Chemistry and biology of natural and designed enediynes.

Nicolaou, K. C.; Smith, Adrian L.; Yue, Eddy W.

doi:10.1073/pnas.90.13.5881

Cited by 250 publications

(177 citation statements)

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“…13 Similar to the conventionally used cytotoxic agent daunorubicin, calicheamicin is an anthracyclin that probably acts by binding to the minor groove of DNA and introduction of double-strand DNA breaks. 14,15 Multicenter phase II trials have shown a 30% overall response rate in relapsed AML patients. 16,17 Surprisingly, similar to the results obtained by others, 18 in the cohort of AML patients treated with GO in our institute, we observed no clear correlation between the CD33 expression on the leukemic blasts and the response to therapy (Table 1).…”

Section: Introductionmentioning

confidence: 99%

Internalization and cell cycle-dependent killing of leukemic cells by Gemtuzumab Ozogamicin: rationale for efficacy in CD33-negative malignancies with endocytic capacity

et al. 2003

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Multicenter phase II trials with Gemtuzumab Ozogamicin (GO/ Mylotarg s ), consisting of a CD33 antibody linked to the cytotoxic drug calicheamicin, have shown a 30% overall response rate in relapsed acute myeloid leukemia patients. However, no clear correlation was observed between CD33 expression on leukemic blasts and response to GO therapy. We analyzed the CD33 specificity of GO-induced cell death and the effect of GO on CD33-negative malignancies. We demonstrate that lysis induced by clinically relevant GO concentrations is partially CD33 mediated, and that efficient non-CD33-mediated GO uptake can occur via endocytosis. In agreement with these results, we observed GO-mediated death of human CD33-negative acute lymphoblastic leukemia cells both in vitro and in vivo in an NOD/SCID mouse model. Finally, sensitivity to GOinduced cell death was at least partially determined by the activation status of leukemic cells, with cells in activated phases of the cell cycle being most effective in both CD33-specific GO internalization, renewed expression of CD33 molecules, and non-CD33-mediated GO uptake via endocytosis. In conclusion, these data provide mechanistic insight into the efficacy of GO in CD33-positive as well as in CD33-negative malignancies with endocytic capacity, and provide a rationale for the use of GO in the treatment of malignancies with endocytic capacity.

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Section: Introductionmentioning

confidence: 99%

Internalization and cell cycle-dependent killing of leukemic cells by Gemtuzumab Ozogamicin: rationale for efficacy in CD33-negative malignancies with endocytic capacity

et al. 2003

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“…Currently, nearly twenty of these natural enediynes have been identified, including calichemicin ␥ 1 I [6,7], dynemicin [8], and the esperamicins [9,10]. While these enediynes offer extremely high cytotoxic activities, their clinical use as anti-tumor agents has been limited due to their delayed activities and general toxicity [2][3][4][5].To overcome the shortcomings of these natural enediynes, a range of synthetic analogs have been explored [3,11], each with the goal of improved properties for clinical use. While still capable of cleaving DNA like the natural products through cycloaromatization reactions and subsequent hydride abstraction by the diradical intermediate [2-4, 11, 12], these analogs offer potential advantages, such as more controlled activation of the compound in vivo [13][14][15][16][17][18][19][20][21][22][23] or increased selectivity for tumor cells [24 -30].…”

mentioning

confidence: 99%

“…To overcome the shortcomings of these natural enediynes, a range of synthetic analogs have been explored [3,11], each with the goal of improved properties for clinical use. While still capable of cleaving DNA like the natural products through cycloaromatization reactions and subsequent hydride abstraction by the diradical intermediate [2-4, 11, 12], these analogs offer potential advantages, such as more controlled activation of the compound in vivo [13][14][15][16][17][18][19][20][21][22][23] or increased selectivity for tumor cells [24 -30].…”

