Total synthesis of (+)-negamycin and its 5-epi-derivative

Nishiguchi, Shigenobu; Sydnes, Magne O.; Taguchi, Akihiro; Regnier, Jérémi; Kajimoto, Tetsuya; Node, Manabu; Yamazaki, Yoshihiro; Yakushiji, Fumika; Kiso, Yoshiaki; Hayashi, Yoshio

doi:10.1016/j.tet.2009.10.097

Cited by 18 publications

(19 citation statements)

References 39 publications

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“…1A) was synthesized in a novel sequence (Fig. S1) from an intermediate previously used by Nishiguchi et al (22). Biochemical and microbiological activity was indistinguishable from negamycin that was purified as a fermentation product (Table 1).…”

Section: Significancementioning

confidence: 99%

“…In an effort to identify the negamycin binding site on the E. coli ribosome, mutant cells resistant to negamycin were isolated from an E. coli strain containing only a single genomeencoded rrn operon (SQ110) (22). Spontaneous resistant mutants were identified at a frequency of 10 −9 when selected at 128 μg/mL, fourfold the minimum inhibitory concentration (MIC) of 32 μg/mL (∼128 μM) (Table 1) (23).…”

Section: Negamycinmentioning

confidence: 99%

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Negamycin induces translational stalling and miscoding by binding to the small subunit head domain of the Escherichia coli ribosome

Olivier

Altman

Noeske

et al. 2014

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

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Negamycin is a natural product with broad-spectrum antibacterial activity and efficacy in animal models of infection. Although its precise mechanism of action has yet to be delineated, negamycin inhibits cellular protein synthesis and causes cell death. Here, we show that single point mutations within 16S rRNA that confer resistance to negamycin are in close proximity of the tetracycline binding site within helix 34 of the small subunit head domain. As expected from its direct interaction with this region of the ribosome, negamycin was shown to displace tetracycline. However, in contrast to tetracycline-class antibiotics, which serve to prevent cognate tRNA from entering the translating ribosome, single-molecule fluorescence resonance energy transfer investigations revealed that negamycin specifically stabilizes near-cognate ternary complexes within the A site during the normally transient initial selection process to promote miscoding. The crystal structure of the 70S ribosome in complex with negamycin, determined at 3.1 Å resolution, sheds light on this finding by showing that negamycin occupies a site that partially overlaps that of tetracycline-class antibiotics. Collectively, these data suggest that the small subunit head domain contributes to the decoding mechanism and that small-molecule binding to this domain may either prevent or promote tRNA entry by altering the initial selection mechanism after codon recognition and before GTPase activation.egamycin, a natural product originally isolated from cultures of Streptomyces purpeofuscus, exhibits broad-spectrum antibacterial activity against key pathogens for which clinical treatment options are dwindling (1, 2). The chemical structure of negamycin, [2-[(3R, 5R)-3,6-diamino-5-hydroxyhexanoyl]-1-methylhydrazino]acetic acid, and synthetic routes for its synthesis were elucidated in the early 1970s ( Fig. 1A) (3,4). Early toxicity studies in dogs revealed that daily administration of negamycin led to the formation of N-methylhydrazinoacetic acid, an inhibitor of glutamate pyruvate transaminase, an outcome that caused reversible hepatic coma. Consequently, further clinical studies were not pursued (5). Although the antimicrobial activity and efficacy of negamycin have since been confirmed, analogs exhibiting an improved therapeutic window have yet to be found (6, 7). Progress on this front has been hampered, at least in part, by the fact that the molecular mechanisms of negamycin-induced cell growth inhibition have yet to be discerned conclusively.Negamycin decreases the viability of Escherichia coli by preferentially targeting protein synthesis (8). Early mechanistic investigations proposed that negamycin may act by inhibiting translation initiation (8), decreasing translational fidelity during the elongation phase of protein synthesis (9, 10), and disrupting proper translation termination (9,(11)(12)(13). Uncertainties regarding negamycin's inhibition mechanism, its highly polar physicochemical properties, and the lack of streptomycin cross-resistance led som...

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Section: Significancementioning

confidence: 99%

Section: Negamycinmentioning

confidence: 99%

Negamycin induces translational stalling and miscoding by binding to the small subunit head domain of the Escherichia coli ribosome

Olivier

Altman

Noeske

et al. 2014

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

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“…Synthesis was previously described. [38] Following this procedure gave (R)-ethyl 4-azido-hydroxybutanoate (85 %) as a yellow oil: R f = 0. 24 Saponification of (R)-ethyl 4-azido-hydroxybutanoate was previously described.…”

Section: Synthesis Of the Middle Fragmentsmentioning

confidence: 99%

“…24 Saponification of (R)-ethyl 4-azido-hydroxybutanoate was previously described. [38] Following this procedure gave 28 (97 %) as a colorless oil: …”

