Design and Synthesis of Potential Mechanism-Based Inhibitors of the Aminotransferase BioA Involved in Biotin Biosynthesis

摘要

BioA, a pyridoxal 5′-phosphate (PLP) dependentnaminotransferase, catalyzes the second step of biotin biosynthesis,nconverting 7-keto-8-aminopelargonic acid (KAPA) into 7,8-ndiaminopelargonic acid (DAPA). Amiclenomycin (ACM) isolatednfrom cultures of different Streptomyces strains is a potentnmechanism-based inhibitor of BioA that operates via annaromatization mechanism, irreversibly labeling the PLP cofactor.nHowever, ACM is plagued by inherent chemical stability. Hereinnwe describe the synthesis of four inhibitors, inspired by ACM butncontaining an allylic amine as the chemical warhead, designed tonboth improve stability and operate via a complementary Michaelnaddition-pathway upon enzymatic oxidation of the allylic aminensubstrate to an enimine. Acyclic analogue M-1 contains a terminalnolefin as the pro-Michael acceptor. The synthesis of M-1 featuresnan alkyne-zipper reaction and the Overman rearrangement as key synthetic operations. The cyclic analogues M-2/3/4 containneither an endocyclic or exocyclic olefin as the pro-Michael acceptor. These were all prepared using a common strategy employingnDIBAL reduction of a precursor bicyclic lactam, followed by in situ Horner−Wadsworth−Emmons (HWE) olefination as the keynsynthetic steps.