Modification of cellular DNA by synthetic aziridinomitosenes

Mallory, Chris; Carfi, Ryan; Moon, SangPhil; Cornell, Ken; Warner, Don L.

doi:10.1016/j.bmc.2015.10.028

Cited by 5 publications

(4 citation statements)

References 35 publications

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“…The activated species generated ( 13 or 14 ) determine the outcome of DNA alkylation both with DNA extract and within cells [11]. Although all mitomycin C-DNA adducts obtained upon reductive activation have been isolated and characterized, questions remain regarding the activation and the reactivity of both mitomycins [21] and aziridinomitosenes [22]. …”

Section: Resultsmentioning

confidence: 99%

Synthesis of Mitomycin C and Decarbamoylmitomycin C N2 deoxyguanosine-adducts

Champeil

Cheng

Huang

et al. 2016

Bioorganic Chemistry

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Mitomycin C (MC) and Decarbamoylmitomycin C (DMC) -a derivative of MC lacking the carbamate on C10- are DNA alkylating agents. Their cytotoxicity is attributed to their ability to generate DNA monoadducts as well as intrastrand and interstrand cross-links (ICLs). The major monoadducts generated by MC and DMC in tumor cells have opposite stereochemistry at carbon one of the guanine-mitosene bond: trans (or alpha) for MC and cis (or beta) for DMC. We hypothesize that local disruptions of DNA structure from trans or cis adducts are responsible for the different biochemical responses produced by MC and DMC. Access to DNA substrates bearing cis and trans MC/DMC lesions is essential to verify this hypothesis. Synthetic oligonucleotides bearing trans lesions can be obtained by bio-mimetic methods. However, this approach does not yield cis adducts. This report presents the first chemical synthesis of a cis mitosene DNA adduct. We also examined the stereopreference exhibited by the two drugs at the mononucleotide level by analyzing the formation of cis and trans adducts in the reaction of deoxyguanosine with MC or DMC using a variety of activation conditions. In addition, we performed Density Functional Theory calculations to evaluate the energies of these reactions. Direct alkylation under autocatalytic or bifunctional conditions yielded preferentially alpha adducts with both MC and DMC. DFT calculations showed that under bifunctional activation, the thermodynamically favored adducts are alpha, trans, for MC and beta, cis, for DMC. This suggests that the duplex DNA structure may stabilize/oriente the activated pro-drugs so that, with DMC, formation of the thermodynamically favored beta products are possible in a cellular environment.

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Section: Resultsmentioning

confidence: 99%

Synthesis of Mitomycin C and Decarbamoylmitomycin C N2 deoxyguanosine-adducts

Champeil

Cheng

Huang

et al. 2016

Bioorganic Chemistry

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“…To evaluate the anticancer activity of the DIDOX analogs, several different cell lines were employed in cytotoxicity assays. Specifically, all the analogs, DIDOX, and DOX were subjected to a series of resazurin reduction assays-results of which are shown in Table 2.1-to compare antiproliferative activity (Mallory, 2015). This assay followed the reduction of non-fluorescent blue resazurin to fluorescent pink resorufin, which only occurs in healthy and metabolically active cells.…”

Section: In Vitro Cytotoxicity Results Of Didox Analogsmentioning

confidence: 99%

“…A resazurin reduction assay was used to determine the cytotoxicity of DOX, DIDOX, and DIDOX analogs against an array of cancer lines (Mallory, 2015). Cells were washed with 1x PBS three times and suspended in trypsin-EDTA while incubating at 37 °C for five minutes.…”

Section: In Vitro Assaysmentioning

confidence: 99%

Potent and Potentially Non-Cardiotoxic Anthracyclines: Their Synthesis, Biological Evaluation, and Comparison of Hydrozone-Mediated Reductions

Holdaway¹

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“…Warner and coworkers reported that the synthetic AZMs 19 and 20 were able to form DNA crosslinks and DNA-protein adducts (DPCs) in Jurkat and HeLa cancer cells after one hour of treatment in an aerobic environment. 45 Cytotoxicity assays showed that 20 was up to 72 and 520 times more potent than MC and 19, respectively, against a variety of adherent and non-adherent cancer cell lines. The IC₅₀ values for MC and 19…”

Section: Reactivity and Cytotoxicity Of Synthetic Aziridinomitosenesmentioning

confidence: 99%

Total Synthesis of 6,7-Dimethyl-N-Methyl Aziridinomitosene

Muhammed¹

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Mitomycin C (MC) is a naturally occurring antitumor agent isolated from a soil bacterium. MC is effective against solid hypoxic tumors that respond poorly to radiotherapy, such as colorectal, gastric, and lung tumors. Also, it has a role in the treatment of bladder, head and neck, and non-small cell lung cancers in combination with other chemotherapeutic. MC and other members of the mitomycin family of antitumor agents fight cancer by forming DNA interstrand crosslinks (ICLs), which leads to apoptosis. In order to form ICLs, MC requires a reductive activation step that produces reactive oxygen species. This activation step is proposed to lead to adverse side effects, such as myelosuppression and hemolytic uremic syndrome. Aziridinomitosenes (AZMs) are structurally related to MC and are believed to form during in vivo reduction of MC. AZMs are relatively stable but are more sensitive than the parent mitomycins due to an activated aziridine ring. Consequently, AZMs do not require the reductive activation step in order to alkylate DNA. The purpose of this work is to synthesize and study an AZM that is substituted with methyl groups at two potential electrophilic sites. It is hypothesized that certain synthetic AZMs crosslink DNA under non-reductive conditions as a result of a nucleophilic activation sequence involving the quinone ring. To test this hypothesis, analogs were prepared that would either reduce the rate of the activation step or prevent it from occurring. The synthetic route starts with commercially available reagents to form an oxazole, followed by the addition of a protected aldehyde that is converted to the required aziridine vii ring via a Mitsunobu reaction. Once the aziridine ring is formed, all of the reaction conditions must be conducted using mild conditions in order to prevent ring-opening. The completion of the synthesis and formation of the tetracyclic core was achieved by performing an oxazolium salt/azomethine ylide [3+2] cycloaddition sequence. This sequence was conducted multiple times, and the highest yield obtained was 44%. The final steps were the most challenging, requiring several transformations to accomplish a deprotection and oxidation to give a diketone that was oxidized to a quinone. Finally, the carbamate was attached in two steps using FmocNCO to yield the desired AZM product in an overall yield of 0.04% from the starting diol over the 22 step reaction sequence. The stability of the AZM was tested in buffered methanolic solutions, and the results were compared to other aziridinomitosenes. While unsubstituted AZMs decompose in basic solutions, the C6/C7 dimethyl AZM showed high stability under these conditions. viii TABLE OF CONTENTS

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Modification of cellular DNA by synthetic aziridinomitosenes

Cited by 5 publications

References 35 publications

Synthesis of Mitomycin C and Decarbamoylmitomycin C N2 deoxyguanosine-adducts

Synthesis of Mitomycin C and Decarbamoylmitomycin C N2 deoxyguanosine-adducts

Potent and Potentially Non-Cardiotoxic Anthracyclines: Their Synthesis, Biological Evaluation, and Comparison of Hydrozone-Mediated Reductions

Total Synthesis of 6,7-Dimethyl-N-Methyl Aziridinomitosene

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