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confidence: 99%

“…Collisionally activated dissociation of the observed adducts confirmed the strength of the interactions between the enediyne and DNA and supports a direct linkage between the enediyne and the cytosine nucleobase, likely the result of a nucleophilic attack of the phenylethynyl group by the cytosine amine. ollowing the initial elucidation of the structure of the neocarzinostatin chromophore [1], much effort has been directed towards identifying additional natural enediynes and evaluating their activities [2][3][4][5]. Currently, nearly twenty of these natural enediynes have been identified, including calichemicin ␥ 1 I [6,7], dynemicin [8], and the esperamicins [9,10].…”

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confidence: 99%

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Identification of the adduct between a 4-aza-3-ene-1,6-diyne and DNA using electrospray ionization mass spectrometry

Sherman

Pierce

Brodbelt

et al. 2006

J. Am. Soc. Mass Spectrom.

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The interactions between a novel enediyne [1-methyl-2-(phenylethynyl)-3-(3-phenylprop-2-ynyl)-3H-benzimidazolium] (1) and various cytosine-containing oligonucleotides were studied using electrospray ionization mass spectrometry (ESI-MS) in a flow injection analysis mode useful for small volumes. This enediyne ligand, developed as a potential alternative to the highly cytotoxic natural enediynes, some of which have been successfully used as anti-tumor agents, has previously been shown to interact with DNA through frank strand scission as well as via the formation of adducts that lead to 2=-deoxycytidine-specific cleavage. Through ESI-MS, the structures of these adducts were examined and a sequence dependence of the 2=-deoxycytidine-specific cleavage was noted. Collisionally activated dissociation of the observed adducts confirmed the strength of the interactions between the enediyne and DNA and supports a direct linkage between the enediyne and the cytosine nucleobase, likely the result of a nucleophilic attack of the phenylethynyl group by the cytosine amine. , much effort has been directed towards identifying additional natural enediynes and evaluating their activities [2][3][4][5]. Currently, nearly twenty of these natural enediynes have been identified, including calichemicin ␥ 1 I [6,7], dynemicin [8], and the esperamicins [9,10]. While these enediynes offer extremely high cytotoxic activities, their clinical use as anti-tumor agents has been limited due to their delayed activities and general toxicity [2][3][4][5].To overcome the shortcomings of these natural enediynes, a range of synthetic analogs have been explored [3,11], each with the goal of improved properties for clinical use. While still capable of cleaving DNA like the natural products through cycloaromatization reactions and subsequent hydride abstraction by the diradical intermediate [2-4, 11, 12], these analogs offer potential advantages, such as more controlled activation of the compound in vivo [13][14][15][16][17][18][19][20][21][22][23] or increased selectivity for tumor cells [24 -30].To better evaluate the activities and properties of the many enediyne drug candidates as well as various other classes of drugs being developed, we present a technique for analyzing the interactions between these compounds and DNA using a flow injection analysis (FIA) mode coupled to an electrospray ionization mass spectrometer (ESI-MS). This analysis offers several key advantages over the traditional gel-based electrophoretic techniques. First, the dramatically better resolution of mass spectrometry versus polyacrylamide gel electrophoresis (PAGE) allows differentiation of similarly sized species, enabling the detection of very small molecules adducted to DNA. Second, while gel electrophoresis typically requires micrograms of sample, with our FIA method, a mass spectrum can easily be collected with nanograms, a sensitivity advantage of up to three orders of magnitude. Lastly, FIA-ESI-MS is easily adaptable to high-throughput analyses [31][32][33].In recent y...

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“…1A), representative of a class of enediyne glycoconjugate DNA ligands, binds to and cleaves DNA at specific 4-bp sequences. Double-strand DNA cleavage occurs through bioreduction of the trisulfide and subsequent 1,4-benzenoid diradical formation, which results in hydrogen abstraction from adjacent nucleotide bases (10)(11)(12)(13). Affinity cleavage experiments (7,8) demonstrate that CLM preferentially cleaves DNA at cytosine-containing homopyrimidine tracts, preferentially TCCT.…”

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confidence: 99%

Specific inhibition of formation of transcription complexes by a calicheamicin oligosaccharide: a paradigm for the development of transcriptional antagonists.

