Structure of natural antibiotic CP-47,444

Celmer, Walter D.; Chmurny, Gwendolyn N.; Moppett, C. E.; Ware, R.; Watts, Paul; Whipple, Earl B.

doi:10.1021/ja00532a036

Cited by 83 publications

(46 citation statements)

References 2 publications

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“…This configuration is the same as that found in nodusmicin (7) and nargenicin (8), which have a chemical structure quite similar with luminamicin (Fig. 4).…”

Section: Determination Of Absolute Stereochemistry Of Luminamicinsupporting

confidence: 80%

“…Luminamicin showed selective activity against anaerobic and microaerophilic bacteria, including pathogenic species of Clostridium, Neisseria, and Haemophilus, whereas it was not active against most aerobic bacteria (3,6). Interestingly, structurally related antibiotics, nodusmicin (7) and nargenicin (8), are reported to inhibit some aerobic bacteria. Therefore, the additive macrocyclic structure of luminamicin seems to be important in exerting its selective antianaerobic microbial activity.…”

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confidence: 99%

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Stereostructure of luminamicin, an anaerobic antibiotic, via molecular dynamics, NMR spectroscopy, and the modified Mosher method

Gouda

Sunazuka²,

Ui³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The absolute stereostructure of luminamicin, an anaerobic antibiotic, has been determined by using conformational analysis via high-temperature molecular dynamics, NMR spectroscopy, and the modified Mosher method. It was found that luminamicin has the S, S, R, R, R, R, S, S, S, R, and S configurations at C2, C4, C7, C9, C10, C11, C12, C13, C16, C28, and C29, respectively. This configuration is the same as that found in nodusmicin, which has a chemical structure quite similar to luminamicin. The structure of luminamicin consists of three different rings, i.e., a decalin ring, a 10-membered macrolactone ring, and a 14-membered macrolactone ring. The resulting three-dimensional structure of luminamicin shows an interesting feature in that the maleic anhydride functionality in conjugation with the enol ether group of the 14-membered macrolactone is nearly perpendicular to the plane of the other two rings.

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“…This configuration is the same as that found in nodusmicin (7) and nargenicin (8), which have a chemical structure quite similar with luminamicin (Fig. 4).…”

Section: Determination Of Absolute Stereochemistry Of Luminamicinsupporting

confidence: 80%

mentioning

confidence: 99%

Stereostructure of luminamicin, an anaerobic antibiotic, via molecular dynamics, NMR spectroscopy, and the modified Mosher method

Gouda

Sunazuka²,

Ui³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…The new methodology and protection tactics described here will enable generation of chemical derivatives of this exceedingly complex structure [41][42][43][44] and have further application to total syntheses of biologically active natural products with pyrrole esters. [45][46][47] …”

Section: )mentioning

confidence: 99%

Chemical Conversion of Ryanodol to Ryanodine

Masuda

Nagatomo

Inoue

2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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Ryanodine (1) is a plant-derived natural product with powerful pharmacological and insecticidal action, and is a potent modulator of intracellular calcium release channels. Compound 1 possesses a 1H-pyrrole-2-carboxylate ester at the C3-position of heptahydroxylated terpenoid ryanodol (2). Whereas 2 was readily obtained from 1 by basic hydrolysis, 1 has never been synthesized from 2, due to the extreme difficulty in selectively introducing the bulky pyrrole moiety at the severely hindered C3-hydroxyl group of heptaol 2. Here we report chemical conversion of 2 to 1 for the first time. The derivatization was realized through the use of a new protective group strategy and the application of on-site construction of the pyrrole-2-carboxylate ester from the glycine ester and 1,3-bis(dimethylamino)allylium tetrafluoroborate.Key words acylation; protecting group; regioselectivity; ryanodine; terpenoid Ryanodine (1, Chart 1) has been isolated from the wood of Ryania speciosa VAHL and shown to possess potent insecticidal and pharmacological actions.1) Compound 1 binds specifically to a high-conductance intracellular calcium channel known as the ryanodine receptor (RyR), altering its conductance.2,3) Since the RyR plays an important role in many biological processes and malfunctions in its action have been linked to skeletal and cardiac diseases, 4-7) 1 has been used as a biological probe for investigations of RyR function, and is regarded as a strong candidate in the development of therapeutic agents for various diseases. [8][9][10] In 1968, the structure of ryanodine (1) was determined to be the ester between 1H-pyrrole-2-carboxylic acid (3) and the C3-hydroxyl group of ryanodol (2). [11][12][13][14] Compound 2 is a diterpenoid containing the exceedingly complex five fused rings (ABCDE-rings) with eleven contiguous stereocenters. Interestingly, the affinity of 2 toward RyRs of vertebrate skeletal muscle is 1700 times weaker than that of 1 (K D =7 nM), [15][16][17] demonstrating that the pyrrole group is a primary determinant for strong interactions of 1. Because of its important biological activities and intriguing structural features, many studies attempting the chemical construction of 1 has been carried out, which resulted in the total syntheses of ryanodol (2) by the Deslongchamps group in 1979 18,19) and by our laboratory in 2014. [20][21][22] In 1951, before the complete structure of 1 was known, Wiesner and colleagues found that basic hydrolysis of ryanodine (1) generated 2 and 3.11) However, the reverse reaction has not been realized even to date. The difficulty of the transformation arises from the need to control the regioselectivity of the four tertiary (C2, 4, 6, 12), two secondary (C3, 10) and one acetalic (C15) alcohols within heptaol 2 and to accommodate the bulky pyrrole moiety at the hindered C3-hydroxyl group. The computer-generated 23) structure of 2 revealed that its axially oriented C3-OH was shielded by the proximal C14-hydrogen atom and by the C19-, 20-methyl groups (Fig. 1). In fact, direct esteri...