Section: Synthesis Of the Middle Fragmentsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Simplified Side Chain Hybrids of the Potent Actin Binding Polyketides Rhizopodin and Bistramide

et al. 2015

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The natural products rhizopodin and bistramide belong to an elite class of highly potent actin binding agents. They show powerful antiproliferative activities against a range of tumor cell lines, with IC50 values in the low-nanomolar range. At the molecular level they disrupt the actin cytoskeleton by binding specifically to a few critical sites of G-actin, resulting in actin filament stabilization. The important biological properties of rhizopodin and bistramide, coupled with their unique and intriguing molecular architectures, render them attractive compounds for further development. However, this is severely hampered by the structural complexity of these metabolites. We initiated an interdisciplinary approach at the interface between molecular modeling, organic synthesis, and chemical biology to support further biological applications. We also wanted to expand structure-activity relationship studies with the goal of accessing simplified analogues with potent biological properties. We report computational analyses of actin-inhibitor interactions involving molecular docking, validated on known actin binding ligands, that show a close match between the crystal and modeled structures. Based on these results, the ligand shape was simplified, and more readily accessible rhizopodin-bistramide mimetics were designed. A flexible and modular strategy was applied for the synthesis of these compounds, enabling diverse access to dramatically simplified rhizopodin-bistramide hybrids. This novel analogue class was analyzed for its antiproliferative and actin binding properties.

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“…One was L-carnitine (3), 25) which is an γ-amino acid derivative involved in lipid metabolism in the human body. The unprotected polar functional group of the azide 4 26) is a β-hydroxycarboxylic acid moiety, that is similar to the serine-type structure used in prodrug 2, with a higher number of carbon atoms. These slight changes were expected to provide interesting effects on the water solubility and half-life of the prodrug.…”

mentioning

confidence: 99%

Prodrug Study of Plinabulin Using a Click Strategy Focused on the Effects of a Replaceable Water-Solubilizing Moiety

Yakushiji

Tanaka

Muguruma

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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Plinabulin (1) is a potent anti-microtubule agent, however, its low water solubility has to be improved for the advantage in pharmacokinetics and chemotherapy. In this report, the replaceable water-solubilizing moiety of the water-soluble prodrug of plinabulin (1) was investigated. The properties of the water-soluble prodrugs of plinabulin (1), in which the water-solubilizing part was replaced with a new functionality, were evaluated. The newly introduced water-solubilizing moiety provided interesting effects on the water solubility and half-life of the prodrugs.Key words water-soluble prodrug; anti-microtubule agent; click chemistry; plinabulin; monolactim 'Prodrug' research is one of the most important fields of medicinal chemistry. In particular, improvements in water solubility have been studied extensively.1) Paclitaxel, for example, exhibited potent anti-microtubule activity 2) as intravenous (i.v.) injection. Due to its low water solubility (0.25 µg/mL), 3) it was initially formulated with the detergent cremophor EL, which induced hypersensitivity. 4) Therefore, a variety of water-soluble paclitaxel prodrugs have been developed to improve the patient's burden. 5-9)Previously, we reported the design and synthesis of a water-soluble prodrug of plinabulin (1) 10) as a monolactim serine-type derivative 2 11) using click chemistry 12-14) (Fig. 1). Plinabulin (NPI-2358) (1) (cytotoxic activity: IC 50 =15 nM in HT-29 cells) is a derivative of S-(−)-phenylahistin 15,16) and phase II clinical trials have been undertaken worldwide [17][18][19] by way of i.v. injection as a promising vascular disrupting agent (VDA). [20][21][22][23][24] Plinabulin (1) showed low water solubility (<0.1 µg/mL), which forced the co-injection of a solubilizing agent, such as paclitaxel. To improve the pharmacokinetics and chemotherapeutic index, the water-soluble prodrug 2 was developed. The water solubility of α-amino acid type derivative 2 was determined to be 6.38 mg/mL, and the in vitro halflife (t 1/2 ) in the presence of porcine liver esterase was found to be 59.9 min. These values make the compound appropriate for i.v. injection without inclusion of a solubilizing agent. Furthermore, the water-solubilizing triazole auxiliary, which was cleaved from the mother skeleton via an esterase hydrolysis reaction, was shown to be cellularly non-toxic.11) These results suggested that it was worthwhile to pursue further optimization of this prodrug system.In this paper, we investigated the replaceable water-solubilizing moiety to evaluate its influence on prodrug water solubility and half-life. As a water-solubilizing moiety, we focused on two types of polar groups. One was L-carnitine (3), 25) which is an γ-amino acid derivative involved in lipid metabolism in the human body. The unprotected polar functional group of the azide 4 26) is a β-hydroxycarboxylic acid moiety, that is similar to the serine-type structure used in prodrug 2, with a higher number of carbon atoms. These slight changes were expected to provide interesting effects on th...

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Total synthesis of (+)-negamycin and its 5-epi-derivative

Cited by 18 publications

References 39 publications

Negamycin induces translational stalling and miscoding by binding to the small subunit head domain of the Escherichia coli ribosome

Negamycin induces translational stalling and miscoding by binding to the small subunit head domain of the Escherichia coli ribosome

Design, Synthesis, and Biological Evaluation of Simplified Side Chain Hybrids of the Potent Actin Binding Polyketides Rhizopodin and Bistramide

Prodrug Study of Plinabulin Using a Click Strategy Focused on the Effects of a Replaceable Water-Solubilizing Moiety

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