Boyer

Schreiber

et al. 1994

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

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Sequence-specific DNA ligands that antagonize DNA-protein interactions represent a potentially powerful means of modulating gene expression. Calicheamicin -il, a member of the DNA-cleaving enedlyne class of anticancer antibiotics, binds to specific DNA sequences through an aryltetrasaccharide domain. To take advantage of this unique sequence-specific recognition capability, the methyl glycoside of the aryltetrasaccharide of caliche min yi (CLM-MG) was used to investigate the ability of glycoconjugate DNA ligands to inhibit DNA-protein interactions. CLM-MG inhibits the formation of DNA-protein complexes at micromolar concentrations in a sequence-specific manner and rapidly dissociates preformed complexes. CLM-MG also inhibits transcription in vivo with similar sequence specificity. These results suggest a strategy for the development of a class of novel biological probes and therapeutic agents.The ordered regulation of gene expression underlying specific developmental programs or cellular responses to physiologic stimuli relies on sequence-specific DNA-protein interactions (1). This requisite DNA sequence specificity suggests a means to control cellular responses through the use of DNA ligands that interfere with these specific DNA-protein interactions. To be biologically useful such ligands would need to (i) bind DNA with a high degree of sequence specificity, (ii) antagonize DNA-protein interactions either by inhibition of DNA-protein complex formation or by displacement of preformed complexes, and (iii) exhibit sufficient hydrophobicity to pass through cell membranes and thereby function in vivo. Several types of DNA ligands have been shown to satisfy some of these criteria, including oligodeoxynucleotides involved in triple-helix formation (2, 3), peptide nucleic acids (4), and nonintercalating minor groove DNA ligands such as netropsin and distamycin A (5). However, none of these adequately satisfy all the requirements for specific and biologically useful transcriptional antagonists.The enediyne compound calicheamicin 'yI (CLM; Fig. 1A), representative of a class of enediyne glycoconjugate DNA ligands, binds to and cleaves DNA at specific 4-bp sequences. Double-strand DNA cleavage occurs through bioreduction of the trisulfide and subsequent 1,4-benzenoid diradical formation, which results in hydrogen abstraction from adjacent nucleotide bases (10-13). Affinity cleavage experiments (7,8) MATERIALS AND METHODS Preparation of Nuclear Extracts and DNA-Bhin Assays. Nuclear extracts were prepared as previously described (19) from TAg Jurkat cells (20) stimulated for 2 hr with 2 pM ionomycin plus phorbol 12-tetradecanoate 13-acetate (PTA) at 20 ng/ml, HeLa cells stimulated for 2 hr with PTA at 20 ng/ml, or MDCK cells. CLM-MG was solubilized in 10% (vol/vol) EtOH or 2% (vol/vol) dimethyl sulfoxide (DMSO) to a maximum concentration of 10 mM (for reference, this resulted in an extinction coefficient of 24,600 ± 1300 M-1'cm-1 at a A,, of 213 nm in aqueous solution containing <0.01% DMSO). Electrophoretic mob...

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Chemistry and biology of natural and designed enediynes.

Abstract: Ever since the initial re-

Cited by 250 publications

References 50 publications

Internalization and cell cycle-dependent killing of leukemic cells by Gemtuzumab Ozogamicin: rationale for efficacy in CD33-negative malignancies with endocytic capacity

Internalization and cell cycle-dependent killing of leukemic cells by Gemtuzumab Ozogamicin: rationale for efficacy in CD33-negative malignancies with endocytic capacity

Identification of the adduct between a 4-aza-3-ene-1,6-diyne and DNA using electrospray ionization mass spectrometry

Specific inhibition of formation of transcription complexes by a calicheamicin oligosaccharide: a paradigm for the development of transcriptional antagonists.

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