A novel class of achiral seco-analogs of CC-1065 and the duocarmycins: design, synthesis, DNA binding, and anticancer properties

Kupchinsky, Stanley; Centioni, Sara; Howard, Tiffany T.; Trzupek, John D.; Roller, Shane; Carnahan, Virginia; Townes, Heather M.; Purnell, Bethany L.; Price, Carly A.; Handl, Heather L.; Summerville, Kaitlin; Johnson, K.A.; Toth, John E.; Hudson, Stephen J.; Kiakos, Konstantinos; Hartley, John A.; Lee, Moses

doi:10.1016/j.bmc.2004.08.051

Cited by 22 publications

(23 citation statements)

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“…4), and indeed comparison of hypersensitivity factors suggests a similar mechanism of action [22]. reported [25,26]. These agents react with adenine-N3 with an alkylation pattern similar to CC-1065 ( Fig.…”

Section: 277a-tetrahydrocyclopropa[c]indol-4-one (Ci)supporting

confidence: 57%

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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: 277a-tetrahydrocyclopropa[c]indol-4-one (Ci)supporting

confidence: 57%

“…In particular, compound 12 was very active against melanoma cell lines. A subsequent in vivo study with the UACC-257 human melanoma cell line showed activity, with increased mean time for tumour weight doubling of 27.7 days (control 15.8 days) and no bone marrow toxicity [25]. …”

Section: 277a-tetrahydrocyclopropa[c]indol-4-one (Ci)mentioning

confidence: 95%

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 cytotoxic activity of compounds 3a-3g were studied against the growth of murine B16 and L1210 cells in culture and using the MTT assay (Sato et al, 2005;Kupchinsky et al, 2004;Carmichael et al, 1987). Cells were treated continuously for 3 days and their cytotoxicity was compared to that of untreated cells.…”

Section: In Vitro Studies On B16 and L1210 Cellsmentioning

confidence: 99%

“…Based on the cytotoxic activity against the growth of L1210 and B16 cells in culture, as well as the increased polarity of compound 3f over 3c, the 5-methoxyindole compound 3f was selected for flow cytometry studies for the purpose of probing its apoptosis-inducing properties (Sato et al, 2005;Kupchinsky et al, 2004). The first test utilized PI staining, which detects living versus dead cells, and those cells that are most likely going through the dying process.…”

Section: Flow Cytometry Studiesmentioning

confidence: 99%

Synthesis and cytotoxicity of 1-phenylethanolamine carboxamide derivatives: effects on the cell cycle

et al. 2009

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Seven novel analogues of 1-phenylethanolamine carboxamide derivatives, 3a-3g, related to carboxamides isolated from Isodon excisus were synthesized and evaluated for their cytotoxic and apoptosis-induction properties against murine B16 and leukemia L1210 cell lines. Compounds containing no substitution at the 4 0 -position (3a-3d) or containing a 4 0 -amino (3e-3g) group were investigated. Generally, the amino-containing compounds were slightly more active than their unsubstituted congeners. Also, the indole-containing compounds 3c and 3f gave the strongest cytotoxic activity (IC 50 = 25-87 lM) against the growth of L1210 and B16 cancer cells. Compound 3f was subjected to flow cytometry studies and it was found to induce L1210 cells grown in culture to undergo apoptosis.

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“…The first evidence that the chiral center present in the natural products is not absolutely required for DNA interaction, cytotoxicity, and anticancer activity came from the study of agents bearing the achiral seco-cyclopropylindolone (CI) pharmacophore. An achiral seco-hydroxy-CI-trimethoxyindole (hydroxy-CI-TMI) agent readily alkylated the adenine-N3 in the 5 ¶-AAAAA-3 ¶ sequence, possessed an IC 50 in the micromolar range against several human (K562, LS174T, PC3, and MCF-7) and murine (L1210 and P815) cancer cell lines, and showed significant activity, particularly against several solid tumor cell lines, in the National Cancer Institute (NCI) in vitro screen (25). Furthermore, this compound was relatively nontoxic to murine bone marrow cells.…”

Section: Introductionmentioning

confidence: 99%

DNA sequence–selective adenine alkylation, mechanism of adduct repair, andin vivoantitumor activity of the novel achiralseco-amino-cyclopropylbenz[e]indolone analogue of duocarmycin AS-I-145

Kiakos

Sato

Asao

et al. 2007

Molecular Cancer Therapeutics

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AS-I-145 is a novel achiral seco-amino-cyclopropylbenz[e]indolone (seco-amino-CBI) analogue of duocarmycin that has evolved from an alternative strategy of designing CC-1065/duocarmycin agents lacking the characteristic chiral center of the natural agents. The sequence specificity of this compound was assessed by a Taq polymerase stop assay, identifying the sites of covalent modification on plasmid DNA. The adenine-N3 adducts were confirmed at AT-rich sequences using a thermally induced strand cleavage assay. These studies reveal that this compound retains the inherent sequence selectivity of the related natural compounds. The AS-

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A novel class of achiral seco-analogs of CC-1065 and the duocarmycins: design, synthesis, DNA binding, and anticancer properties

Cited by 22 publications

References 50 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

Synthesis and cytotoxicity of 1-phenylethanolamine carboxamide derivatives: effects on the cell cycle

DNA sequence–selective adenine alkylation, mechanism of adduct repair, andin vivoantitumor activity of the novel achiralseco-amino-cyclopropylbenz[e]indolone analogue of duocarmycin AS-I-145

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