Saccharothriolides A–C, novel phenyl-substituted 10-membered macrolides isolated from a rare actinomycete Saccharothrix sp.

Abstract

Three new 10-membered macrolides, saccharothriolides A-C (1-3), were discovered from a rare actinomycete Saccharothrix sp. A1506. All of the sp(3) carbons in the 10-membered ring had chirality, which was determined by extensive spectroscopic analysis and TDDFT-calculation of ECD spectra. Saccharothriolide B (2) exhibited cytotoxicity against human tumor cell lines HeLa and HT1080.

Isolation and Structure Elucidation of Cytotoxic Saccharothriolides D to F from a Rare Actinomycete Saccharothrix sp. and Their Structure–Activity Relationship

“…The characteristic UV absorption at 341 nm revealed the presence of an anthranilic acid moiety, also present in 4. 7 The 1 H and 13 C NMR data were also similar to those of 4, except for slight differences in chemical shifts for atoms in the right part of the lactone ring (Table 1). The 1 H NMR chemical shifts corresponding to H-2 and CH 3 -11 in compound 1 were shifted upfield, while those for H-3 and CH 3 -10 were shifted downfield compared with compound 4 ( Figure S2).…”

“…A1506 by LC-MS analysis of the metabolic components of 30 000 culture broths. 7 Saccharothriolides A−C (4−6) possessed unique phenyl-substituted 10-membered macrolide structures. They could be biosynthesized from an aryl acid, and all sp 3 carbons on the lactone ring possess chirality.…”

Precursor-directed in situ synthesis of Saccharothriolides G and H by the Actinomycete Saccharothrix sp. A1506

“…A1506 have afforded saccharothriolides A-F (3-8) (Supplementary Figure S1). 8,9 Saccharothriolides possess unique phenyl-substituted 10-membered macrolide structures, and some exhibited moderate cytotoxicity to human fibrosarcoma HT1080 cells. Since they contain a variety of substituents at C-7, we expected the presence of 'precursor A', with an α,β-unsaturated ketone that can function as a Michael acceptor.…”

“…Since they contain a variety of substituents at C-7, we expected the presence of 'precursor A', with an α,β-unsaturated ketone that can function as a Michael acceptor. 8 However, to date, our attempts to isolate precursor A from culture broth have not been successful, probably because of its high reactivity. Instead, we have investigated the presence of precursor A by modifying the culture conditions.…”

“…9 We previously investigated the SAR of saccharothriolides A-F (3-8) which revealed that substitution at C-7 affects the cytotoxicity against human fibrosarcoma HT1080 cells. 8,9 Saccharothriolides B (4) and E (7), both of which have a 2-aminophenol group at C-7, exhibited moderate cytotoxicity (IC 50 values, 13.9 and 29.2 μM, respectively). When the C-7 substituent was anthranilic acid or a hydroxyl group, that is, saccharothriolides A (3), D (6) or C (5), compounds were inactive even at 100 μM.…”