Saquayamycins G-K, cytotoxic angucyclines from Streptomyces sp. Including two analogues bearing the aminosugar rednose.

The angucycline group of antibiotics is one of the largest groups of polycyclic aromatic polyketides, rich in chemical scaffolds and biological activities, predominantly anticancer and antibacterial.1–3 Saquayamycins,4–8 urdamycins,9–17 and landomycins,18–24 are well known angucycline antitumor antibiotics. The structures of both saquayamycins and urdamycins contain the same aquayamycin (17)25–27 as aglycone with the C-glycosidic sugar D-olivose attached at C-9 of the angucycline chromophore. So far, seven saquayamycin analogues were reported from Streptomyces spp. Saquayamycins differ from urdamycins by their saccharide patterns, which are attached at C-9 and C-3 positions in the saquayamycins, but at C-9- and C-12b-positions in urdamycins. Saquayamycins A-D (7–10) were first isolated from Streptomyces nodosus MH190-16F3 and were reported as platelet aggregation inhibitors.4 Saquayamycins A-B (7–8) contain three different O-glycosidically linked deoxysugars, L-rhodinose, L-aculose, and L-cinerulose (only in saquayamycin B). Saquayamycin A (7) was reported to be unstable to acid, and even contact with silica gel led to its conversion to saquayamycin B (8). Saquayamycins A1 (11), B1 (6), and C1 (12) were generated by partial acid hydrolysis of saquayamycins A-C (7–9), respectively.4 The two isomers, saquayamycins E (13) and F (14) were produced by Actinomyces strain MK290-AF1 and reported to inhibit the FPTase from bovine brain with IC50 values of 1.8 and 2.0 μM, respectively.5 They differ slightly from the saquayamycins A (7) and C (9) with respect to their sugar moieties. The saquayamycin analogue A-7884 (16) was isolated from the Streptomyces sp. #AM1699; it has a trisaccharide side chain connected at C-9, which contains an L-rhodinose sugar moiety between the first sugar, a C-glycosidic bound D-olivose, and L-aculose of saquayamycin A1 (11).28 Compound 16 showed inhibitory activity in the inducible nitric oxide synthase (iNOS) assay with IC50 values of 43.5 μM, better than saquayamycin A1 (11; IC50 values of 101.2 μM).28 Recently, the largest saquayamycin analogue, saquayamycin Z (15), was reported from Micromonospora sp. strain Tu6368.6 Saquayamycin Z (15) contains tetra- and pentasaccharide side chains linked at C-3- and C-9-positions of the benz[a]anthracene core. The tetrasaccharide side chain of saquayamycin Z (15) is striking due to the presence of an L-oliose, which is not a usual sugar constituent of the angucyclines.6, 29 Very recently, Ren et al., reported three novel members of the angucycline family named N05WA963 A, B and D, with the same aglycones as in the moromycins A (18) and B (19), except for an additional methoxy group attached at C-5.30 N05WA963 A, B and D were reported to have antiproliferative effects on a panel of cancer cell lines such as SW620 (colon cancer), K-562 (chronic myelogeneous leukemia), MDA-MB-231 (estrogen receptor negative breast cancer), YES-4 (esophageal cancer), T-98 and U251SP (both glioblastomae). To study the structure-activity relationship (SAR) of this saquayamycin group of antibiotics, we looked for further saquayamycin analogues produced by Streptomyces sp. K40-1, the strain earlier reported as the producer of moromycins A-B (18–19).7 The saccharide attachments in moromycins A (18) and B (19) are like those of saquayamycins B (8) and B1 (6), respectively, however, their tetracyclic angucyclinone core has an aromatic ring B, and thus no angular hydroxy groups at C-4a and C-12b positions. We found five new metabolites, designated as saquayamycins G-K (1–5), produced by repeated fermentations of the same strain, along with saquayamycin B1 (6), which was previously not described as a natural product, and known saquayamycins. Two of the new angucyclines, saquayamycins H (2) and I (3), bear the unusual aminosugar rednose, which was found for the first time in an angucycline compound. Aminosugar-containing angucyclines are very rare, and previously only three examples had been reported, namely the marmycins A and B,31, 32 and mayamycin.33 The marmycins contain an unusual branched and doubly (C- and N)-linked aminosugar, 3-epi-, 4-epi-vancosamine, and mayamycin contains a unique C-glycosidically linked aminosugar, N-demethylangolosamine, attached at the C-5-position of the benz[a]anthracenone core.