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Total synthesis of vinblastine, related natural products, and key analogues and development of inspired methodology suitable for the systematic study of their structure-function properties.

Sears JE, Boger DL - Acc. Chem. Res. (2015)

Bottom Line: With use of the newly developed methodology and in addition to ongoing efforts to systematically define the importance of each embedded structural feature of vinblastine, two classes of analogues already have been discovered that enhance the potency of the natural products >10-fold.Unlike the removal of vinblastine structural features or substituents, which typically has a detrimental impact, the additions of new structural features have been found that can enhance target tubulin binding affinity and functional activity while simultaneously disrupting Pgp binding, transport, and functional resistance.Already analogues are in hand that are deserving of full preclinical development, and it is a tribute to the advances in organic synthesis that they are readily accessible even on a natural product of a complexity once thought refractory to such an approach.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States.

ABSTRACT
Biologically active natural products composed of fascinatingly complex structures are often regarded as not amenable to traditional systematic structure-function studies enlisted in medicinal chemistry for the optimization of their properties beyond what might be accomplished by semisynthetic modification. Herein, we summarize our recent studies on the Vinca alkaloids vinblastine and vincristine, often considered as prototypical members of such natural products, that not only inspired the development of powerful new synthetic methodology designed to expedite their total synthesis but have subsequently led to the discovery of several distinct classes of new, more potent, and previously inaccessible analogues. With use of the newly developed methodology and in addition to ongoing efforts to systematically define the importance of each embedded structural feature of vinblastine, two classes of analogues already have been discovered that enhance the potency of the natural products >10-fold. In one instance, remarkable progress has also been made on the refractory problem of reducing Pgp transport responsible for clinical resistance with a series of derivatives made accessible only using the newly developed synthetic methodology. Unlike the removal of vinblastine structural features or substituents, which typically has a detrimental impact, the additions of new structural features have been found that can enhance target tubulin binding affinity and functional activity while simultaneously disrupting Pgp binding, transport, and functional resistance. Already analogues are in hand that are deserving of full preclinical development, and it is a tribute to the advances in organic synthesis that they are readily accessible even on a natural product of a complexity once thought refractory to such an approach.

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Hydrogen atom transfer (HAT) free radical oxidation of anhydrovinblastineand generalization of the methodology for unactivated alkene functionalization.
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fig10: Hydrogen atom transfer (HAT) free radical oxidation of anhydrovinblastineand generalization of the methodology for unactivated alkene functionalization.

Mentions: Similarly, detailedinvestigations of the second stage of the couplingprocess, the Fe(III)-mediated free radical oxidation of the anhydrovinblastinetrisubstituted alkene to introduce the vinblastine C20′ tertiaryalcohol, revealed insights into not only its mechanism but also thesynthesis of previously inaccessible vinblastine analogues. Initialstudies revealed that it is a free radical mediated oxidation reaction,that the reaction is initiated by the addition of NaBH4 to the Fe(III) salt, and that reactions in the absence of air (O2) led to reduction of the double bond (Figure 10).16 Subsequent studies providedadditional details of the mechanism of the reaction, entailing a hydrogenatom transfer (HAT) initiated free radical reaction,44 and defined a new method for the direct functionalizationof unactivated alkenes.36 Included in thesestudies was a definition of the alkene substrate broad scope, thereaction’s extensive functional group tolerance, the establishmentof exclusive Markovnikov addition regioselectivity, the use of a widerange of alternative free radical traps for O, N, S, C, and halidesubstitution, an examination of the Fe(III) salt and the hydride sourcebest suited to initiate the reaction, the introduction of alternativereaction solvents beyond the water and aqueous buffer27 originally disclosed, and the exploration of catalyticvariants of the reactions.36 The reactionwas extended to a powerful Fe(III)/NaBH4-mediated freeradical hydrofluorination of unactivated alkenes using Selectfluoras the fluorine atom source.45 Unlike thetraditional and unmanageable free radical hydrofluorination of alkenes,the Fe(III)/NaBH4-mediated reaction is conducted underexceptionally mild conditions (0 °C, 5 min, CH3CN/H2O), uses a technically nondemanding reaction protocol, isconducted open to the air with water as a cosolvent, demonstratesan outstanding substrate scope and functional group tolerance, andis suitable for 18F introduction (t1/2 =110 min) used in PET imaging.45


Total synthesis of vinblastine, related natural products, and key analogues and development of inspired methodology suitable for the systematic study of their structure-function properties.

