Synthesis of Novel 25-Substituted Milbemycin A<sub>4</sub>Derivatives and Their Acaricidal Activity against<i>Tetranychus urticae</i>

Tsukamoto, Yoshihisa; Nakagawa, Harumi; Kajino, Hisaki; Sato, Kazuo; Tanaka, Keiji; Yanai, Toshiaki

doi:10.1271/bbb.61.1650

Cited by 9 publications

(5 citation statements)

References 3 publications

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“…Next, the azido moiety of 25 was reduced by treatment with zinc and acetic acid in DCM, and the amine of the resulting compound acylated with 7 in the presence of DCC to afford 26 as the common intermediate for the synthesis of target molecules 3 and 4 . For the synthesis of 3 , the Alloc protecting group of 26 was removed by reaction with Pd(PPh 3 ) 4 in the presence of HCOOH and n-BuNH 2 ,41 and the resulting hydroxyl acylated with ( R )-3-benzyloxy-hexadecanoic acid 10 using DCC and DMAP as the activation reagent to give 27 . Next, removal of the Lev group of 27 was easily accomplished by treatment with hydrazine acetate to give 28 , which treated with Bu 4 NF in the presence of acetic acid to give the desired product 29 in a yield of 72% and a small amount of a side product arising from elimination of the 3-acyloxyl group.…”

Section: Resultsmentioning

confidence: 99%

Synthetic tetra-acylated derivatives of lipid A from Porphyromonas gingivalis are antagonists of human TLR4

et al. 2008

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SummaryTetra-acylated lipid As derived from Porphyromonas gingivalis LPS have been synthesized using a key disaccharide intermediate functionalized with levulinate (Lev), allyloxycarbonate (Alloc) and anomeric dimethylthexylsilyl (TDS) as orthogonal protecting groups and 9-fluorenylmethoxycarbamate (Fmoc) and azido as amino protecting groups. Furthermore, an efficient cross metathesis has been employed for the preparation of the unusual branched R-(3)-hydroxy-13-methyltetradecanic acid and (R)-3-hexadecanoyloxy-15-methyl-hexadecanoic acid of P. gingivalis lipid A. Biological studies have shown that the synthetic lipid As can not activate human and mouse TLR2 and TLR4 to produce cytokines. However, it has been found that the compounds are potent antagonist of cytokine secretion by human monocytic cells induced by enteric LPS.

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Section: Resultsmentioning

confidence: 99%

Synthetic tetra-acylated derivatives of lipid A from Porphyromonas gingivalis are antagonists of human TLR4

et al. 2008

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“…Thus, the Fmoc protecting group of 18 was removed using 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) in DCM and the resulting amino group acylated with (R)-3-dodecanoyl-tetradecanoic acid (9) using DCC as the activating agent to give compound 19. Removal of the Alloc group of 19 was easily accomplished by treatment with Pd(PPh 3 ) 4 in the presence of BuNH 2 and HCOOH, [38] and subsequent acylation of the resulting hydroxyl with 8 using DCC and DMAP as activating agent afforded 20. Next, reduction of the azido function of 20 with zinc in a mixture of acetic acid and DCM followed by acylation of the resulting amine with 9 using standard conditions furnished fully acylated 21.…”

Section: Chemical Synthesismentioning

confidence: 99%

Innate Immune Responses of Synthetic Lipid A Derivatives of Neisseria meningitidis

Zhang

Gaekwad

Wolfert

et al. 2007

Chemistry A European J

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Differences in the pattern and chemical nature of fatty acids of lipid A of Neisseria meningitides lipooligosaccharides (LOS) and Escherichia coli lipopolysaccharides (LPS) may account for differences in inflammatory properties. Furthermore, there are indications that dimeric 3-deoxy-Dmanno-oct-2-ulosonic acid (KDO) moieties of LOS and LPS enhance biological activities. Heterogeneity in the structure of lipid A and possible contaminations with other inflammatory components have made it difficult to confirm these observations. To address these problems, a highly convergent approach for the synthesis of a lipid A derivative containing KDO has been developed, which relies on the ability to selectively remove or unmask in a sequential manner an isopropylidene acetal, 9-fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonate (Alloc), azide, and thexyldimethylsilyl (TDS) ether. The strategy was employed for the synthesis of N. meningitidis lipid A containing KDO (3). Mouse macrophages were exposed to the synthetic compound and its parent LOS, E. coli lipid A (2), and a hybrid derivative (4) that has the asymmetrical acylation pattern of E. coli lipid A, but the shorter lipids of meningococcal lipid A. The resulting supernatants were examined for tumor necrosis factor alpha (TNF-α) and interferon beta (IFN-β) production. The lipid A derivative containing KDO was much more active than lipid A alone and just slightly less active than its parent LOS, indicating that one KDO moiety is sufficient for full activity of TNF-α and IFN-β induction. The lipid A of N. meningitidis was a significantly more potent inducer of TNF-α and IFN-β than E. coli lipid A, which is due to a number of shorter fatty acids. The compounds did not demonstrate a bias towards a MyD88-or TRIF-dependent response.

