A progressive synthetic strategy for class B synergimycins

Robinson, Jennifer L.; Taylor, Rachel E.; Liotta, L.; Bolla, Megan L.; Azevedo, Enrique V.; Medina, Irene; McAlpine, Shelli R.

doi:10.1016/j.tetlet.2004.01.048

Cited by 6 publications

(4 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Possibly a more viable strategy for circumventing resistance mediated by Vgb is altering type B streptogramins so as to reduce the affinity to Vgb without affecting binding to the ribosome. There is a rich literature on the synthesis of type B streptogramin variants using diverse strategies including synthetic (24), semisynthetic (25), chemoenzymatic (23,26), and solid-phase synthesis approaches (27). The analysis presented here on the similarities and differences between the binding of quinupristin to Vgb vs. the natural target can guide which alterations may reduce the drugs' susceptibility to bacterial resistance.…”

Section: Discussionmentioning

confidence: 99%

Structural basis for streptogramin B resistance in Staphylococcus aureus by virginiamycin B lyase

Korczynska

Mukhtar

Wright

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The streptogramin combination therapy of quinupristin-dalfopristin (Synercid) is used to treat infections caused by bacterial pathogens, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. However, the effectiveness of this therapy is being compromised because of an increased incidence of streptogramin resistance. One of the clinically observed mechanisms of resistance is enzymatic inactivation of the type B streptogramins, such as quinupristin, by a streptogramin B lyase, i.e., virginiamycin B lyase (Vgb). The enzyme catalyzes the linearization of the cyclic antibiotic via a cleavage that requires a divalent metal ion. Here, we present crystal structures of Vgb from S. aureus in its apoenzyme form and in complex with quinupristin and Mg 2؉ at 1.65-and 2.8-Å resolution, respectively. The fold of the enzyme is that of a seven-bladed ␤-propeller, although the sequence reveals no similarity to other known members of this structural family. Quinupristin binds to a large depression on the surface of the enzyme, where it predominantly forms van der Waals interactions. Validated by site-directed mutagenesis studies, a reaction mechanism is proposed in which the initial abstraction of a proton is facilitated by a Mg 2؉ -linked conjugated system. Analysis of the Vgb-quinupristin structure and comparison with the complex between quinupristin and its natural target, the 50S ribosomal subunit, reveals features that can be exploited for developing streptogramins that are impervious to Vgb-mediated resistance.antibiotic resistance ͉ enzyme mechanism ͉ crystal structure

show abstract

Section: Discussionmentioning

confidence: 99%

Structural basis for streptogramin B resistance in Staphylococcus aureus by virginiamycin B lyase

Korczynska

Mukhtar

Wright

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Thus, the cyclic peptides 2 and 3 were also obtained in good yields when DEPC/DEPBT cyclisation conditions were employed. A similar application of two or more coupling reagents at the same time (one-pot) has previously been reported to facilitate efficient ring-closing reactions by providing a choice of reagents for the specific substrate, which is in lieu of optimising each individual reaction for each individual coupling agent [10,37]. So far, no bioassays have been performed with the prepared cyclopeptides.…”

Section: Resultsmentioning

confidence: 99%

New 21‐ and 24‐atom Aib‐containing cyclopeptides

Jeremic

Linden

Heimgartner

2008

Journal of Peptide Science

View full text Add to dashboard Cite

The synthesis of two Aib-containing cyclic octapeptides, cyclo(Leu-Aib-Phe-Aib-Gly-Aib-Phe-Aib) (1) and cyclo(Gly-Aib-Aib-Val-Aib-Leu-Aib-Phe) (2), and a cyclic heptapeptide cyclo(Gly-Aib-Val-Aib-Leu-Aib-Phe) (3), is described. The linear precursors of 1-3 were prepared using solution-phase techniques, and the cyclisation was also accomplished in solution. Among the coupling reagents examined in the final macrolactamisation step, PyAOP, HATU and DEPC/DEPBT efficiently yielded cyclised products. However, the success of the cyclisation was found to be dependent on the coupling reagent used. The two octapeptides 1 and 2 were obtained in much better yields (up to 63%) than the cycloheptapeptide 3 (30-37%). In addition, crystal-state conformational analysis of 2 was performed by X-ray crystallography. Six intramolecular hydrogen bonds stabilise the structure characterised by two consecutive type II'/I beta-turns, two consecutive type II/III' beta-turns, one gamma-turn, and one inverse gamma-turn.

show abstract

“…The amine was deprotected in Fragment 1 using TFA, and the acid was deprotected in Fragment 2 using lithium hydroxide. Fragments 1 and 2 were coupled using multiple coupling agents, yielding 14 examples of linear pentapeptides (50−74% yield) (Scheme ) 2 Cyclization of Sansalvamide Derivatives a a Conditions: (a) coupling agent [for linear peptides, typically HATU and TBTU (∼0.75 equiv ea); for cyclizations, HATU, DEPBT, PyAOP, PyBROP, and/or TBTU (∼0.5 equiv ea)], DIPEA (3 equiv), CH 3 CN; (b) HCl, anisole (2 equiv), CH 2 Cl 2 ; (c) LiOH (4 equiv), MeOH. …”

mentioning

confidence: 99%

“…Upon completion, the reaction was concentrated in vacuo, and the acid was deprotected by neutralizing the reaction with lithium hydroxide and then adding an additional 4 equiv of lithium hydroxide in methanol to give pH = ∼11 . Following acid deprotection, the reaction was concentrated in vacuo and subjected to HATU, TBTU, PyAOP, PyBrop, and/or DEPBT coupling reagents (∼0.5 equiv each) and DIPEA (∼6 equiv until pH = 8) . The final macrocyclizations took approximately 4 days because of the low concentration (0.005−0.01 M) required to maximize the yield.…”

mentioning

confidence: 99%

Synthesis and Cytotoxicity of Novel Sansalvamide A Derivatives

et al. 2005

Self Cite

View full text Add to dashboard Cite

Described are the syntheses of 14 derivatives of the natural product Sansalvamide A, where two are more active against HCT 116 colon cancer cell lines than the natural product. These derivatives were synthesized using a combinatorial-type strategy that permits elucidation of the amino acid role in the cytotoxicity, and they lay the groundwork for development of new anticancer agents. [structure: see text]

show abstract

A progressive synthetic strategy for class B synergimycins

Cited by 6 publications

References 15 publications

Structural basis for streptogramin B resistance in Staphylococcus aureus by virginiamycin B lyase

Structural basis for streptogramin B resistance in Staphylococcus aureus by virginiamycin B lyase

New 21‐ and 24‐atom Aib‐containing cyclopeptides

Synthesis and Cytotoxicity of Novel Sansalvamide A Derivatives

Contact Info

Product

Resources

About