The Structure of Cyclodecatriene Collinolactone, its Biosynthesis, and Semisynthetic Analogues: Effects of Monoastral Phenotype and Protection from Intracellular Oxidative Stress

Abstract

Recently described rhizolutin and collinolactone isolated from Streptomyces Gç 40/10 share the same novel carbon scaffold. Analyses by NMR and X-Ray crystallography verify the structure of collinolactone and propose a revision of rhizolutins stereochemistry. Isotope-labeled precursor feeding shows that collinolactone is biosynthesized via type I polyketide synthase with Baeyer-Villiger oxidation. CRISPR-based genetic strategies led to the identification of the biosynthetic gene cluster and a high-production strain. Chemical semisyntheses yielded collinolactone analogues with inhibitory effects on L929 cell line. Fluorescence microscopy revealed that only particular analogues induce monopolar spindles impairing cell division in mitosis. Inspired by the Alzheimerprotective activity of rhizolutin, we investigated the neuroprotective effects of collinolactone and its analogues on glutamate-sensitive cells (HT22) and indeed, natural collinolactone displays distinct neuroprotection from intracellular oxidative stress.

Complete Genome Sequence of the Collinolactone Producer Streptomyces sp. Strain Gö40/10

“…strain Gö40/10 was isolated from soil collected in Bolivia in 1991 and grown in medium NL 8711, which is used routinely for agar slopes ( 1 ). This isolate has the ability to produce various complex secondary/specialized metabolites, including collinolactone ( 2 – 4 ), which exhibits neuroprotective properties through inhibition of intracellular oxidative stress on glutamate-sensitive cells and hence has potential as a drug against Alzheimer’s disease ( 4 ). Furthermore, Streptomyces sp.…”

Conformations and Rearrangements of Collinolactone – Experiments and Theory on a Dynamic Cyclodecatriene

“…The natural product collinolactone A (1, Figure 1) has recently gained attention due to its unique 6-10-7 tricyclic structure in which six-and seven-membered lactones flank the inner cyclodecatriene ring. [1] Collinolactone A (1), first described as a metabolite from the highly proficient producer strain Streptomyces sp. Gö 40/10, originates from a rare non-linear polyketide biosynthesis involving a proposed ketolactone precursor 2.…”

“…Gö 40/10, originates from a rare non-linear polyketide biosynthesis involving a proposed ketolactone precursor 2. [1][2] Agents derived from semisynthetic modifications of the 7membered lactone have a discernible effect on microtubule dynamics. Moreover, collinolactone A (1) itself exerts a protective effect against intracellular oxidative stress.…”

“…[5] The conformations of these molecules can significantly impact their biological activities and pharmacological properties. [6] Therefore, we aimed to explore the conformational behavior of 1 by a combination of experimental and computational methods, which led to experimental access to yet unknown collinolactones B (5-7) and C (8) and the discovery of rearrangements in the cyclodecatriene system of collinolactone A (1).…”

“…[1] 2D NMR exchange spectroscopy (EXSY), temperature-dependent 1 H NMR experiments and quantum chemical predictions of the 13 C NMR shifts revealed that the double set of signals can be attributed to the presence of two distinct conformers with a varying ratio of 3 : 1 to 4 : 1 depending on solvent and temperature. [1] The major (1 a) and minor (1 b) conformers interconvert by rotation of the entire H 3 C19À C15 = C16 propenyl entity (Figure 2, marked in gray) around both adjacent CÀ C single bonds. In the more stable conformer 1 a, the C19-methyl group, unlike that of C18, is located above the hypothetical plane formed by the tenmembered ring, whereas the syn-conformer 1 b displays the C19 methyl group below the ring plane (Figure 2).…”