Synthesis of New unnatural Macrocyclic Trichothecenes: 4‐epiverrucarin A. 47th Communication on verrucarins and roridins

Jeker, N.; Tamm, Christoph

doi:10.1002/hlca.19880710809

Cited by 22 publications

(3 citation statements)

References 20 publications

(17 reference statements)

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“…Miscellaneous Mixed Anhydrides. Several other mixed anhydrides, obtained from pivaloyl chloride, 396,397 trifluoroacetic anhydride, 398,399 acetic anhydride 400,401 (Scheme 29), and Boc 2 O 402-404 have also been described, but with only limited synthetic development.…”

Section: Mixed Anhydrides and Basic Activationmentioning

confidence: 99%

Macrolactonizations in the Total Synthesis of Natural Products

2006

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Section: Mixed Anhydrides and Basic Activationmentioning

confidence: 99%

Macrolactonizations in the Total Synthesis of Natural Products

2006

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“…The naturally occurring trichothecenes are classified as verrucarins (mainly C 27 compounds) and roridins (mainly C 29 metabolites). Because of their multiple functions, such as cytotoxic [1], antifungal [6], antimalarial [7], immunomodulatory [8], and phytotoxic [9] activities, the trichothecene macrolides are attracting expanding attention from multidisciplinary fields, explaining the frequent reports on their structure [2,5,10], bioactivity [1,11], biosynthesis [12][13][14], and chemosynthesis [15,16]. In our continuous research on trichothecene macrolides from Myrothecium sp.…”

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A New Cytotoxic Trichothecene Macrolide from the EndophyteMyrothecium roridum

et al. 2010

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A new cytotoxic roridin-type trichothecene macrolide named roritoxin E(1) was characterized from the solid culture of Myrothecium roridum IFB-E091 (residing originally inside Artemisia annua root), together with the known compounds lumichrome (2), (22 E,24 S)-cerevisterol (3), and (22 E,24 R)-6 beta-methoxy-ergosta-7,22-diene-3 beta,5 alpha-diol (4). The structure of the new macrolide (1) was elucidated by a combination of spectroscopic (UV, IR, MS, and 1D and 2D NMR) analyses. Compound 1 was demonstrated to be inhibitory in vitro against the gastric carcinoma SGC-7901 and hepatocarcinoma SMMC-7721 cell lines, with IC (50) values of 0.26 and 10.54 microg/mL, respectively. 5-Fluorouracil co-assayed as a positive control had an IC (50) value of 6.66 microg/mL against SGC-7901 cells, and it demonstrated only a 9.98 % growth inhibition against SMMC-7721 cells at 10 microg/mL.

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“…After evaluation of a range of protecting groups, including benzoate and acetate, the final candidate for protection of the 2′, 3′ hydroxyl positions was the levulinate group. The levulinate group can survive the synthesis conditions for these prodrugs and can be easily removed by treating with 1 ml of 2 M hydrazine hydrate in pyridine-acetic acid buffer for 10 min,18,19 conditions under which normal esters are not cleaved 20,21. In addition, the levulinate is less prone to migration between adjacent hydroxyl groups on the sugar residue than other ester protection group such as benzoate and acetate 22,23.…”

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Design and synthesis of vidarabine prodrugs as antiviral agents

Shen

Kim

Kish

et al. 2009

Bioorganic & Medicinal Chemistry Letters

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Abstract5′-O-D-and L-amino acid derivatives and 5′-O-(D-and L-amino acid methyl ester phosphoramidate) derivatives of vidarabine (ara-A) were synthesized as vidarabine prodrugs. Some compounds were equi-or more potent in vitro than vidarabine against two pox viruses and their uptake by cultured cells was improved compared to the parent drug. KeywordsVidarabine; ara-A; Amino acid ester prodrug; Phosphoramidate prodrug; Antiviral activity; Selective protection of nucleoside; Levulinate ester; Oral bioavailability; Adenosine deaminase; Arahypoxanthine; ara-H; Caco-2 permeability There has been continued interest in the synthesis and biological evaluation of nucleoside analogs capable of delivering the corresponding nucleotides inside cells. 1 1-Beta-Darabinofuranosyladenine (vidarabine or ara-A) is an antiviral drug with activity against herpes viruses, poxviruses, and certain rhabdoviruses, hepadnarviruses, and RNA tumor viruses. [2][3][4] Vidarabine also is active against vaccinia virus both in vitro 5 and in vivo. 6 However, it is more toxic and less metabolically stable than other current antivirals such as acyclovir and ganciclovir; further it is poorly soluble with low oral bioavailability. It is readily deaminated by adenosine deaminase (ADA) to ara-hypoxanthine (ara-H), 7 which possesses some antiviral activity but is at least 10-fold less potent than vidarabine. 6-8 Adenosine deaminase (ADA) is a cytosolic enzyme that participates in purine metabolism where it degrades either adenosine or 2′-deoxyadenosine to inosine or 2′-deoxyinosine, respectively. Further metabolism of these deaminated nucleosides leads to hypoxanthine. ADA also degrades vidarabine to ara-H by same mechanism. 7 Our current interest in prodrugs of vidarabine was triggered by the report of the activity of vidarabine against cowpox virus 9 and by our discovery that vidarabine was 3-to 5-fold more active against vaccinia and cowpox viruses than cidofovir in plaque reduction assays. 10 Cidofovir is a broad spectrum antiviral agent, [11][12][13] that is, limited in its usage because of nephrotoxicity and poor oral bioavailability (~2% in humans) [14][15][16] and for which prodrugs have been developed. 17 Furthermore, we found that the activity of vidarabine against these viruses was enhanced approximately 10-fold when combined with 2′-deoxycoformycin (pentostatin, a potent inhibitor of ADA), thus providing significant superiority to cidofovir. Based on these results and earlier studies on 5′-substituted vidarabine analogs, we hypothesized that minimizing the conversion of vidarabine to its hypoxanthine analog could yield a significantly more potent anti-pox virus agent. With this goal in mind, we have developed a prodrug strategy that protects the vidarabine from metabolic conversion by making 5′-amino acid esters and 5′-phosphoramidates of the drug. Further, our rationale includes the design of prodrugs that increase aqueous solubility over that of the parent drug and also increase the potential for membrane transport by the dipeptide intest...

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Synthesis of New unnatural Macrocyclic Trichothecenes: 4‐epiverrucarin A. 47th Communication on verrucarins and roridins

Cited by 22 publications

References 20 publications

Macrolactonizations in the Total Synthesis of Natural Products

Macrolactonizations in the Total Synthesis of Natural Products

A New Cytotoxic Trichothecene Macrolide from the EndophyteMyrothecium roridum

Design and synthesis of vidarabine prodrugs as antiviral agents

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