Chemical variation from the neoantimycin depsipeptide assembly line

Rare Streptomyces N-Formyl Amino-salicylamides Inhibit Oncogenic K-Ras

“…HRESI(+)MS measurements supported by analysis of NMR (DMSO- d 6 and CDCl 3 ) data (Supporting Information (SI), Tables S1a-b and S2a-b) permitted assignment of planar structures to 1 (C 36 H 46 N 2 O 12 ) and 2 (C 35 H 44 N 2 O 12 ), consistent with those previously ascribed to neoantimycin 5,7 and neoantimycin F. 6 Comparison of [α] D measurements for the cometabolites 1 (+58.7) and 2 (+55.2), with that published for neoantimycin (+58.3), 7b supported the proposition that these compounds belong to a common antipodal series. Comparable HRESI(+)MS and NMR analyses (SI, Tables S3 and S4) permitted assignment of planar structures to 3 (C 37 H 48 N 2 O 12 ) and 4 (C 36 H 44 N 2 O 12 ), consistent with two new neoantimycin homologues allocated the trivial names neoantimycin G and H respectively.…”

“…Planar structures were assigned to 1 – 4 on the basis of detailed spectroscopic analysis, with microscale C 3 Marfey’s and C 3 Mosher analyses permitting assignment of absolute configurations, including revisions to 1 5 and 2 . 6 To support structure–activity relationship (SAR) investigations into the K-Ras modulatory properties of neoantimycins, we obtained the biosynthetically related microbial metabolites, antimycin A2a ( 5 ), antimycin A4a ( 6 ), and respirantin ( 7 ), and prepared the novel benzoxazolone analog 8 (Figure 1). SAR studies established that the natural products 1 – 7 were all potent inhibitors of K-Ras PM localization and correlated this activity with the presence of an N -formyl amino-salicylamide moiety.…”

“…The absolute configurations of 9 and 11 were subsequently determined in 2007 12 by chemical degradation and derivatization. Neoantimycins D ( 14 ), E ( 15 ), and F ( 2 ) were reported in 2013 6 using a genome mining approach on S. orinoci , although configurational assignments made at that time were inferred rather than proven. In summary, despite a history extending back several decades, inclusive of chemical, spectroscopic, biosynthetic, and pharmacological investigations across nine metabolites ( 1–2 and 9–15 ), knowledge of the neoantimycin structures (in particular relative and absolute configuration) remains incomplete.…”

Antimycin-type depsipeptides: discovery, biosynthesis, chemical synthesis, and bioactivities

“…5 Spectroscopic data showed its relationship to antimycins A 1 and A 3 and was used to elucidate its structure. 43,44 Several variants of neoantimycins differing in the 3-formamidosalicylate moiety and/or oxidation have also been reported. SNA 15896 (soil, Ibaraki Prefecture, Japan) during screening for immunosuppressants.…”

The regulation and biosynthesis of antimycins

“…The gene clusters for JBIR-06 (12-membered ring), neoantimycin (15-membered ring), and 18-membered ringed respirantin were recently identified [43–44]. JBIR-06 and neoantimycin inhibit GRB78 chaperone involved in the unfolded protein response [45–46].…”