DNA Cleavage Potency, Cytotoxicity, and Mechanism of Action of a Novel Class of Enediyne Prodrugs

Dai, Wei‐Min; Lai, Kwong Wah; Wu, Anxin; Hamaguchi, Wataru; Lee, Mavis Yuk Ha; Zhou, Ling; Ishii, and Atsushi; Nishimoto, Sei‐ichi

doi:10.1021/jm015588e

Cited by 36 publications

(16 citation statements)

References 21 publications

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“…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%

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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confidence: 99%

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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“…At present, the Sonogashira reaction has been widely used in the synthesis of substituted alkynes and conjugated alkynes [13] [14] [15] [16]. It also plays a key role in the synthesis of many natural products [17], pesticides, pharmaceuticals [18] [19] and new materials and nano-molecular devices [20] [21] [22] [23]. Since the discovery of the Sonogashira reactions [24]- [29], the most widely used catalysts have been Pd-type compounds.…”

Section: Introductionmentioning

confidence: 99%

Palladium-Catalyzed Sonogashira Coupling Reaction of 2-Amino-3-Bromopyridines with Terminal Alkynes

Zhu¹,

Liao²,

Guo³

et al. 2017

MRC

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Palladium-catalyzed the Sonogashira coupling reaction of 3-halogen-2-aminopyridines 1 with terminal alkynes 2 afforded the corresponding 21 target products 3a-3u in the presence of palladium catalyst. The structure of target products 3a-3u was confirmed and characterized by 1 H NMR, 13C NMR, and HRMS. The influences of different kinds of catalyst loading, bases, substrates and temperature were also investigated. Under the optimized conditions, including 2.5 mol% Pd (CF 3 COO) 2 , 5 mol% PPh 3 and 5 mol% CuI as additive, 1 mL Et 3 N, substrate 1 with terminal alkynes 2 for the cross-coupling reactions at 100˚C for 3 h in DMF afforded the corresponding products of 2-amino-3-alkynylpyridines 3 in moderate to excellent yields (72% -96%). The present methodology has provided an effective synthetic method including operational convenience, high efficiency and wide-application.

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“…[3][4][5][6][7][8] In addition, Suzuki-Miyaura cross-coupling reaction is one of the most versatile and utilized reactions for carbon-carbon bond formation in the synthesis of natural products and pharmaceuticals. [9][10][11][12][13] Water as an available, cheap, renewable, safe and green solvent and allows easy work up and separation, has been exploited in several catalytic C-C bond formation reactions and was reported as an important partner in improving the catalyst activity.…”

Section: Introductionmentioning

confidence: 99%

“…Under the typical conditions above, when water was replaced with toluene at reflux for 4 hr, the product 6 was obtained in 73% yield ( Pd-Cat II When Suzuki coupling of the 1-bromo-4-(2-phenylethynyl)benzene (4) with 3-chlorophenylboronic acid (6b) was similarly carried out in H 2 O/K 2 CO 3 /TBAB reaction system under thermal heating at 100 °C using 1 mol% Pd-cat. I (Table 2, run 1) or at 60 °C using 1 mol% Pd-cat II (Table 2, run 2), it resulted in the formation of 1-(3-chlorophenyl)-2-(4-biphenylyl)acetylene (8) in excellent isolated yields.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of ethynylated biaryls and asymmetric diethynylated benzene via sequential Sonogashira and Suzuki couplings in water

Hassaneen¹,

Dawood²,

Ahmed³

et al. 2015

Arkivoc

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Two 1-bromo-4-ethynylbenzene candidates were synthesized from 1-bromo-4-iodobenzene via Sonogashira coupling then sequentially employed in Suzuki coupling with arylboronic acids in water to give ethynylated biaryl derivatives. Optimization of the reaction condition was done using two different palladium sources and various bases/solvents systems. Further sequential Sonogashira coupling of 1-bromo-4-ethynylbenzene candidates, in aqueous medium, afforded asymmetric diethynylated benzene derivatives.

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DNA Cleavage Potency, Cytotoxicity, and Mechanism of Action of a Novel Class of Enediyne Prodrugs

Cited by 36 publications

References 21 publications

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

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

Palladium-Catalyzed Sonogashira Coupling Reaction of 2-Amino-3-Bromopyridines with Terminal Alkynes

Synthesis of ethynylated biaryls and asymmetric diethynylated benzene via sequential Sonogashira and Suzuki couplings in water

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