Flexible Synthesis and Evaluation of Diverse Anti-Apicomplexa Cyclic Peptides

Abstract

A modular approach to synthesize anti-Apicomplexa parasite inhibitors was developed that takes advantage of a pluripotent cyclic tetrapeptide scaffold capable of adjusting appendage and skeletal diversities in only a few steps (one to three steps). The diversification processes make use of selective radical coupling reactions and involve a new example of a reductive carbon-nitrogen cleavage reaction with SmI2. The resulting bioactive cyclic peptides have revealed new insights into structural factors that govern selectivity between Apicomplexa parasites such as Toxoplasma and Plasmodium and human cells.

Hydroxyl Ketone-Based Histone Deacetylase Inhibitors To Gain Insight into Class I HDAC Selectivity versus That of HDAC6

“…The goal of this study was to replace the cyclotetrapeptide part by a simple cap, like the aniline amide group found on SAHA. Given that the ZBG seems to be necessary for the activity and on the basis of previous studies, 22 various ZBGs could easily be grafted onto any cap group having a linker ending with a terminal olefin. Aniline amides with various linker lengths, 6a – c , were synthesized from aniline 4 ( Scheme 1 ) to determine the optimal linker length.…”

“…In the course of our attempts to synthesize new HDACi analogues inspired by FR235222, 22 we found evidence that modulating the ZBG could also increase the potency. Keeping the cyclotetrapeptide part unchanged (with R 1 , R 2 = H; Figure 1 ), compound 3 , having the ( R )-hydroxyl ketone ZBG, was shown to be more efficient in inhibiting the T. gondii RH strain (IC 50 = 28.6 nM) than the corresponding analogue with an ethyl ketone group (IC 50 = 172 nM).…”

Diversity-oriented synthesis of analogues of the novel macrocyclic peptide FR-225497 through late stage functionalization

“…Accommodating some of these common features, we prepared the macrocyclic template 13 ( Scheme 1 ) through the acyclic tetrapeptide Boc-L-Bhag-L-Phe-L-Phe-D-Pro-OMe ( 11 ) (Bhag = bishomoallylglycine) [ 19 ]. The latter was accessed by solution phase peptide coupling between L-Phe-D-Pro-OMe ( 6 ) (prepared by hydrogenolysis of the corresponding carbamate 5 ) and L-Cbz-Phe-OH ( 7 ) followed by elaboration of the resulting tripeptide 8 via N-terminus deprotection leading to 9 followed by a second peptide coupling of the latter with the known Boc-L-Bhag 10 [ 20 ].…”

The Synthesis of Macrocycles for Drug Discovery

“…321 The resulting structures are three atoms larger than the original macrocycle and provide an interesting avenue to create skeletal diversity. This process seems to be favoured by the strain caused by the fused 5-membered ring system in conjunction with the quaternary carbon on the larger ring.…”