620568-02-7Relevant academic research and scientific papers
Total Synthesis of the Depsipeptide FR901375 and Preliminary Evaluation of Its Biological Activity
Narita, Koichi,Katoh, Yuya,Ojima, Ken-Ichi,Dan, Singo,Yamori, Takao,Ito, Akihiro,Yoshida, Minoru,Katoh, Tadashi
, p. 5667 - 5677 (2016/12/14)
The bicyclic depsipeptide FR901375 was efficiently synthesized in a highly convergent manner. The synthesis involved the condensation of a d-valine–d-valine–d-cysteine-containing segment with a (3S,4E)-3-hydroxy-7-mercapto-4-heptenoic acid–l-threonine-containing segment to directly assemble the corresponding seco-amino acid, followed by cyclization to construct the desired 16-membered macrocyclic ring. The potency of the synthesized FR901375 was determined in assays for histone deacetylase (HDAC) inhibition and cell-growth inhibition, and the results were compared to those obtained for the clinically approved depsipeptide FK228 (romidepsin). It was found that FR901375 shows extremely high selectivity (957-fold) for a class I HDAC 1 (GI50= 1.7 nm) over a class II HDAC 6 (GI50= 1627 nm), and shows cell-growth inhibition GI50values in the low nanomolar region. Furthermore, new aspects of the structure–activity relationship of bicyclic depsipeptide HDAC inhibitors were revealed.
Total Synthesis of the Depsipeptide FR-901375
Chen, Yanping,Gambs, Celine,Abe, Yoshito,Wentworth Jr., Paul,Janda, Kim D.
, p. 8902 - 8905 (2007/10/03)
The first total synthesis of FR-901375, a novel bicyclic depsipeptide isolated from the fermentation broth of Pseudomonas chloroaphis No. 2522, has been achieved. The synthetic approach involves 13 reaction steps and is achieved in 12% overall yield. The key points in the successful synthetic strategy are a concise asymmetric synthesis of the key building block (3R,4E)-3-hydroxy-7-mercapto-4-heptenoic acid, a mild Mitsunobu macrolactonization step, and an I2-mediated deprotection with concomitant disulfide-bridge formation.
