Molecular basis for sequence selective DNA alkylation by (+)- and ent-(−)-CC-1065 and related agents: Alkylation site models that accommodate the offset AT-rich adenine N3 alkylation selectivity

Boger, Dale L.; Johnson, Douglas S.; Yun, Weiya; Tarby, Christine M.

doi:10.1016/s0968-0896(00)82007-6

Cited by 78 publications

(47 citation statements)

References 69 publications

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“…27, 35 The DNA damage results in cleavage of full-length caspase-9, subsequent activation of caspase-3 and, ultimately, cell death. 25, 26 As shown in Figure 2, apoptosis induction via the intrinsic pathway was confirmed by the detection of cleaved PARP, cleaved caspase-3 and the full-length caspase-8, as well as the decrease of full-length caspase-3 and -9, in cells treated with a mixture of prodrug and purified β-galactosidase.…”

Section: Discussionmentioning

confidence: 99%

Enhanced tumor therapy using vaccinia virus strain GLV-1h68 in combination with a β-galactosidase-activatable prodrug seco-analog of duocarmycin SA

et al. 2010

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Breast cancer is the most common cause of cancer-related death worldwide, thus remaining a crucial health problem among women despite advances in conventional therapy. Therefore, new alternative strategies are needed for effective diagnosis and treatment. One approach is the use of oncolytic viruses for gene-directed enzyme prodrug therapy. Here, the lacZ-carrying vaccinia virus (VACV) strain GLV-1h68 was used in combination with a β-galactosidase-activatable prodrug derived from a seco-analog of the natural antibiotic duocarmycin SA. Tumor cell infection with the VACV strain GLV-1h68 led to production of β-galactosidase, essential for the conversion of the prodrug to the toxic compound. Furthermore, drug-dependent cell kill and induction of the intrinsic apoptosis pathway in tumor cells was also observed on combination therapy using the prodrug and the GLV-1h68 strain, despite the fact that VACV strains encode antiapoptotic proteins. Moreover, GI-101A breast cancer xenografts were effectively treated by the combination therapy. In conclusion, the combination of a β-galactosidase-activatable prodrug with a tumor-specific vaccinica virus strain encoding this enzyme, induced apoptosis in cultures of the human GI-101A breast cancer cells, in which a synergistic oncolytic effect was observed. Moreover, in vivo, additional prodrug treatment had beneficial effects on tumor regression in GLV-1h68-treated GI-101A-xenografted mice.

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Section: Discussionmentioning

confidence: 99%

Enhanced tumor therapy using vaccinia virus strain GLV-1h68 in combination with a β-galactosidase-activatable prodrug seco-analog of duocarmycin SA

et al. 2010

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“…Investigation of DSA has revealed that the natural (+)-enantiomer alkylates adenine N3 within selected AT-rich regions with a binding orientation that extends in a 3' to 5' direction from the site of alkylation, whereas the unnatural (-)-enantiomer similarly alkylates adenine N3, but with a binding orientation that extends in the opposite 5' to 3' direction [65].…”

Section: Bifunctional Alkylating Agentsmentioning

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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“…The first family of natural products on which we systematically examined the impact of deep-seated structural changes is composed of the duocarmycins, yatakemycin, and CC-1065, and a number of these modifications involved single atom changes in their structures. The natural products are exceptionally potent antitumor compounds that derive their activity through a sequence selective DNA alkylation. − Our studies provided not only total syntheses of the natural products, − but also the characterization of their DNA alkylation properties, including that of their unnatural enantiomers. − In these studies, we defined their DNA alkylation selectivity, rates, and reversibility, isolated and characterized their adenine N3 adducts, ,, and defined their stereoelectronically controlled reaction regioselectivity. − We defined the source of their alkylation selectivity as arising from their noncovalent binding selectivity preferentially in the narrower, deeper AT-rich minor groove (shape selective recognition), − and identified the unusual source of catalysis for the alkylation reaction that is derived from a DNA binding induced conformation change that disrupts the stabilizing vinylogous amide conjugation (shape dependent catalysis). − We demonstrated and quantified the fundamental role the hydrophobic character of the compounds plays in the expression of the biological activity, driving the intrinsically reversible DNA alkylation reaction, and defined the stunning magnitude of its effect (hydrophobic binding-driven-bonding) . In collaboration with Walter Chazin, we provided high-resolution NMR-derived structures of the natural products and their unnatural enantiomers bound to DNA (Figure ) − and established that they are subject to an exquisite “target-based activation” .…”

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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Molecular basis for sequence selective DNA alkylation by (+)- and ent-(−)-CC-1065 and related agents: Alkylation site models that accommodate the offset AT-rich adenine N3 alkylation selectivity

Cited by 78 publications

References 69 publications

Enhanced tumor therapy using vaccinia virus strain GLV-1h68 in combination with a β-galactosidase-activatable prodrug seco-analog of duocarmycin SA

Enhanced tumor therapy using vaccinia virus strain GLV-1h68 in combination with a β-galactosidase-activatable prodrug seco-analog of duocarmycin SA

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

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

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