Probing the Biology of Natural Products: Molecular Editing by Diverted Total Synthesis

Szpilman, Alex M.; Carreira, Erick M.

doi:10.1002/anie.200904761

Cited by 189 publications

(103 citation statements)

References 361 publications

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“…This strategy is also finding increasing success in other laboratories (12)(13)(14)(15)(16) and resonates in part with the goals and related concept of diverted total synthesis (17,18). The starting point of FOS is function and the view that function could be emulated with a wide range of designed structures, as many structural types could mimic a natural product's shape and electron density features.…”

mentioning

confidence: 88%

Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity

Wender

Baryza

Brenner

et al. 2011

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

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Modern methods for the identification of therapeutic leads include chemical or virtual screening of compound libraries. Nature's library represents a vast and diverse source of leads, often exhibiting exquisite biological activities. However, the advancement of natural product leads into the clinic is often impeded by their scarcity, complexity, and nonoptimal properties or efficacy as well as the challenges associated with their synthesis or modification. Function-oriented synthesis represents a strategy to address these issues through the design of simpler and therefore synthetically more accessible analogs that incorporate the activity-determining features of the natural product leads. This study illustrates the application of this strategy to the design and synthesis of functional analogs of the bryostatin marine natural products. It is specifically directed at exploring the activity-determining role of bryostatin A-ring functionality on PKC affinity and selectivity. The resultant functional analogs, which were prepared by a flexible, modular synthetic strategy, exhibit excellent affinity to PKC and differential isoform selectivity. These and related studies provide the basic information needed for the design of simplified and thus synthetically more accessible functional analogs that target PKC isoforms, major targets of therapeutic interest.

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mentioning

confidence: 88%

Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity

Wender

Baryza

Brenner

et al. 2011

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

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“…12 The strategic design of our synthesis allowed for the late-stage derivatization of the natural product scaffold to elaborate on earlier SAR work, an approach referred to as Diverted Total Synthesis (DTS) (Figure 1). 13 Both Danishefsky and Myers have beautifully applied DTS to the development of novel anticancer 14 and antibiotic 15 compounds, respectively, with improved bioactivity. DTS endeavors from our laboratory have uncovered new phenotypes for the antibiotic promysalin 16 and we sought to use our initial total synthesis of carolacton toward this end.…”

mentioning

confidence: 99%

Diverted Total Synthesis of Carolacton-Inspired Analogs Yields Three Distinct Phenotypes in Streptococcus mutans Biofilms

et al. 2017

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The oral microbiome is a dynamic environment inhabited by both commensals and pathogens. Among these is Streptococcus mutans, the causative agent of dental caries, the most prevalent childhood disease. Carolacton has remarkably specific activity against S. mutans, causing acid-mediated cell death during biofilm formation; however, its complex structure limits its utility. Herein, we report the diverted total synthesis and biological evaluation of a rationally designed library of simplified analogs that unveiled three unique biofilm phenotypes further validating the role of natural product synthesis in the discovery of new biological phenomena.

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“…Substitution of the isoindoline was well tolerated and the series displayed a trend where electron-donating substituents (30,(35)(36)(37)(38)(39) proved slightly more potent than compounds bearing electron-withdrawing substituents (31)(32)(33)(34). Within the former series, further alkylation (37)(38)(39) or acylation (40-53) of the aniline 36 was well tolerated. Simple acetylation to provide the acetamide 40 provided a derivative with IC 50 values of 470-500 pM in the vinblastine-sensitive tumor cell lines and N-benzoylation maintained this activity with 50 displaying IC 50 values of 400 pM.…”

Section: Resultsmentioning

confidence: 99%

“…Approaches to improving the biological properties of natural products typically involve efforts to simplify their structures or to modify their structures through semisynthetic transformations, diverted total synthesis (37), or late-stage functionalizations (38,39). Rarely does one consider adding molecular complexity to the underlying structure in a way that requires chemical synthesis of a modified natural product.…”

Section: Discussionmentioning

confidence: 99%

Ultrapotent vinblastines in which added molecular complexity further disrupts the target tubulin dimer–dimer interface

Carney

Lukesh

Brody

et al. 2016

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

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Approaches to improving the biological properties of natural products typically strive to modify their structures to identify the essential pharmacophore, or make functional group changes to improve biological target affinity or functional activity, change physical properties, enhance stability, or introduce conformational constraints. Aside from accessible semisynthetic modifications of existing functional groups, rarely does one consider using chemical synthesis to add molecular complexity to the natural product. In part, this may be attributed to the added challenge intrinsic in the synthesis of an even more complex compound. Herein, we report synthetically derived, structurally more complex vinblastines inaccessible from the natural product itself that are a stunning 100-fold more active (IC50 values, 50–75 pM vs. 7 nM; HCT116), and that are now accessible because of advances in the total synthesis of the natural product. The newly discovered ultrapotent vinblastines, which may look highly unusual upon first inspection, bind tubulin with much higher affinity and likely further disrupt the tubulin head-to-tail α/β dimer–dimer interaction by virtue of the strategic placement of an added conformationally well-defined, rigid, and extended C20′ urea along the adjacent continuing protein–protein interface. In this case, the added molecular complexity was used to markedly enhance target binding and functional biological activity (100-fold), and likely represents a general approach to improving the properties of other natural products targeting a protein–protein interaction.

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Probing the Biology of Natural Products: Molecular Editing by Diverted Total Synthesis

Cited by 189 publications

References 361 publications

Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity

Design, synthesis, and evaluation of potent bryostatin analogs that modulate PKC translocation selectivity

Diverted Total Synthesis of Carolacton-Inspired Analogs Yields Three Distinct Phenotypes in Streptococcus mutans Biofilms

Ultrapotent vinblastines in which added molecular complexity further disrupts the target tubulin dimer–dimer interface

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