Ribosomal Synthesis of an Amphotericin‑B Inspired Macrocycle

Here we report in vitro ribosomal synthesis of a natural product-like macrocyclic peptide, inspired by the structure of amphotericin B (AmB), an amphiphilic and membrane-interacting antifungal natural product. This AmB-inspired macrocyclic peptide (AmP), one side of which is composed of hydrophobic terpene, and the other side comprises a peptidic chain, was synthesized utilizing flexizyme-assisted in vitro translation via an unusual but successful initiation with a d-cysteine derivative. The established method for the synthesis of AmPs is applicable to the generation of a diverse AmP library coupled with an in vitro display format, with the potential to lead to the discovery of artificial bioactive amphiphilic macrocycles

2‑Naphthylmethoxymethyl as a Mildly Introducible and Oxidatively Removable Benzyloxymethyl-Type Protecting Group

2-Naphthylmethoxymethyl (NAPOM) was developed for the protection of various hydroxy (including phenolic hydroxy and carboxy) and mercapto groups. The NAPOM group can be introduced in extremely mild conditions (naphthyl­methoxy­methyl chloride, 2,6-lutidine, room temperature) without concomitant acyl migration in a 1,2-diol system. Furthermore, selective removal of NAPOM in the presence of naphthylmethyl (NAP) and <i>p</i>-methoxybenzyl (PMB) groups and, conversely, that of PMB in the presence of NAPOM were realized. These results, as well as its easy handling and compatibility with various solvents, show that NAPOM is a novel and useful choice as a protecting group

Synthesis and Biological Activity of the C′D′E′F′ Ring System of Maitotoxin

Stereoselective synthesis of the C′D′E′F′ ring system of maitotoxin was achieved starting from the E′ ring through successive formation of the D′ and C′ rings based on SmI₂-mediated reductive cyclization. Construction of the F′ ring was accomplished via Suzuki–Miyaura cross-coupling with a side chain fragment and Pd­(II)-catalyzed cyclization of an allylic alcohol. The C′D′E′F′ ring system inhibited maitotoxin-induced Ca²⁺ influx in rat glioma C6 cells with an IC₅₀ value of 59 μM

Syntheses and Biological Activities of the LMNO, <i>ent</i>-LMNO, and NOPQR(S) Ring Systems of Maitotoxin

Structure–activity relationship studies of maitotoxin (MTX), a marine natural product produced by an epiphytic dinoflagellate, were conducted using chemically synthesized model compounds corresponding to the partial structures of MTX. Both enantiomers of the LMNO ring system were synthesized via aldol reaction of the LM ring aldehyde and the NO ring ketone. These fragments were derived from a common cis-fused pyranopyran intermediate prepared through a sequence involving Nozaki–Hiyama–Kishi reaction, intramolecular oxa-Michael addition, and Pummerer rearrangement. The NOPQR­(S) ring system, in which the original seven-membered S ring was substituted with a six-membered ring, was also synthesized through the coupling of the QR­(S) ring alkyne and the NO ring aldehyde and the construction of the P ring via 1,4-reduction, dehydration, and hydroboration. The inhibitory activities of the synthetic specimens against MTX-induced Ca²⁺ influx were evaluated. The LMNO ring system and its enantiomer induced 36 and 18% inhibition, respectively, at 300 μM, whereas the NOPQR­(S) ring system elicited no inhibitory activity