Total synthesis and biological evaluation of (−)-atrop–abyssomicin C

Abstract

Enantioselective synthesis of a marine antibiotic (-)-atrop-abyssomicin C was accomplished in 21 steps, in 1.8% overall yield (4%, based on the recovered starting material). The key steps of the synthesis are the formation of the functionalized cyclohexane core by an organocatalyzed Tsuji-Trost reaction, the formation of a tricyclic spirotetronate unit by a gold-catalyzed reaction sequence and the highly efficient eleven-membered ring closure by a Nozaki-Hiyama-Kishi reaction. Biological tests showed all abyssomicin derivatives to possess strong antibacterial activity against methicillin resistant S. aureus strains; however, they also proved to be cytotoxic, both to malignant and to normal somatic cells.

A twist of nature – the significance of atropisomers in biological systems

“…Though concise and relatively high yielding, this synthetic approach has since been paralleled or superseded by alternate strategies; 53 notably Bihelovic and Saicic's approach, which avoids epoxide ring opening of the tetronate in the hope of higher tolerance in the generation of analogues for SAR studies. [54][55][56] Scheme 4: Convergent synthesis of atrop-abyssomicin (24) via connection of spirotetronate intermediate 25 with aldehyde 26 over 6 steps to give 27, which is subjected to ring closing metathesis, oxidation and final deprotection to give 24.…”

“…Activities against Mycobacterium bovis, Mycobacterium smegmatis and Mycobacterium tuberculosis have also been reported, 60 however cytotoxicity against both HeLa and normal somatic cells for several derivatives of abyssomicin C was observed. 54 The recently generated atrop-O-benzyldesmethylabyssomicin C derivative shows decreased cytotoxicity while maintaining antibacterial strength, and may therefore have future medicinal applications. 55 …”

Review on Abyssomicins: Inhibitors of the Chorismate Pathway and Folate Biosynthesis

“…Antitumor properties [ 37 ], along with latent human immunodeficiency virus (HIV) reactivator properties [ 38 ], anti-HIV properties [ 51 ], and HIV replication inducer properties [ 51 ], are also reported for this class of compounds. No activity against Gram-negative bacteria or fungi was recorded for any of the natural or synthetic abyssomicins [ 27 , 28 , 34 , 37 ]. To date, the antimalarial activity of these agents has not been explored.…”

“…(AB-18-032) in 2004 [ 27 , 28 , 29 ], inhibits the biosynthesis of pABA, a key cofactor required for folic acid biosynthesis, by trapping irreversibly the 4-amino-4-deoxychorismate synthase (ADCS) enzyme within the chorismate pathway through a Michael addition to a cysteine residue [ 30 , 31 , 32 , 33 ]. Abyssomicin C exhibits promising effects against methicillin resistant Staphylococcus aureus (MRSA) [ 34 ] and mycobacteria causing tuberculosis [ 27 , 35 , 36 ], validating pABA synthesis as a potential useful antifolate target. This discovery highlights the abyssomicin pharmacophore as the next generation of antifolates, and the first generation of pABA synthesis inhibitors.…”

“…The antibacterial activity of abyssomicins has been explored through biosynthetic evaluation, total synthesis, and pharmacological studies. Elegant synthetic routes have given access to new chemistries and the synthesis of several naturally occurring abyssomicins, as well as various novel analogues [ 12 , 26 , 31 , 32 , 33 , 34 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ].…”