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“…They are ubiquitously found in soil, water, decaying vegetation, animal fecal deposits, and dust [1]. A number of interesting metabolites having antibiotic activity have been reported from the genus Nocardia including antibacterial and antifungal compounds, bis-(2-ethylhexyl) phthalate and bis-(5-ethylheptyl) phthalate from Nocardia levis MK-VL_113 [2], antifungal antibiotic transvalencin A from Nocardia transvalensis IFM 10065 [3], cytotoxic antibiotics brasiliquinones A, B, and C from Nocardia brasiliensis IFM 0089 [4], potent immunosuppressive activity and antifungal compounds, nocarasins A, B, and C from N. brasiliensis IFM 0677 [5], and an antibiotic nargenicin A 1 from Nocardia argentinensis [6]. Nocardia species that have been isolated from soil are used industrially for the production of various biologically active compounds [7].…”

Section: Introductionmentioning

confidence: 99%

“…Structurally, it is closely related to nodusmicin [8]. Nargenicin A 1 was first isolated as antibioticum CP-47,444 from cultures of N. argentinensis in 1977 [6]. Recently, we isolated and purified nargenicin A 1 from the novel Nocardia sp.…”

Section: Introductionmentioning

confidence: 99%

Metabolic Engineering of Nocardia sp. CS682 for Enhanced Production of Nargenicin A1

Maharjan

Koju

Lee

et al. 2011

Appl Biochem Biotechnol

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A number of secondary metabolites having therapeutic importance have been reported from the genus Nocardia. One of the polyketide antibiotic compounds isolated from Nocardia is nargenicin A(1). Recently, nargenicin A(1) has been isolated from Nocardia sp. CS682, a new Nocardia strain isolated from soil in Jeonnam, South Korea. It possesses strong antibacterial activity against methicillin-resistant Staphylococcus aureus. In this study, we applied a metabolic engineering approach based on recombinant DNA technology in order to boost the production of nargenicin A(1) from Nocardia sp. CS682. Initially, we optimized the transformation of this new strain by electroporation method. Heterologous expression of S-adenosylmethionine synthetase (MetK1-sp) in Nocardia sp. CS682 enhanced the production of nargenicin A(1) by about 2.8 times due to transcriptional activation of biosynthetic genes as revealed by reverse transcription polymerase chain reaction analysis. Similarly, expression of acetyl-CoA carboxylase genes improved nargenicin A(1) production by about 3.8 times in Nocardia sp. ACC18 compared to that in Nocardia sp. CS682 and Nocardia sp. NV18 by increasing precursor pool. Thus, enhanced production of nargenicin A(1) from Nocardia sp. CS682 can be achieved by expression of transcriptional activator genes and precursor genes from Streptomyces strains.

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Structure of natural antibiotic CP-47,444

Cited by 83 publications

References 2 publications

Stereostructure of luminamicin, an anaerobic antibiotic, via molecular dynamics, NMR spectroscopy, and the modified Mosher method

Stereostructure of luminamicin, an anaerobic antibiotic, via molecular dynamics, NMR spectroscopy, and the modified Mosher method

Chemical Conversion of Ryanodol to Ryanodine

Metabolic Engineering of Nocardia sp. CS682 for Enhanced Production of Nargenicin A1

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