Total Syntheses of Cathepsin D Inhibitory Izenamides A, B, and C and Structural Confirmation of Izenamide B

Abstract

The first total syntheses of izenamides A, B, and C, which are depsipeptides inhibitor of cathepsin D, were accomplished. In addition, the stereochemistry of izenamide B was confirmed by our syntheses. The key features of our synthetic route involve the avoidance of critical 2,5-diketopiperazine (DKP) formation and the minimization of epimerization during the coupling of amino acids for the target peptides.

Structural Congeners of Izenamides Responsible for Cathepsin D Inhibition: Insights from Synthesis-Derived Elucidation

“…Tetrapeptide 15 was prepared from tripeptide 20 . Fragments 9 , 10 , 14 , and 16 were readily prepared as previously described [ 27 ].…”

“…Tripeptide 20 was synthesized by coupling the known acid 32 [ 27 ] with N -Me- d -Phe-OMe·TFA salt [ 27 ]. The ester hydrolysis of tripeptide 20 and subsequent amidation of the resulting acid with 22 afforded tetrapeptide 15 in a yield of 76% over two steps ( Scheme 5 ).…”

“…Tetrapeptide 14 , acid 9 , and natural Sta precursor 10 were prepared following a previously reported synthetic protocol [ 27 ]. The synthesis of izenamide variants 7 and 8 ( Scheme 6 ) was completed by Boc-deprotection of tetrapeptides 14 and 15 and subsequent EDC-mediated amide coupling with acid 10 .…”

“…Boc- l -Ile- d -Ala-NMe- d -Phe-OMe ( 20 ). To a solution of Boc- N Me- d -Phe-OMe [ 27 ] (660 mg, 2.30 mmol) in CH 2 Cl 2 (9.0 mL) was added TFA (1.5 mL) dropwise at room temperature. After stirring for 1 h, the reaction mixture was concentrated in vacuo.…”

“…Since then, we have been interested in elucidating the pharmacophore of izenamides through systematic structure investigation. We have been particularly interested in the Sta unit, because izenamides C ( 3 ) lacks CTSD inhibition [ 27 ] without Sta. We anticipated that the core component responsible for the biological activity of izenamides could be identified through structural variation, followed by biological evaluation.…”