Selective Treatment of Cancer: Synthesis, Biological Evaluation and Structural Elucidation of Novel Analogues of the Antibiotic CC‐1065 and the Duocarmycins

Tietze, Lutz F.; Major, F.; Schuberth, Ingrid; Spiegl, Dirk A.; Krewer, Birgit; Maksimenka, Katja; Bringmann, Gerhard; Magull, Jörg

doi:10.1002/chem.200700113

Cited by 35 publications

(34 citation statements)

References 49 publications

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“…When tested against the A549 cell line, the galactoside 88a exhibited micro molar activity, but significantly was shown to be more than 5000-fold active in the presence of β-Dgalactosidase (IC 50 = 0.75 nM). In contrast, the (-)-diasteromeric seco-agent showed activity 1000-fold lower than that of (+)-isomer [138,145,146]. Investigation of the role of the sugar moiety found that the identity of this group was important for prodrug stability; after 24 h exposure to culture medium, the prototype galactoside 88a was 72% hydrolyzed, whereas 88b-e were 94-98% intact [141].…”

Section: Adept Strategy Based Prodrugsmentioning

confidence: 97%

“…48) where the phenolic hydroxyl group is protected as glycoside. The N,N-dimethylaminoethoxyindole carboxylic acid component facilitates binding in the DNA minor groove and increases water solubility [137,145]. When tested against the A549 cell line, the galactoside 88a exhibited micro molar activity, but significantly was shown to be more than 5000-fold active in the presence of β-Dgalactosidase (IC 50 = 0.75 nM).…”

Section: Adept Strategy Based Prodrugsmentioning

confidence: 99%

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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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Section: Adept Strategy Based Prodrugsmentioning

confidence: 97%

Section: Adept Strategy Based Prodrugsmentioning

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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“…As examples we chose three different drug molecules (Fig. 3): raloxifen, a partial agonist of the estrogen receptor; 23,24 ibrutinib, a potent covalent kinase inhibitor (IC 50 of 3–6 nM in chronic active BCR signaling B-cell lymphoma 25 ); and a duocarmycin analog, a highly cytotoxic prodrug of a DNA-alkylating agent with IC 50 < 1 nM in human bronchial carcinoma cells 26 . We prepared drug conjugates by attaching each drug to the pyridinium linker and 5-mer PNA (Fig.…”

Section: Resultsmentioning

confidence: 99%

Luciferase-induced photoreductive uncaging of small-molecule effectors

et al. 2018

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Bioluminescence resonance energy transfer (BRET) is extensively used to study dynamic systems and has been utilized in sensors for studying protein proximity, metabolites, and drug concentrations. Herein, we demonstrate that BRET can activate a ruthenium-based photocatalyst which performs bioorthogonal reactions. BRET from luciferase to the ruthenium photocatalyst is used to uncage effector molecules with up to 64 turnovers of the catalyst, achieving concentrations >0.6 μM effector with 10 nM luciferase construct. Using a BRET sensor, we further demonstrate that the catalysis can be modulated in response to an analyte, analogous to allosterically controlled enzymes. The BRET-induced reaction is used to uncage small-molecule drugs (ibrutinib and duocarmycin) at biologically effective concentrations in cellulo.

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“…(13A). In alternative, the trichloro-acetimidate of tetraacetyl galactose can be prepared to exploit Schmidt's galactosidation reaction [25,57,58]. Its preparation consists of a reaction between -Dgalactose pentaacetate, previously treated with HClO 4 adsorbed on SiO 2 , and trichloroacetonitrile [68].…”

Section: Synthetic Strategiesmentioning

confidence: 99%

“…Drug activation is elicited enzymatically by an antibody--D-galactosidase conjugate at the surface of malignant cells Fig. (6) [57][58].…”

Section: Cancermentioning

confidence: 99%

D-Galactose as a Vector for Prodrug Design

Melisi¹,

Curcio²,

Luongo³

et al. 2011

CTMC

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D-galactose is a simple and natural compound that has mainly been exploited in prodrug strategies. Galactosyl prodrugs can be considered a good approach to reach different goals in clinical drug application, especially when traditional drugs are likely to fail therapeutically owing to reasons such as the lack of site specificity, toxicity, and chemical instability. Indeed, of paramount importance is their ability to increase the selectivity of the parent compound, a phenomenon that helps to reduce the incidence of adverse effects, while preserving intact the pharmacodynamic features of the parent drug. Study results have varied according to the type of linkage between the drug and the hydroxyl group exploited. By working with these parameters, researchers have been able not only to generate selective pharmacological targeting of brain, liver, and cancerous cells, but also to improve cellular permeability as well as the pharmacokinetic profile of parent drugs. This review describes the broad spectrum of possibilities for exploiting D-galactose as a vector for prodrug design and the synthetic strategies that allow its realization.

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Selective Treatment of Cancer: Synthesis, Biological Evaluation and Structural Elucidation of Novel Analogues of the Antibiotic CC‐1065 and the Duocarmycins

Cited by 35 publications

References 49 publications

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

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

Luciferase-induced photoreductive uncaging of small-molecule effectors

D-Galactose as a Vector for Prodrug Design

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