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“…The addition of DMAP provides, however, a more reactive reagent and can acylate a less nucleophilic hydroxyl. The removal of the Alloc protecting group of 22 could easily be accomplished by treatment with Pd(PPh 3 ) 4 ; however, the acylation of the resulting hydroxyl of 23 with ( R )-tetradecanoyltetradecanoic acid ( 19 ) using standard conditions did not, unexpectedly, lead to the formation of 24 . Instead, compounds 25 , 26 , and 27 were identified (Figure ).…”

Section: Resultsmentioning

confidence: 99%

Modulation of Innate Immune Responses with Synthetic Lipid A Derivatives

et al. 2007

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The lipid A moiety of lipopolysaccharides (LPS) initiates innate immune responses by interacting with Toll-like receptor 4 (TLR4) which results in the production of a wide range of cytokines. Derivatives of lipid A show potential for use as immuno-modulators for the treatment of a wide range of diseases and as adjuvants for vaccinations. Development to these ends requires a detailed knowledge of patterns of cytokines induced by a wide range of derivatives. This information is difficult to obtain by using isolated compounds due to structural heterogeneity and possible contaminations with other inflammatory components. To address this problem, we have developed a synthetic approach that provides easy access to a wide range of lipid As by employing a common disaccharide building block functionalized with a versatile set of protecting groups. The strategy was employed for the preparation of lipid As derived from E. coli and S. typhimurium. Mouse macrophages were exposed to the synthetic compounds and E. coli 055:B5 LPS and the resulting supernatants examined for tumor necrosis factor alpha (TNF-α), interferon beta (IFN-β), interleukin 6 (IL-6), interferon-inducible protein 10 (IP-10), RANTES, and IL-1β It was found that for each compound, the potencies (EC 50 values) for the various cytokines differed by as much as 100-fold. These differences did not follow a bias towards a MyD88-or TRIF-dependent response. Instead, it was established that the observed differences in potencies of secreted TNF-α and IL-1β were due to differences in the processing of respective pro-proteins. Examination of the efficacies (maximum responses) of the various cytokines showed that each synthetic compound and E. coli 055:B5 LPS induced similar efficacies for the production of IFN-β, and IP-10. However, lipid As 1-4 gave lower efficacies for the production of RANTES and IL-6 compared to LPS. Collectively, the presented results demonstrate that cytokine secretion induced by LPS and lipid A is complex, which can be exploited for the development of immuno-modulating therapies.

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Synthesis of Novel 25-Substituted Milbemycin A₄Derivatives and Their Acaricidal Activity againstTetranychus urticae

Cited by 9 publications

References 3 publications

Synthetic tetra-acylated derivatives of lipid A from Porphyromonas gingivalis are antagonists of human TLR4

Synthetic tetra-acylated derivatives of lipid A from Porphyromonas gingivalis are antagonists of human TLR4

Innate Immune Responses of Synthetic Lipid A Derivatives of Neisseria meningitidis

Modulation of Innate Immune Responses with Synthetic Lipid A Derivatives

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Synthesis of Novel 25-Substituted Milbemycin A4Derivatives and Their Acaricidal Activity againstTetranychus urticae

Cited by 9 publications

References 3 publications

Synthetic tetra-acylated derivatives of lipid A from Porphyromonas gingivalis are antagonists of human TLR4

Synthetic tetra-acylated derivatives of lipid A from Porphyromonas gingivalis are antagonists of human TLR4

Innate Immune Responses of Synthetic Lipid A Derivatives of Neisseria meningitidis

Modulation of Innate Immune Responses with Synthetic Lipid A Derivatives

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Synthesis of Novel 25-Substituted Milbemycin A₄Derivatives and Their Acaricidal Activity againstTetranychus urticae