Biosynthesis of Quinolactacin A, a TNF Production Inhibitor

Abstract

Quinolactacins, which inhibit tumor necrosis factor production, contain a quinolone skeleton conjugated with a g -lactam. The biosynthesis of quinolactacin was investigated by feeding experiments using 13 Keywords quinolactacin, quinolone, biosynthesis, 13 C labeled precursor, Penicillium sp. IntroductionSince entomopathogenic fungi possess a parasitic function, it was expected that novel biologically active compounds such as insecticides and immunosuppressants would be isolated from them [1ϳ7]. In the course of an HPLC-based, chemical screening program of the metabolites of entomopathogenic fungi, the novel pyridone alkaloids, pyridovericin and pyridomacrolidin, possessing protein kinase inhibitory activity, were isolated from the cultured broth of Beauveria bassiana 9]. In addition, novel quinolone alkaloids, quinolactacins A (1), B (2), and C (3) were obtained from the cultured broth of Penicillium sp. EPF-6, which was isolated from the larvae of the mulberry pyralid (Margaronia pyloalis Welker) [10]. Alkaloid 1, the major constituent, exhibited inhibitory activity against tumor necrosis factor (TNF) production by murine macrophages and macrophage-like J774.1 cells stimulated with lipopolysaccharide (LPS).Quinolactacins have a unique quinolone skeleton conjugated with a g-lactam ring [11], as shown in Figure 1. Subsequently, Kim et al., reported the characterization of stereoisomers of 1 through a screening program for inhibitors of acetylcholinesterase [12], and Tatsuta's group reported the biomimetic synthesis of quinolactacin B (2) using acetic acid, valine, and anthranilic acid [13]. In this paper, the biosynthesis of 1 was studied by feeding experiments using several 13 C single-labeled precursors and D-[U-

New Alkaloids and Polyketides from the Marine Sponge-Derived Fungus Penicillium sp. SCSIO41015

“…The chiral phase of HPLC analysis showed that were two conjoint peaks that could not separate well, also 2 dissolved in a solvent that was unstable and then changed to quinolactacin D, as speculated in the reference [10]. Compound 2 appeared to be synthesized from kynurenine and leucine, which was similar to the speculation reported by Nakagawa et al [11]; shown in Figure S1. Thereby, 2 was elucidated as a pair of enantiomers and named quinolactacin E.…”

“…SCSIO41015. The new structures were elucidated by analysis of their NMR data and HR-ESI-MS. Their absolute configurations were established by single-crystal X-ray diffraction analysis or a comparison of the experimental with the reported specific rotation values.The biosynthetic pathway of quinolactacin A has been studied, andspeculated that it is synthesized from tryptophan and isoleucine [11]. Based on the current investigation, possible biosynthetic pathways of alkaloids 1 , 2 , and 4 – 6 were speculated.Compound 2 appeared to be synthesized from tryptophan and leucine, whereas compound 4 was made from tryptophan and valine.…”

Phenalenones: insight into the biosynthesis of polyketides from the marine alga-derived fungus Coniothyrium cereale

“…S11, ESI †). 8 Some biosynthetic studies have been reported for the fungal phenalenones such as deoxyherqueinone 9 and atrovenetin 10 (Fig. Thus, compounds 3, 6, 8, 12 and 15 showed significant inhibition of the protease human leukocyte elastase (HLE) with IC 50 values of 7.2, 10.9, 13.3, 9.3 and 3.0 μM, respectively.…”

Fusarochromene, a novel tryptophan-derived metabolite from Fusarium sacchari

“…EPF-6. 26 With this result to hand, we searched the publicly available F. equiseti genome for a potential biosynthetic gene cluster (BGC) encoding homologues of known tryptophan dioxygenase (TDO) and dimethylallyl diphosphate ( prenyl) transferase (DMAT) enzymes. This immediately revealed a gene cluster (Scheme 2b, Tables 1 and S1 †) encoding 10 predicted proteins Organic & Biomolecular Chemistry Paper of significance.…”