Yatakemycin: total synthesis, DNA alkylation, and biological properties

Tichenor, Mark S.; Boger, Dale L.

doi:10.1039/b705665f

Cited by 72 publications

(41 citation statements)

References 21 publications

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“…The natural products are exceptionally potent antitumor compounds that derive their activity through a sequence selective DNA alkylation. 112–114 Our studies provided not only total syntheses of the natural products, 115–127 but also the characterization of their DNA alkylation properties, including that of their unnatural enantiomers. 128–133 In these studies, we defined their DNA alkylation selectivity, rates, and reversibility, 134 isolated and characterized their adenine N3 adducts, 130,132,135 and defined their stereoelectronically-controlled reaction regioselectivity.…”

Section: Introductionmentioning

confidence: 99%

The Difference a Single Atom Can Make: Synthesis and Design at the Chemistry–Biology Interface

Boger

2017

J. Org. Chem.

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A Perspective of work in our laboratory on the examination of biologically active compounds, especially natural products, is presented. In the context of individual programs and along with a summary of our work, selected cases are presented that illustrate the impact single atom changes can have on the biological properties of the compounds. The examples were chosen to highlight single heavy atom changes that improve activity, rather than those that involve informative alterations that reduce or abolish activity. The examples were also chosen to illustrate that the impact of such single-atom changes can originate from steric, electronic, conformational, or H-bonding effects, from changes in functional reactivity, from fundamental intermolecular interactions with a biological target, from introduction of a new or altered functionalization site, or from features as simple as improvements in stability or physical properties. Nearly all the examples highlighted represent not only unusual instances of productive deep-seated natural product modifications and were introduced through total synthesis but are also remarkable in that they are derived from only a single heavy atom change in the structure.

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Section: Introductionmentioning

confidence: 99%

The Difference a Single Atom Can Make: Synthesis and Design at the Chemistry–Biology Interface

Boger

2017

J. Org. Chem.

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“…13 Detailed structure–function analyses of the colibactins have been impossible to conduct owing to their low yields of natural production and the absence of a synthetic route to the targets. However, the aminocyclopropane fragments within 2 – 6 are reminiscent of yatakemycin, CC-1065, and the duocarmycins, which have been shown to alkylate DNA via nucleophilic ring-opening, 14 and the biheterocyclic fragment may serve as a DNA intercalation motif. 15 …”

Section: Introductionmentioning

confidence: 99%

Convergent and Modular Synthesis of Candidate Precolibactins. Structural Revision of Precolibactin A

et al. 2016

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The colibactins are hybrid polyketide–nonribosomal peptide natural products produced by certain strains of commensal and extraintestinal pathogenic Escherichia coli. The metabolites are encoded by the clb gene cluster as prodrugs termed precolibactins. clb+ E. coli induce DNA double-strand breaks in mammalian cells in vitro and in vivo and are found in 55–67% of colorectal cancer patients, suggesting that mature colibactins could initiate tumorigenesis. However, elucidation of their structures has been an arduous task as the metabolites are obtained in vanishingly small quantities (μg/L) from bacterial cultures and are believed to be unstable. Herein we describe a flexible and convergent synthetic route to prepare advanced precolibactins and derivatives. The synthesis proceeds by late-stage union of two complex precursors (e.g., 28 + 17 → 29a, 90%) followed by a base-induced double dehydrative cascade reaction to form two rings of the targets (e.g., 29a → 30a, 79%). The sequence has provided quantities of advanced candidate precolibactins that exceed those obtained by fermentation, and is envisioned to be readily scaled. These studies have guided a structural revision of the predicted metabolite precolibactin A (from 5a or 5b to 7) and have confirmed the structures of the isolated metabolites precolibactins B (3) and C (6). Synthetic precolibactin C (6) was converted to N-myristoyl-D-asparagine and its corresponding colibactin by colibactin peptidase ClbP. The synthetic strategy outlined herein will facilitate mechanism of action and structure–function studies of these fascinating metabolites, and is envisioned to accommodate the synthesis of additional (pre)colibactins as they are isolated.

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“…This review serves to update the field over the past decade and will describe novel directions in regard to chemical and biological investigations of synthetic analogues and prodrug derivatives, which aim to increase tumour selectivity and prepare agents for clinical progression. (+)-Yatakemycin (10) and related sandwiched small molecules will not be described here, as a recent account of their discovery has already been reported [15]. Due to the intense potency, unique mechanism of action and broad range of activity of the duocarmycins, extensive efforts have been made during the past two decades to find analogues that retain their potency and antitumour activity with potential for clinical progression.…”

Section: Investigations Of Cc-1065 the Duocarmycins And Synthetic Anmentioning

confidence: 99%

Chemical and Biological Explorations of the Family of CC-1065 and the Duocarmycin Natural Products

Ghosh¹,

Sheldrake²,

Searcey³

et al. 2009

CTMC

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CC-1065, the duocarmycins and yatakemycin are members of a family of ultrapotent antitumour antibiotics that have been the subject of extensive investigations due to their mode of action and potential in the design of new anticancer therapeutics. The natural products and their analogues exert their effects through a sequence selective alkylation of duplex DNA in the minor groove at the N3 of adenine. An understanding of their structure and its effect on biological activity has been derived through chemical synthesis and has also generated new potential lead compounds. These studies form the first section of the review. The desire to progress these compounds to clinic has also led to studies of bioconjugation and prodrug formation and this is discussed in the second section of the review. The combination of synthesis with key biological experiments is a powerful tool to define the requirements for the development of natural products as potential therapeutic agents. The studies described herein form an excellent paradigm for the study and development of other natural products

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Yatakemycin: total synthesis, DNA alkylation, and biological properties

Cited by 72 publications

References 21 publications

The Difference a Single Atom Can Make: Synthesis and Design at the Chemistry–Biology Interface

The Difference a Single Atom Can Make: Synthesis and Design at the Chemistry–Biology Interface

Convergent and Modular Synthesis of Candidate Precolibactins. Structural Revision of Precolibactin A

Chemical and Biological Explorations of the Family of CC-1065 and the Duocarmycin Natural Products

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