Targeting duplex DNA with the reversible reactivity of quinone methides

Huang, Chengyun; Liu, Yang; Rokita, Steven E.

doi:10.1038/sigtrans.2016.9

Cited by 17 publications

(20 citation statements)

References 45 publications

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“… 4 , 68–70 Such problems may be mitigated by designing conjugates that are in a protected form during the delivery and activated after binding to the target cells and internalization. 71 Multiple reports further contend that antibody size and valence regulating in vivo tumor targeting and biodistribution are closely correlated with antitumor activity of ADCs. Therefore, ADCs consisting of intact antibodies that have relatively large molecular weight and limited tissue penetrability may be less effective in the treatment of solid tumors.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic potential of an anti-HER2 single chain antibody–DM1 conjugates for the treatment of HER2-positive cancer

Zhang

Wang

et al. 2017

Sig Transduct Target Ther

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Antibody–drug conjugates (ADCs) take the advantage of monoclonal antibodies to selectively deliver highly potent cytotoxic drugs to tumor cells, which have become a powerful measure for cancer treatment in recent years. To develop a more effective therapy for human epidermal growth factor receptor 2 (HER2)-positive cancer, we explored a novel ADCs composed of anti-HER2 scFv–HSA fusion antibodies conjugates with a potent cytotoxic drug DM1. The resulting ADCs, T-SA1–DM1 and T-SA2–DM1 (drug-to-antibody ratio in the range of 3.2–3.5) displayed efficient inhibition in the growth of HER2-positive tumor cell lines and the half-maximal inhibitory concentration on SKBR-3 and SKOV3 cells were both at the nanomolar levels in vitro. In HER2-positive human ovarian cancer xenograft models, T-SA1–DM1 and T-SA2–DM1 also showed remarkable antitumor activity. Importantly, three out of six mice exhibited complete remission without regrowth in the high-dose group of T-SA1–DM1. On the basis of the analysis of luminescence imaging, anti-HER2 scFv–HSA fusion antibodies, especially T-SA1, showed strong and rapid tumor tissue penetrability and distribution compared with trastuzumab. Collectively, the novel type of ADCs is effective and selective targeting to HER2-positive cancer, and may be a promising antitumor drug candidate for further studies.

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Section: Discussionmentioning

confidence: 99%

Therapeutic potential of an anti-HER2 single chain antibody–DM1 conjugates for the treatment of HER2-positive cancer

Zhang

Wang

et al. 2017

Sig Transduct Target Ther

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“…ortho -Quinone methide precursor (2-QMP, compound 5 , see Scheme 2) was generously provided by Professor Steven Rokita (John Hopkins University). 24−26 Acetonitrile (ACN), dimethylformamide (DMF), methanol, water and formic acid were obtained from VWR Chemicals. All solvents were of HPLC grade.…”

Section: Methodsmentioning

confidence: 99%

Discovery of Novel N-(4-Hydroxybenzyl)valine Hemoglobin Adducts in Human Blood

Degner

Carlsson

Karlsson

et al. 2018

Chem. Res. Toxicol.

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Humans are exposed to a wide range of electrophilic compounds present in our diet and environment or formed endogenously as part of normal physiological processes. These electrophiles can modify nucleophilic sites of proteins and DNA to form covalent adducts. Recently, powerful untargeted adductomic approaches have been developed for systematic screening of these adducts in human blood. Our earlier untargeted adductomics study detected 19 unknown adducts to N-terminal valine in hemoglobin (Hb) in human blood. We now describe a full characterization of one of these adducts, which corresponds to the addition of a 4-hydroxybenzyl (4-OHBn) group to N-terminal valine in Hb to form N-(4-hydroxybenzyl)valine (4-OHBn-Val). The adduct structure was determined by comparison of its accurate mass, HPLC retention time, and MS/MS fragmentation to that of authentic standards prepared by chemical synthesis. Average 4-OHBn-Val adduct concentrations in 12 human blood samples were estimated to 380 ± 160 pmol/g Hb. Two possible routes of 4-OHBnVal adduct formation are proposed using two different precursor electrophiles: 4-quinone methide (4-QM) and 4-hydroxybenzaldehyde (4-OHBA). We found that 4-QM reacts rapidly with valine to form the 4-OHBn-Val adduct; however, the quinone methide is unstable under physiological conditions due to hydrolysis. It was shown that 4-OHBA forms reversible Schiff base adducts with valine, which can be stabilized via reduction in blood generating the 4-OHBn-Val adduct. In addition, trace amounts of isomeric 2-hydroxybenzyl-valine (2-OHBn-Val) adducts were detected in 12 human blood samples (estimated mean adduct level, 5.0 ± 1.4 pmol/g Hb). Further studies are needed to quantify the contributions from identified possible precursor electrophiles to the observed hydroxybenzyl adducts in humans.

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“…To further develop this skeleton into a near-infrared (NIR) probe, we recently connected the chromene with a NIR fluorophore using a carbonate ester to provide the probe NIR-HMPC (Figure b), which was successfully applied to elucidate the pathophysiology process in the living organism . However, the formation of para-quinone methides could result in toxic effects through covalent modification of proteins and/or DNA as well as depletion of GSH, leading to an altered redox balance within cells. − …”

mentioning

confidence: 99%

Thiol “Click” Chromene Ring Opening and Subsequent Cascade Nucleophilic Cyclization NIR Fluorescence Imaging Reveal High Levels of Thiol in Drug-Resistant Cells

Zhao

Yue

et al. 2020

Anal. Chem.

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As the structural unit of natural products, chromene derivatives show a wide range of biological activity and pharmacological activity due to their unique photophysical and chemical properties. Ten years ago, our research group discovered the "thiol-chromene" click reaction, which achieved the selective detection of thiols through the change of the optical spectrum. Afterward, we attempted to develop various chromene-based fluorescent probes for imaging including near-infrared (NIR) probe, ratiometric probe, and multifunctional probe. However, how to integrate the fluorophore and reaction sites into the chromenebased skeleton remains challenging. In this work, we connected the chromene motif with the NIR fluorophore methylene blue utilizing a carbamate spacer to provide a new fluorescent probe (CM-NIR), which is triggered by thiols to open the pyran ring followed by attacking the carbamate by phenolate to releases the methylene blue. This novel cascade mechanism avoids the formation of paraquinone methides, which proved to be toxic to normal cells. CM-NIR also showed the specific imaging of thiols in living cells and mice. More importantly, the thiols level in drug-resistant cancer cells was found to be significantly higher than that in the corresponding cancer cell, which indicated that the thiols level may have an important role in cancer cells developing drug resistance.

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Targeting duplex DNA with the reversible reactivity of quinone methides

Cited by 17 publications

References 45 publications

Therapeutic potential of an anti-HER2 single chain antibody–DM1 conjugates for the treatment of HER2-positive cancer

Therapeutic potential of an anti-HER2 single chain antibody–DM1 conjugates for the treatment of HER2-positive cancer

Discovery of Novel N-(4-Hydroxybenzyl)valine Hemoglobin Adducts in Human Blood

Thiol “Click” Chromene Ring Opening and Subsequent Cascade Nucleophilic Cyclization NIR Fluorescence Imaging Reveal High Levels of Thiol in Drug-Resistant Cells

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