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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.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.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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(top) Initial C20′ vinblastine analogues. (bottom) X-raystructure43 of vinblastine bound to tubulinhighlighting the region surrounding vinblastine C20′ site.
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fig11: (top) Initial C20′ vinblastine analogues. (bottom) X-raystructure43 of vinblastine bound to tubulinhighlighting the region surrounding vinblastine C20′ site.

Mentions: Our interest in this Fe(III)/NaBH4-mediated reactionemerged not only from its use in accessing vinblastine but from theopportunity it presented for the late-stage, divergent46 preparation of otherwise inaccessible vinblastineanalogues incorporating alternative C20′ functionality. Althoughthis site is known to be critical to the properties of vinblastineand is found deeply embedded in the tubulin bound complex (Figure 11),43 prior explorationof C20′ substituent effects was limited to semisynthetic O-acylationof the C20′ alcohol, its elimination and subsequent alkenereduction, or superacid-catalyzed additions.47 These invariably led to substantial reductions in biological potencyof the resulting derivative, albeit with examination of only a limitednumber of analogues. Consequently and in the course of the developmentof the Fe(III)/NaBH4-mediated alkene functionalizationreaction, its use was extended to the preparation of a series of keyvinblastine analogues bearing alternative C20′ functionality(e.g., N3, NH2, and SCN vs OH).36 Those of initial interest included the C20′ azideand amine, both of which proved to be approximately 100-fold lesspotent than vinblastine and 10-fold less potent than 20′-deoxyvinblastine.However, acylation of the C20′ amine improved activity 10-fold36 and installation of the unsubstituted C20′urea or thiourea provided compounds that nearly matched the potencyof vinblastine itself (Figure 11).36,37 The requisite NH of the internal nitrogen of the latter series presumablybest recapitulates the H-bond donor property of the vinblastine C20′alcohol.


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)

(top) Initial C20′ vinblastine analogues. (bottom) X-raystructure43 of vinblastine bound to tubulinhighlighting the region surrounding vinblastine C20′ site.
© Copyright Policy - editor-choice
Related In: Results  -  Collection

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

fig11: (top) Initial C20′ vinblastine analogues. (bottom) X-raystructure43 of vinblastine bound to tubulinhighlighting the region surrounding vinblastine C20′ site.
Mentions: Our interest in this Fe(III)/NaBH4-mediated reactionemerged not only from its use in accessing vinblastine but from theopportunity it presented for the late-stage, divergent46 preparation of otherwise inaccessible vinblastineanalogues incorporating alternative C20′ functionality. Althoughthis site is known to be critical to the properties of vinblastineand is found deeply embedded in the tubulin bound complex (Figure 11),43 prior explorationof C20′ substituent effects was limited to semisynthetic O-acylationof the C20′ alcohol, its elimination and subsequent alkenereduction, or superacid-catalyzed additions.47 These invariably led to substantial reductions in biological potencyof the resulting derivative, albeit with examination of only a limitednumber of analogues. Consequently and in the course of the developmentof the Fe(III)/NaBH4-mediated alkene functionalizationreaction, its use was extended to the preparation of a series of keyvinblastine analogues bearing alternative C20′ functionality(e.g., N3, NH2, and SCN vs OH).36 Those of initial interest included the C20′ azideand amine, both of which proved to be approximately 100-fold lesspotent than vinblastine and 10-fold less potent than 20′-deoxyvinblastine.However, acylation of the C20′ amine improved activity 10-fold36 and installation of the unsubstituted C20′urea or thiourea provided compounds that nearly matched the potencyof vinblastine itself (Figure 11).36,37 The requisite NH of the internal nitrogen of the latter series presumablybest recapitulates the H-bond donor property of the vinblastine C20′alcohol.

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.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.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