NGF. However, more recent work has shown that lactacystin acts with exquisite specificity and in a unique fashion to inhibit irreversibly the proteolytic activity of the 20S proteasome, a cylindrical complex of 28 protein subunits which is responsible for the hydrolytic fragmentation of ubiquitinated proteins. Herein, we describe a efficient and concise enantioselective total synthesis of lactacystin (1) which is designed to afford easy access to both the natural product and a variety of analogs with modification at 9(S)-hydroxyisobutyl moiety. We also report structure-activity relationships on 1. The characteristic on new synthetic scheme is summarized as the following, (1) One C_7 stereocenter given by enzymatic hydrolysis of malonic acid methyl ester derivative (4) controls the others on γ-lactarn of lactacystin, namely, the C_7 stereocenter introduces stereochemistry of C_5 quaternary carbon in aldol reaction (7→8), which constructs C_6 stereochemistry in chelation control reduction (8→9). Moreover the C_6 stereocenter leads to the desired C_7 stereochemistry in esulfurization (10→11). All reactions are highly steteoselective. (2) The steric environment of aldehyde 12 constructed permits only Si face attack of Grignard reagent to afford 1,2-adduct with the desired stereochemistry. (3) All reactions are concise and high yield. (4) It is very flexible and efficient for synthesis of analogs with modification at 9(S)-hydroxyisobutyl moiety. Clearly the most active compound of analogs with modification at 9(S)-hydroxyisobutyl moiety is β-lactone (2), corresponding to 1. Thus, it seems clear that the 9(S)-hydroxyisobutyl substituent of 1 and the corresponding β-lactone (2) is optimal for mammalian proteasome inhibition. The analogs with modification at C_7 methyl group prepared by the recently modified original synthetic scheme indicate that whereas the replacement of the methyl group by the smaller hydrogen leads to reduced activity, replacement of the methyl group by the larger substituents ethyl, n-butyl, or isopropyl results in an increased activity. It seems that there are two important hydrophobic pockets in the active site of subunit X for the binding of 1 and 2. And we showed that the structures of lactacystin (1) and the corresponding β-lactone (2) are nearly optimal for proteasome inhibition.
天然有機化合物討論会の論文
1998-08-31

122(P66) Proteasomeの特異的阻害剤lactacystinの全合成と構造活性相関研究(ポスター発表の部)

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