Relationship between Structure and Biological Activity of Novel R106 Analogs.

Rodriguez, Michael J.; Zweifel, Mark J.; Farmer, James; Gordee, Robert S.; Loncharich, Richard J.

doi:10.7164/antibiotics.49.386

Cited by 16 publications

(4 citation statements)

References 6 publications

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“…94 An interesting chemical approach to their modification is a tandem retroaldol,aldol reaction replacing the amino acid that can contribute the acyl moiety of the lactone bond. 95 This work has demonstrated the importance of the configuration and presence of the tertiary alcohol (2hydroxy-L-valine) for biological activity. Nonhydroxylated derivatives were inactive against Cryptococcus.…”

Section: Applications Of Biocatalysts In Peptide Synthesismentioning

confidence: 94%

Multifunctional Peptide Synthetases

H¹,

Keller²,

Vater³

et al. 1997

Chem. Rev.

234

147

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Section: Applications Of Biocatalysts In Peptide Synthesismentioning

confidence: 94%

Multifunctional Peptide Synthetases

H¹,

Keller²,

Vater³

et al. 1997

Chem. Rev.

234

147

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“…Its structure was initially determined by a combination of analytical techniques and the study of degradation products109 and further confirmed by total synthesis110, 111 and X‐ray analysis 112. AbA presents a singular L ‐β‐hydroxy‐ N ‐methylvaline fragment at position 9 (Figure 17) which is crucial for activity 113. Modified analogues at different positions led to compounds with reduced antifungal activity against different species 114…”

Section: Natural Products and Analoguesmentioning

confidence: 99%

Chemical Tools to Investigate Sphingolipid Metabolism and Functions

et al. 2007

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Sphingolipids comprise an important group of biomolecules, some of which have been shown to play important roles in the regulation of many cell functions. From a structural standpoint, they all share a long 2-amino-1,3-diol chain, which can be either saturated (sphinganine), hydroxylated at C4 (phytosphingosine), or unsaturated at C4 (sphingosine) as in most mammalian cells. N-acylation of sphingosine leads to ceramide, a key intermediate in sphingolipid metabolism that can be enzymatically modified at the C1-OH position to other biologically important sphingolipids, such as sphingomyelin or glycosphingolipids. In addition, both ceramide and sphingosine can be phosphorylated at C1-OH to give ceramide-1-phosphate and sphingosine-1-phosphate, respectively. To better understand the biological and biophysical roles of sphingolipids, many efforts have been made to design synthetic analogues as chemical tools able to unravel their structure-activity relationships, and to alter their cellular levels. This last approach has been thoroughly studied by the development of specific inhibitors of some key enzymes that play an important role in biosynthesis or metabolism of these intriguing lipids. With the above premises in mind, the aim of this review is to collect, in a systematic way, the recent efforts described in the literature leading to the development of new chemical entities specifically designed to achieve the above goals.

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“…Furthermore, stabilization of this hydrogen bond leads to an energetic perference of this isomer over the other two l isomers. It should be noted that tertiary hydroxylated derivatives, as with R106-1, are active against the fungal pathogen C. neoformans , but lose activity as steric bulk of this residue is increased …”

Section: Resultsmentioning

confidence: 99%

Aldol-Promoted Reaction of R106-Sarcosine: Synthesis and Conformational Analysis of Novel R106 Analogs

Rodriguez¹,

Zweifel²,

Loncharich³

1996

J. Org. Chem.

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A unique semisynthetic pathway has been used as a route to novel R106 derivatives. R106-sarcosine, 2, was discovered to be a key intermediate to obtain these derivatives using classical aldol alkylation conditions. Surprisingly, the site of alkylation on 2 was found to be conformationally hindered which yielded both the D and L isomers of R106-1 (aureobasidin A), 1, and other new R106 derivatives. The scope of the alkylation was found to be highly dependent upon the reactivity potential of the electrophile. Semiempirical calculations on R106-1 and 8-(N-methylthrenonine)aureobasidin A, 7, were performed to investigate the thermodynamic stabilities of the D and L isomers. By contrast to stable conformations observed by two X-ray crystal structures of aureobasidins, the calculations indicated that the D isomers were significantly more stable. Furthermore, model semiempirical calculations to probe facial selecitivty were consistent with results obtained experimentally.

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Relationship between Structure and Biological Activity of Novel R106 Analogs.

Cited by 16 publications

References 6 publications

Multifunctional Peptide Synthetases

Multifunctional Peptide Synthetases

Chemical Tools to Investigate Sphingolipid Metabolism and Functions

Aldol-Promoted Reaction of R106-Sarcosine: Synthesis and Conformational Analysis of Novel R106 Analogs

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