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

Abstract

Three new 10-membered macrolides, saccharothriolides D-F (1-3), were isolated from a rare actinomycete, Saccharothrix sp. A1506. The planar structures were determined from analysis of extensive NMR and HR-ESI-MS data, and the absolute configurations were established by ECD spectroscopy analysis. Saccharothriolides D (1) and E (2) were determined to be C-2 epimers of saccharothriolides A (4) and B (5), respectively. Saccharothriolide F (3) was identified to be a demethylated congener of saccharothriolides D (1) and A (4) at the C-2 position. The availability of compounds 1-6 enabled a structure-activity relationship study that revealed the importance of the phenolic hydroxy group at C-2″ and the stereochemistry of C-2 for the inhibition of human fibrosarcoma HT1080 cell growth.

Structurally diverse metabolites from the rare actinobacterium Saccharothrix xinjiangensis

“…The elemental formula C 22 H 37 NO 3 ( 13 C HMBC correlations which provided the connection through secondary amide bond and the attachment of carboxyl residue (Figure 4). The E configuration of the Δ 5,6 The structure of 3 bearing 1,3-dimethylated hydrocarbon segment appears frequently as structural elements in polyketide natural products. 22 Some macrocyclic polyketides such as narbonolide and methymycin isolated from Streptomyces species have been previously reported to occupy syn conformation of their 1,3-dimethyl substituted chain segment.…”

“…4,5 In recent years other genera of the so-called rare actinobacteria have increasingly become attractive resources of novel biological active secondary metabolites. 6,7,8,9,10 Of these, the genus Saccharothrix has been reported to produce a range of bioactive compounds such as the antibacterial agents tianchimycins A-B from Saccharothrix xinjiangensis, 11 the antitumor agent saccharothriolide B from Saccharothrix sp. 1212 and the antifungal antibiotic formamicin from Saccharothrix tangerines sp.…”

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.…”

“…The absolute stereochemistry of Precursor-directed in situ synthesis of substances S Lu et al 2 was proven to be 2S, 3R, 4S, 6R, 7R, 8R and 9S, the same as that of 7 on the basis of the coupling constants and optical rotation values. 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).…”

“…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.…”