A Chemical Approach to Generate Molecular Diversity Based on the Scaffold of Cyclic Decapeptide Antibiotic Tyrocidine A

Qin, Chuanguang; Bu, Xianzhang; Wu, Xiaoming; Guo, Zhihong

doi:10.1021/cc0300255

Cited by 34 publications

(34 citation statements)

References 37 publications

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“…Molecular modeling contributes importantly to all approaches [9, 28, 31]. Development of peptides as innovative pharmaceutical agents should utilize a variety of design approaches [35]. …”

Section: Introductionmentioning

confidence: 99%

“…[14, 15, 19] or through structural modifications of peptides. Incorporation of moieties that are not amino acids, e.g ., to generate peptidomimetics, can offer enhanced diversity [35], specificity and functionality but may come with an attendant risk of toxicity beyond that associated with simple amino acids. Minimal host toxicity (conceptualized in terms of a continuum from simple side effects to frank cytotoxicity) is desirable and achievable when using peptides as pharmaceutical agents because peptides: (a) can offer exquisite specificity to limit side effects, (b) eventually get metabolized only to byproducts that are non-toxic ( i.e ., amino acids), and (c) deliver sustained efficacy because peptides mimic the epitope-based action of naturally occurring proteins in regulating biological response.…”

Section: Introductionmentioning

confidence: 99%

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Design and synthesis of biologically active peptides: A ‘tail’ of amino acids can modulate activity of synthetic cyclic peptides

et al. 2011

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In earlier work, we synthesized a cyclic 9-amino acid peptide (AFPep, cyclo[EKTOVNOGN]) and showed it to be useful for prevention and therapy of breast cancer. In an effort to explore the structure-function relationships of AFPep, we have designed analogs that bear a short ‘tail’ (one or two amino acids) attached to the cyclic peptide distal to its pharmacophore. Analogs that bore a tail of either one or two amino acids, either of which had a hydrophilic moiety in the side chain (example: cyclo[EKTOVNOGN]FS) exhibited greatly diminished biological activity (inhibition of estrogen-stimulated uterine growth) relative to AFPep. Analogs that bore a tail of either one or two amino acids which had hydrophobic (aliphatic or aromatic) side chains (example: cyclo[EKTOVNOGN]FI) retained (or had enhanced) growth inhibition activity. Combining in the same biological assay a hydrophilic-tailed analog with either AFPep or a hydrophobic-tailed analog resulted in decreased activity relative to that for AFPep or for the hydrophobic-tailed analog alone, suggesting that hydrophilic-tailed analogs are binding to a biologically active receptor. An analog with a disrupted pharmacophore (cyclo[EKTOVGOGN]) exhibited little or no growth inhibition activity. An analog with a hydrophilic tail and a disrupted pharmacophore (cyclo[EKTOVGOGN]FS) exhibited no growth inhibition activity of its own and did not affect the activity of a hydrophobic-tailed analog, but enhanced the growth inhibition activity of AFPep. These results are discussed in the context of a two-receptor model for binding of AFPep and ring-and-tail analogs. We suggest that tails on cyclic peptides may comprise a useful method to enhance diversity of peptide design and specificity of ligand-receptor interactions.

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“…Molecular modeling contributes importantly to all approaches [9, 28, 31]. Development of peptides as innovative pharmaceutical agents should utilize a variety of design approaches [35]. …”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Design and synthesis of biologically active peptides: A ‘tail’ of amino acids can modulate activity of synthetic cyclic peptides

et al. 2011

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“…It is therefore of interest to synthesize these compounds and to generate molecular diversity based on these peptides in a search of new biological activities or to optimize their original activities. 8 Over the past 20 years, several anticancer cyclic peptides have been isolated from the Western Pacific Ocean (Federated States of Micronesia-Ckuuk) marine sponge Phakellia sp. [9][10][11][12][13][14] As a result of these studies, a series of 14 members of phakellistatin (phakellistatin 1-14) have been isolated in addition to many other linear and cyclic peptides.…”

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confidence: 99%

Solid-Phase Total Synthesis of Cyclic Decapeptide Phakellistatin 12

2008

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Pakellistatin 12 (1) is a new cancer cell growth inhibitory (P388 ED 50 2.8 microg/mL) cyclodecapeptide that was isolated from a marine sponge Phakellia sp. The first total synthesis of compound 1 is reported here using solid-phase methodology with safety-catch linker strategy. For the sequence of amino acids in the cycle, the peptide product was analyzed with a MALDI TOF/TOF instrument, and the structure of the synthetic product was found to be chemically and spectroscopically identical to the natural substance.

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“…Recently, we found that the biosynthetic precursors of tyrocidine A [15] and gramicidin S [16] adopt a preorganized conformation, which is highly favorable for specific head-to-tail cyclization. This led to a simpler synthesis of tyrocidine A using an acylsulfonamide safety-catch linker [17], without the need to protect the reactive side-chain functionalities in the cyclization and product-releasing steps.…”

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confidence: 99%

“…Synthesis and Structure Elucidation. The precursors of loloatins A -D (1 -4) were synthesized and cyclized in analogy to the method described previously for the preparation of tyrocidine A (Scheme) [17]. However, in the present protocol, there was no need for protection of the side-chain NH 2 groups of ornithine (Orn 2 ) and asparagine (Asn 6 ), or of the OH groups of tyrosine (d-Tyr 10 ) or HPro 9 (in 4), during cyclization.…”

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confidence: 99%

Solid‐Phase Total Synthesis and Antimicrobial Activities of Loloatins A–D

Ding¹,

Qin²,

Guo³

et al. 2007

Chemistry & Biodiversity

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The first total synthesis of the decapeptide antibiotics loloatins A-D (1-4), originally isolated from the marine bacterial isolate MK-PNG-276A, possibly in the genus Bacillus, was accomplished by solid-phase peptide synthesis (SPPS), followed by 'head-to-tail' cyclization of the activated linear precursors, without protection of nucleophilic side-chain functions, on a safety-catch resin. The synthetic peptides were equally active as the natural products isolated from the bacterial source and found to possess similar bacterial selectivity as other members in the family of amphipathic antimicrobial cyclic decapeptides.

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A Chemical Approach to Generate Molecular Diversity Based on the Scaffold of Cyclic Decapeptide Antibiotic Tyrocidine A

Cited by 34 publications

References 37 publications

Design and synthesis of biologically active peptides: A ‘tail’ of amino acids can modulate activity of synthetic cyclic peptides

Design and synthesis of biologically active peptides: A ‘tail’ of amino acids can modulate activity of synthetic cyclic peptides

Solid-Phase Total Synthesis of Cyclic Decapeptide Phakellistatin 12

Solid‐Phase Total Synthesis and Antimicrobial Activities of Loloatins A–D

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