A Novel Property of Duocarmycin and Its Analogs for Covalent Reaction with DNA

Asai, Akira; Nagamura, Satoru; Saito, Hiromitsu

doi:10.1021/ja00089a004

Cited by 68 publications

(35 citation statements)

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“…KW-2189 (69), a semi-synthetic derivative of duocarmycin B2 (4) [107], was selected for clinical trials due to favorable water solubility (10 mg/mL) and antiproliferative activity in experimental animal models [108][109][110]. In spite of the deactivating carbamate functionality, KW-2189 (69) has been shown to form a covalent adduct with adenine at N3, although it is a 1000-fold more active after cleavage of the carbamoyl moiety by carboxyl esterases in vivo [110,111].…”

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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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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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“…The event, sequence selectivity, quantitation, reversibility, and structure determination of the predominant DNA alkylation reaction by 1-3 have been defined (42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59). The alkylation site identification and the assessment of relative selectivity were derived through thermally induced depurination and strand cleavage of labeled DNA after exposure to the agents (Scheme I).…”

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“…The quantitation of the adenine-N3 alkylation, confirmation of its structure through isolation and characterization of the thermally released adducts, and the search for unde- tPercentage composition within the DNA examined. (50), within oligodeoxynucleotides lacking a high-affinity adenine-N3 alkylation site (51), or when the adenine alkylation sites within AT-rich regions of DNA were protected from alkylation with high-6, Duocarmycin B1: X = Br 7, Duocarmycin Ci: X= Cl affinity AT-rich minor groove binding agents (52). In contrast, duocarmycin SA (3) showed no evidence of guanine-N3 alkylation when subjected to similar or more forcing conditions (43 consequence of the diastereomeric relationship of the adducts and the reversed binding orientation in the minor groove with respect to the alkylation site is required to permit adenine-N3 addition to the least substituted carbon of the electrophilic cyclopropane.…”

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CC-1065 and the duocarmycins: unraveling the keys to a new class of naturally derived DNA alkylating agents.

Boger

Johnson

1995

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

214

100

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Key studies defining the DNA alkylation properties and selectivity of a new class of exceptionally potent, naturally occurring antitumor antibiotics including CC-1065, duocarmycin A, and duocarmycin SA are reviewed. Recent studies conducted with synthetic agents containing deep-seated structural changes and the unnatural enantiomers of the natural products and related analogs have defined the structural basis for the sequence-selective alkylation of duplex DNA and fundamental relationships between chemical structure, functional reactivity, and biological properties. The agents undergo a reversible, stereoelectronicaily controlled adenine-N3

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“…Some previous studies indicate that the seg-A ring structure influences the electrophilicity of cyclopropane (Asai et al, 1994). On the other hand, the seg-B moiety has been considered to play an important role in noncovalent binding to DNA (Boger et al, 1990a;Warpehoski et al, 1992;Boger and Yun, 1993).…”

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Structural influence of indole C5-N-substitutents on the cytotoxicity of seco-duocarmycin analogs

Choi

Sook

2011

Arch. Pharm. Res.

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A series of racemic indole C5-substituted seco-cyclopropylindoline compounds (2,3 and 5-7) were prepared by coupling 1-(tert-butyloxycarbonyl)-3-(chlorocarbonyl)indoline (seg-A) with 5,6,7-trimethoxy-, 5,6-dimethoxy-, 5-amino-, 5-methylsulfonylamino- and 5-(N,N-dimethylaminosulfonylamino) indole-2-carboxylic acid as seg-B in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide. The synthetic compounds (2,3 and 5-7) were tested for cytotoxic activity against human cancer cell lines (COLO 205, SK-MEL-2, A549, and JEG-3) using the MTT assay.

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A Novel Property of Duocarmycin and Its Analogs for Covalent Reaction with DNA

Cited by 68 publications

References 0 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

CC-1065 and the duocarmycins: unraveling the keys to a new class of naturally derived DNA alkylating agents.

Structural influence of indole C5-N-substitutents on the cytotoxicity of seco-duocarmycin analogs

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