Designed Enediynes: A New Class of DNA-Cleaving Molecules with Potent and Selective Anticancer Activity

Nicolaou, K. C.; Dai, Wei; Tsay, S.‐C.; Estevez, Virginia A.; Wrasidlo, Wolfgang

doi:10.1126/science.256.5060.1172

Cited by 312 publications

(101 citation statements)

References 58 publications

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“…Several analogues were also made by using the same approach. In the following years, copious synthetic and SAR studies of enediyne analogues of the dynemicin core were performed by the groups of Schreiber,61a,61d Wender,63 Nicolaou,61b, 64 Isobe,65 Myers,62a, 66 Danishefsky,61g, 67 Maier,68 Magnus,69 and others 64a,64d, 70. These studies probed the effects of triggering groups or initiators on the nitrogen atom or aryl ring, which could be activated under basic or photochemical conditions that could be mimicked by intracellular processes.…”

Section: Natural Product Derived Fragments In Drug Discoverymentioning

confidence: 99%

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

2016

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Natural products have had an immense influence on science and have directly led to the introduction of many drugs. Organic chemistry, and its unique ability to tailor natural products through synthesis, provides an extraordinary approach to unlock the full potential of natural products. In this Review, an approach based on natural product derived fragments is presented that can successfully address some of the current challenges in drug discovery. These fragments often display significantly reduced molecular weights, reduced structural complexity, a reduced number of synthetic steps, while retaining or even improving key biological parameters such as potency or selectivity. Examples from various stages of the drug development process up to the clinic are presented. In addition, this process can be leveraged by recent developments such as genome mining, antibody–drug conjugates, and computational approaches. All these concepts have the potential to identify the next generation of drug candidates inspired by natural products.

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Section: Natural Product Derived Fragments In Drug Discoverymentioning

confidence: 99%

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

2016

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“…CalC-Á1 belongs to enedyine family of antibiotics and these molecules (23,24) are similar in size and structure to known substrates of the MDR1-Pgp. Early studies conducted in drug-sensitive/resistant cell pairs with mAb-linked CalC-Á1 indicated a modulating effect of MDR1-Pgp on cytotoxicity (19).…”

Section: Resultsmentioning

confidence: 99%

Multidrug transporter proteins and cellular factors involved in free and mAb linked calicheamicin-γ1 (gentuzumab ozogamicin, GO) resistance and in the selection of GO resistant variants of the HL60 AML cell line

Cianfriglia

Mallano²,

Ascione³

et al. 2010

Int J Oncol

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Abstract. In this study we elucidated the role of ATPbinding cassette (ABC) multi-drug transporter proteins and cellular factors such as Bcl-2 expression and CD33 downmodulation contributing to free and hP67.6 mAb linked calicheamicin-Á1 (CalC-Á1) resistance. We analyzed in a well designed HL60 cell system the relationship between the expression of ABC proteins, Bcl-2 and CD33 modulation with the activity of free and mAb-linked CalC-Á1. The results herein reported and discussed, strongly suggest that both MDR1-Pgp and MRP1 efflux systems are engaged by CalC-Á1, but only MDR1-Pgp over-expression efficiently abrogates drug cytotoxicity in MDR cells. Paradoxically, Bcl-2 expression, as observed for other anticancer compounds belonging to the enediyne family of drugs, confers CalC-Á1 susceptibility rather than resistance in HL60 cells. Further, the isolation of a resistant HL60 subline (HL60AL) that was developed by exposing the parental sensitive cells to subeffective doses of gemtuzumab ozogamicin (GO) over an extended period of time shows a reduced level of CD33 expression that represents an important escape mechanism of HL60 MDR cells to the cytotoxic effect of GO. IntroductionGemtuzumab ozogamicin (GO) is the first clinically validated cytotoxic immunoconjugate in which a humanised anti-CD33 antibody (hP67.6) is covalently linked to a derivative of Calicheamicin-Á1 (CalC-Á1) (1). More recently, the therapeutic potential of CD22-specific antibody-targeted chemotherapy using inotuzumab ozogamicin (CMC-544) is being evaluated at present in Phase I clinical trials in patients with non-Hodgkin's lymphoma (2). Further, a number of tumor-targeted immunoconjugates of CalC-Á1 is being explored preclinically for their therapeutic potential (3,4). However, several factors may affect the efficacy of CalC-Á1 immunoconjugates. These include the common issues of mAb therapy such as antibody specificity, heterogeneous target antigen expression and large inter-individual differences in cellular sensitivity to CalC-Á1 (5). Further, among individuals with de novo AML, the overexpression of the MDR1-P-glycoprotein (MDR1-Pgp), a 170-kDa protein that belongs to the ABC superfamily of proteins, is identified in the 20-75% of malignant cells (6). MDR1-Pgp acts as an efflux pump to remove anticancer drugs from cells, resulting in a simultaneous cross-resistance or multi-drug resistance (MDR) to various chemotherapeutics (7). Although MDR1-Pgp appears to be of biologic and clinical relevance (8), other ABC proteins may be involved in the outcome of GO-treated AML patients (9,10). One such protein, the multi-drug resistance-associated protein (MRP1), is distantly related to MDR1-Pgp, and like MDR1-Pgp, lowers intracellular drug accumulation by promoting drug efflux and MDR (11).Previous studies hypothesized an association between MDR1-Pgp and MRP1 expression and clinical responses to GO (8,12,13), others reported discrepant results attributed to the multi-factorial nature of drug resistance (14,15). Engagement of CD33 by GO results in im...

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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.…”

mentioning

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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Designed Enediynes: A New Class of DNA-Cleaving Molecules with Potent and Selective Anticancer Activity

Cited by 312 publications

References 58 publications

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

Multidrug transporter proteins and cellular factors involved in free and mAb linked calicheamicin-γ1 (gentuzumab ozogamicin, GO) resistance and in the selection of GO resistant variants of the HL60 AML cell line

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

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