Conglobatins B–E: cytotoxic analogues of the C2-symmetric macrodiolide conglobatin

Abstract

Chemical investigation of a previously unreported indigenous Australian Streptomyces strainMST-91080 has identified six novel analogues related to the oxazole-pendanted macrodiolide, conglobatin. Phylogenetic analysis of the 16S rRNA gene sequence identified MST-91080 as a species of Streptomyces, distinct from reported conglobatin producer, S. conglobatus ATCC 31005. Conglobatins B -E diverge from conglobatin through differing patterns of methylation on the macrodiolide skeleton. The altered methyl positions suggest a deviation from the published biosynthetic pathway, which proposed three successive methylmalonyl-CoA extender unit additions to the conglobatin monomer. Conglobatins B1, C1 and C2 exhibited more potent cytotoxic activity selectively against the NS-1 myeloma cell line (IC50 0.084, 1.05 and 0.45 µg ml -1 , respectively) compared to conglobatin (IC50 1.39 µg ml -1 ).

Total Synthesis of the Antitumor–Antitubercular 2,6′-Bijuglone Natural Product Diospyrin and Its 3,6′-Isomer

“…The activity of diospyrin ( 1 ), idospyrin ( 7 ), and precursors was assessed against the murine myeloma-derived NS-1 (ATCC TIB-18) cell line and noncancerous neonatal foreskin fibroblasts (Nff) (ATCC PCS-201), using a resazurin assay . The results are presented in Table .…”

Recently Discovered Secondary Metabolites from Streptomyces Species

“…Six new analogues of oxazole-bearing macrodiolide conglobatin (56) were isolated from the previously unreported Australian Streptomyces strain MST-91080 (Figure 17) [37]. Conglobatins B-E (57-62) vary in the distribution of methyl groups around the macrocyclic core, proposed to arise via variable addition of methylmalonyl-CoA extender units during their biosynthesis.…”

“…Three of the new conglobatins (B1 56, C1 57, and C2 58) displayed enhanced cytotoxicity against NS-1 myeloma cells, IC 50 = 0.084, 1.05, and 0.45 µg mL −1 respectively, an increase in potency relative to the parent compound (IC 50 = 1.39 µg mL −1 ). Six new analogues of oxazole-bearing macrodiolide conglobatin (56) were isolated from the previously unreported Australian Streptomyces strain MST-91080 (Figure 17) [37]. Conglobatins B-E (57-62) vary in the distribution of methyl groups around the macrocyclic core, proposed to arise via variable addition of methylmalonyl-CoA extender units during their biosynthesis.…”

“…Structures of conglobatins 56-62 isolated from Streptomyces sp. MST-91080; the parent compound conglobatin (56) was previously reported as a secondary metabolite of Streptomyces conglobatus ATCC 31005; the others, conglobatins B1 (57), C1 (58), C2 (59), D1 (60), D2 (61), and E (62), were reported for the first time in 2020[37,38].…”

Natural Occurrence of Hybrid Polyketides from Two Distinct Biosynthetic Pathways in Streptomyces pactum

“…pactum ATCC 27456 also produces conglobatin ( 3 ), a C 2 -symmetric macrodiolide antitumor compound. This cyclic dimeric polyketide was first isolated from Streptomyces conglobatus but later was found in several other strains of Streptomyces. ,, It binds to heat shock protein 90 (Hsp90), resulting in the inhibition of cell proliferation and the induction of apoptosis . Conglobatin is synthesized by modular type-I PKSs, involving a cyclase/thioesterase (TE) domain that acts iteratively, couples two monomers head-to-tail, rebinds the dimer product, and then cyclizes it …”