Total Synthesis of Mycocyclosin

Cochrane, James R.; White, Jonathan M.; Wille, Uta; Hutton, Craig A.

doi:10.1021/ol300831t

Cited by 64 publications

(76 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S4-S8 †) and by NMR-1 H. Nuclear magnetic resonance spectra were recorded on a Bruker Avance III 400 in CD 3 CN/D 2 O (v/v 0 ; 20/80). Spectra were consistent with literature reports (Br-Tyr (7), 26 I-Tyr (8), 27 3,5-dichloro-Tyr (9), 28 3,5-dibromo-Tyr (10) 28 and 3,5-diiodo-Tyr (11) 28 ). solid phase peptide synthesis (SPPS) (scale 0.05 mmol).…”

Section: Protein Expression and Puricationsupporting

confidence: 91%

A proof-reading mechanism for non-proteinogenic amino acid incorporation into glycopeptide antibiotics

et al. 2019

View full text Add to dashboard Cite

Non-ribosomal peptide biosynthesis produces highly diverse natural products through a complex cascade of enzymatic reactions that together function with high selectivity to produce bioactive peptides. The modification of non-ribosomal peptide synthetase (NRPS)-bound amino acids can introduce significant structural diversity into these peptides and has exciting potential for biosynthetic redesign. However, the control mechanisms ensuring selective modification of specific residues during NRPS biosynthesis have previously been unclear. Here, we have characterised the incorporation of the non-proteinogenic amino acid 3-chloro-b-hydroxytyrosine during glycopeptide antibiotic (GPA) biosynthesis. Our results demonstrate that the modification of this residue by trans-acting enzymes is controlled by the selectivity of the upstream condensation domain responsible for peptide synthesis. A proofreading thioesterase works together with this process to ensure that effective peptide biosynthesis proceeds even when the selectivity of key amino acid activation domains within the NRPS is low. Furthermore, the exchange of condensation domains with altered amino acid specificities allows the modification of such residues within NRPS biosynthesis to be controlled, which will doubtless prove important for reengineering of these assembly lines. Taken together, our results indicate the importance of the complex interplay of NRPS domains and trans-acting enzymes to ensure effective GPA biosynthesis, and in doing so reveals a process that is mechanistically comparable to the hydrolytic proofreading function of tRNA synthetases in ribosomal protein synthesis.Peptide synthesis for tripeptide 3T-CoA, tetrapeptide 4T-CoA and pentapeptide 5T-CoA CoAs was performed manually by 9470 | Chem. Sci., 2019, 10, 9466-9482This journal is

show abstract

Section: Protein Expression and Puricationsupporting

confidence: 91%

A proof-reading mechanism for non-proteinogenic amino acid incorporation into glycopeptide antibiotics

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Spectra were acquired in positive mode from 100 to 1000 m / z . cYY and mycocyclosin were synthesized as described . Experimental details on modification of cYY and mycocyclosin synthesis and analytical data can be found in the Supporting Information (SI, section 4).…”

Section: Methodsmentioning

confidence: 99%

“…cYY and mycocyclosin were synthesized as described. [11,51] Experimental details on modification of cYY and mycocyclosin synthesis and analytical data can be found in the Supporting Information (SI, section 4). The synthesis of library compounds has been described previously:c lass I, [40,[52][53][54][55][56] class II, [57,58] class III, [59] class IV, [60] class V, [61] and class VI.…”

Section: Methodsmentioning

confidence: 99%

Biophysical Screening of a Focused Library for the Discovery of CYP121 Inhibitors as Novel Antimycobacterials

et al. 2017

View full text Add to dashboard Cite

The development of novel antimycobacterial agents against Mycobacterium tuberculosis (Mtb) is urgently required due to the appearance of multidrug resistance (MDR) combined with complicated long‐term treatment. CYP121 was shown to be a promising novel target for inhibition of mycobacterial growth. In this study, we describe the rational discovery of new CYP121 inhibitors by a systematic screening based on biophysical and microbiological methods. The best hits originating from only one structural class gave initial information about molecular motifs required for binding and activity. The initial screening procedure was followed by mode‐of‐action studies and further biological characterizations. The results demonstrate superior antimycobacterial efficacy and a decreased toxicity profile of our frontrunner compound relative to the reference compound econazole. Due to its low molecular weight, promising biological profile, and physicochemical properties, this compound is an excellent starting point for further rational optimization.

show abstract

“…The difficulties associated with forging strained connectivities in complex molecules have led to the development of new synthetic strategies. 1 Strained natural products from Nature often possess potent biological activities due to their unique three-dimensional structures. An effective method used by Nature to introduce strain is oxidative cyclization of acyclic precursors.…”

mentioning

confidence: 99%

Biosynthesis of Strained Piperazine Alkaloids: Uncovering the Concise Pathway of Herquline A

Liu²,

Zou³

et al. 2016

J. Am. Chem. Soc.

View full text Add to dashboard Cite

Nature synthesizes many strained natural products that have diverse biological activities. Uncovering these biosynthetic pathways may lead to biomimetic strategies for organic synthesis of such compounds. In this work, we elucidated the concise biosynthetic pathway of herquline A, a highly strained and reduced fungal piperazine alkaloid. The pathway builds on a nonribosomal peptide synthetase derived di-tyrosine piperazine intermediate. Following enzymatic reduction of the P450-crosslinked di-cyclohexadienone, N-methylation of the piperazine serves as a trigger that leads to a cascade of stereoselective and nonenzymatic transformations. Computational analysis of key steps in the pathway rationalizes the observed reactivities.

show abstract

Total Synthesis of Mycocyclosin

Cited by 64 publications

References 31 publications

A proof-reading mechanism for non-proteinogenic amino acid incorporation into glycopeptide antibiotics

A proof-reading mechanism for non-proteinogenic amino acid incorporation into glycopeptide antibiotics

Biophysical Screening of a Focused Library for the Discovery of CYP121 Inhibitors as Novel Antimycobacterials

Biosynthesis of Strained Piperazine Alkaloids: Uncovering the Concise Pathway of Herquline A

Contact Info

Product

Resources

About