Sears JE, Boger DL - Acc. Chem. Res. (2015)

Hydrogen atom transfer (HAT) free radical oxidation of anhydrovinblastineand generalization of the methodology for unactivated alkene functionalization.
© Copyright Policy - editor-choice
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4363169&req=5

fig10: Hydrogen atom transfer (HAT) free radical oxidation of anhydrovinblastineand generalization of the methodology for unactivated alkene functionalization.
Mentions: Similarly, detailedinvestigations of the second stage of the couplingprocess, the Fe(III)-mediated free radical oxidation of the anhydrovinblastinetrisubstituted alkene to introduce the vinblastine C20′ tertiaryalcohol, revealed insights into not only its mechanism but also thesynthesis of previously inaccessible vinblastine analogues. Initialstudies revealed that it is a free radical mediated oxidation reaction,that the reaction is initiated by the addition of NaBH4 to the Fe(III) salt, and that reactions in the absence of air (O2) led to reduction of the double bond (Figure 10).16 Subsequent studies providedadditional details of the mechanism of the reaction, entailing a hydrogenatom transfer (HAT) initiated free radical reaction,44 and defined a new method for the direct functionalizationof unactivated alkenes.36 Included in thesestudies was a definition of the alkene substrate broad scope, thereaction’s extensive functional group tolerance, the establishmentof exclusive Markovnikov addition regioselectivity, the use of a widerange of alternative free radical traps for O, N, S, C, and halidesubstitution, an examination of the Fe(III) salt and the hydride sourcebest suited to initiate the reaction, the introduction of alternativereaction solvents beyond the water and aqueous buffer27 originally disclosed, and the exploration of catalyticvariants of the reactions.36 The reactionwas extended to a powerful Fe(III)/NaBH4-mediated freeradical hydrofluorination of unactivated alkenes using Selectfluoras the fluorine atom source.45 Unlike thetraditional and unmanageable free radical hydrofluorination of alkenes,the Fe(III)/NaBH4-mediated reaction is conducted underexceptionally mild conditions (0 °C, 5 min, CH3CN/H2O), uses a technically nondemanding reaction protocol, isconducted open to the air with water as a cosolvent, demonstratesan outstanding substrate scope and functional group tolerance, andis suitable for 18F introduction (t1/2 =110 min) used in PET imaging.45

Bottom Line: With use of the newly developed methodology and in addition to ongoing efforts to systematically define the importance of each embedded structural feature of vinblastine, two classes of analogues already have been discovered that enhance the potency of the natural products >10-fold.Unlike the removal of vinblastine structural features or substituents, which typically has a detrimental impact, the additions of new structural features have been found that can enhance target tubulin binding affinity and functional activity while simultaneously disrupting Pgp binding, transport, and functional resistance.Already analogues are in hand that are deserving of full preclinical development, and it is a tribute to the advances in organic synthesis that they are readily accessible even on a natural product of a complexity once thought refractory to such an approach.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States.

ABSTRACT
Biologically active natural products composed of fascinatingly complex structures are often regarded as not amenable to traditional systematic structure-function studies enlisted in medicinal chemistry for the optimization of their properties beyond what might be accomplished by semisynthetic modification. Herein, we summarize our recent studies on the Vinca alkaloids vinblastine and vincristine, often considered as prototypical members of such natural products, that not only inspired the development of powerful new synthetic methodology designed to expedite their total synthesis but have subsequently led to the discovery of several distinct classes of new, more potent, and previously inaccessible analogues. With use of the newly developed methodology and in addition to ongoing efforts to systematically define the importance of each embedded structural feature of vinblastine, two classes of analogues already have been discovered that enhance the potency of the natural products >10-fold. In one instance, remarkable progress has also been made on the refractory problem of reducing Pgp transport responsible for clinical resistance with a series of derivatives made accessible only using the newly developed synthetic methodology. Unlike the removal of vinblastine structural features or substituents, which typically has a detrimental impact, the additions of new structural features have been found that can enhance target tubulin binding affinity and functional activity while simultaneously disrupting Pgp binding, transport, and functional resistance. Already analogues are in hand that are deserving of full preclinical development, and it is a tribute to the advances in organic synthesis that they are readily accessible even on a natural product of a complexity once thought refractory to such an approach.

Show MeSH
Related in: MedlinePlus