Destruction of the platelet aggregating activity of ristocetin A

Kuwahara, Steven S.; Chambers, Will

doi:10.1007/bf01935974

Cited by 3 publications

(3 citation statements)

References 11 publications

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“…162–164 Later, studies identified an aspect of the ristocetin structure that could be easily removed through selective enzymatic cleavage of rhamnose, which eliminated the induced platelet aggregation in vivo . 165 …”

Section: Total Synthesis Of Ristocetin a Aglyconmentioning

confidence: 99%

“…Shortly following this initial disclosure, the complex was introduced into the clinic in 1957. Reports of incidents of patient mortality forced this antibiotic to be pulled from the market after two years of clinical use. , A common link was identified where patients missing a platelet factor, those with von Willebrand’s disease, suffered platelet aggregation, attributing to the deaths. − As a result, ristocetin A aggregation of patient platelets in drawn blood samples is used today to diagnosis this disease and to detect abnormalities in this protein. − Later, studies identified an aspect of the ristocetin structure that could be easily removed through selective enzymatic cleavage of rhamnose, which eliminated the induced platelet aggregation in vivo …”

Section: Total Synthesis Of Ristocetin a Aglyconmentioning

confidence: 99%

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Total Syntheses of Vancomycin-Related Glycopeptide Antibiotics and Key Analogues

2017

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A review of efforts that have provided total syntheses of vancomycin and related glycopeptide antibiotics, their agylcons, and key analogues is provided. It is a tribute to developments in organic chemistry and the field of organic synthesis that not only can molecules of this complexity be prepared today by total synthesis, but that such efforts can be extended to the preparation of previously inaccessible key analogues that contain deep-seated structural changes. With the increasing prevalence of acquired bacterial resistance to existing classes of antibiotics and with the emergence of vancomycin resistant pathogens (VRSA and VRE), the studies pave the way for the examination of synthetic analogues rationally designed to not only overcome vancomycin resistance, but to provide the foundation for the development of even more powerful and durable antibiotics.

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Section: Total Synthesis Of Ristocetin a Aglyconmentioning

confidence: 99%

Section: Total Synthesis Of Ristocetin a Aglyconmentioning

confidence: 99%

Total Syntheses of Vancomycin-Related Glycopeptide Antibiotics and Key Analogues

2017

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“…Isolated from Nocardia lurida and patented for use as an antibacterial by Abbott in 1961, ristocetin A was discontinued in clinical use 2 years after being introduced due to incidences of patient mortality attributable to platelet aggregation . Subsequently, this latter activity was found to be eliminated through enzymatic cleavage of rhamnose from the pendant tetrasaccharide . Currently, ristocetin A is used clinically to diagnose von Willebrand's disease, a common genetic hemorrhagic disorder 11 and has found use as an electrophoretic and chromatographic chiral selector .…”

mentioning

confidence: 99%

Total Synthesis of the Ristocetin Aglycon

et al. 2004

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The first total synthesis of the ristocetin aglycon is described employing a modular and highly convergent strategy. An effective 12-step (12% overall) synthesis of the ABCD ring system 3 from its amino acid subunits sequentially features an intramolecular aromatic nucleophilic substitution reaction for formation of the diaryl ether and closure of the 16-membered CD ring system (65%), a respectively diastereoselective (3:1, 86%) Suzuki coupling for installation of the AB biaryl linkage on which the atropisomer stereochemistry can be further thermally adjusted, and an effective macrolactamization (51%) for closure of the 12-membered AB ring system. A similarly effective 13-step (14% overall) synthesis of the 14-membered EFG ring system 4 was implemented employing a room-temperature intermolecular S(N)Ar reaction of an o-fluoronitroaromatic for formation of the FG diaryl ether (69%) and a key macrolactamization (92%) with formation of the amide linking residues 1 and 2. The two key fragments 3 and 4 were coupled, and the remaining 16-membered DE ring system was closed via diaryl ether formation to provide the ristocetin tetracyclic ring system (15 steps, 8% overall) enlisting an unusually facile (25 degrees C, 8 h, DMF, >/=95%) and diastereoselective (>/=15:1) aromatic nucleophilic substitution reaction that benefits from substrate preorganization.

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Biological properties of ristocetin-.PSI.-aglycone.

Nielsen¹,

Hyldig-Nielsen²,

Jacobsen³

1982

J. Antibiot.

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Ristocetin-aglycone obtained by acid hydrolysis of ristocetin A, has a substantially greater antimicrobial activity against Gram-positive bacteria than the parent compound. None of the substances are active against Gram-negative bacteria, yeast or fungi. The ?P-aglycone is several times more toxic than ristocetin A when administered intravenously. Both substances are well-tolerated when given subcutaneously, intraperitoneally and perorally. Both ristocetin A and the IIT-aglycone have a very low absorption after oral administration. Plasma levels following intravenous administration of ristocetin A and the 7h'-aglycone are comparable, with both showing a rapid decline during the first 60 minutes followed by a somewhat slower elimination. The aggregating properties of the IF-aglycone could not be determined due to its low solubility at neutral pH.

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Destruction of the platelet aggregating activity of ristocetin A

Abstract: Hydrolysis of ristocetin A in 0.1 N HCl at 37 degrees C for 2 h resulted in the loss of its ability to induce platelet aggregation in platelet-rich plasma derived from guinea-pigs and humans. However its antibiotic activity against Staph. aureus was not lost.

Cited by 3 publications

References 11 publications

Total Syntheses of Vancomycin-Related Glycopeptide Antibiotics and Key Analogues

Total Syntheses of Vancomycin-Related Glycopeptide Antibiotics and Key Analogues

Total Synthesis of the Ristocetin Aglycon

Biological properties of ristocetin-.PSI.-aglycone.

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