Antitumour benzothiazoles. Part 32: DNA adducts and double strand breaks correlate with activity; synthesis of 5F203 hydrogels for local delivery

Stone, Erica L.; Citossi, Francesca; Singh, Rajinder; Kaur, Bhavneet; Gaskell, Margaret; Farmer, Peter B.; Monks, Anne; Hose, Curtis; Stevens, Malcolm F. G.; Leong, Chee‐Onn; Stocks, Michael J.; Kellam, Barrie; Marlow, Maria; Bradshaw, Tracey D.

doi:10.1016/j.bmc.2015.09.052

Cited by 41 publications

(37 citation statements)

References 41 publications

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“…In a library of more than 35 close structural analogues, one compound 5‐fluoro‐2‐(3,4‐dimethoxyphenyl) benzothiazole (GW 610), showed outstanding potent and selective anticancer activity against, eg, colorectal and breast carcinoma models . GW 610 is a potent aryl hydrocarbon receptor (AhR) ligand, bioactivated via cytochrome P450 (CYP) 1A1 and 2W1 catalysis to electrophilic species that generate lethal DNA adducts in sensitive cancer cells …”

Section: Introductionmentioning

confidence: 99%

“…15 GW 610 is a potent aryl hydrocarbon receptor (AhR) ligand, bioactivated via cytochrome P450 (CYP) 1A1 and 2W1 catalysis to electrophilic species that generate lethal DNA adducts in sensitive cancer cells. [20][21][22] However, GW 610 is highly lipophilic and poorly water soluble; hence, drug delivery tools are needed to help solubilize and target GW 610. During biotransformation, GW 610 initially undergoes regiospecific demethylation to give 5-fluoro-2-(4-hydroxy-3methoxyphenyl) benzothiazole (GW 608).…”

Section: Introductionmentioning

confidence: 99%

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Development of novel apoferritin formulations for antitumour benzothiazoles

et al. 2019

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Background The benzothiazole structure is important in medicinal chemistry, and 5‐fluoro‐2‐(3,4‐dimethoxyphenyl) benzothiazole (GW 610) is of particular interest as it shows outstanding anticancer activity in sensitive breast and colorectal carcinoma cell lines via generation of lethal DNA adducts in sensitive cancer cells. Despite promising activity, poor water solubility limits its applications. The apoferritin (AFt) protein cage has been proposed as a robust and biocompatible drug delivery vehicle. Aims Here, we aim to enhance solubility of GW 610 by developing amino acid prodrug conjugates and utilizing the AFt capsule as drug delivery vessel. Methods and results The potent experimental antitumour agent, GW 610, has been successfully encapsulated within AFt with more than 190 molecules per AFt cage. The AFt‐GW 610 complex exhibits dose‐dependent growth inhibition and is more potent than GW 610 alone in 5/7 cancer cell lines. To enhance both aqueous solubility and encapsulation efficiency, a series of amino acid esters of GW 608 prodrug were synthesized via N,N′‐dicyclohexylcarbodiimide ester coupling to produce molecules with different polarity. A dramatic increase in encapsulation efficiency was achieved, with more than 380 molecules of GW 608‐Lys molecules per AFt cage. Release studies show sustained release of the cargo over 12 hours at physiologically relevant pH. The AFt‐encapsulated amino acid modified GW 608 complexes are sequestered more rapidly and exhibit more potent anticancer activity than unencapsulated agent. Conclusion These results indicate that AFt‐encapsulation of GW 610 prodrug provides a biocompatible delivery option for this potent, selective experimental antitumour agent and for amino acid‐modified GW 608. Of particular interest is the encapsulation efficiency and in vitro antitumour activity of AFt‐GW 608‐Lys, which warrants further preclinical evaluation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development of novel apoferritin formulations for antitumour benzothiazoles

et al. 2019

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“…[1][2][3] There already exist examples of low molecular weight gelating entities with potential for use in drug delivery, whether they be therapeutic molecular gels, such as the recent linifinib 4 and benzothiazole 5 examples or inert gelator matrices such as the extensively studied tri-/dipeptide gelators. [6][7][8] Whilst there is extensive literature describing the applications of LMWGs in drug delivery, there are only a few published examples of these inert matrix gelators that possess self-healing properties i.e.…”

Section: Introductionmentioning

confidence: 99%

Developing a self-healing supramolecular nucleoside hydrogel

et al. 2016

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A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription. Low molecular weight gelator hydrogels provide a viable alternative to traditional polymer based drug delivery platforms, owing to their tunable stability and in most cases inherent biocompatibility. Here we report the first self-healing nucleoside hydrogel using N4-octanoyl-2ʹ-deoxycytidine (0.5 % w/v) for drug delivery. The hydrogel's cross-linked nanofibrillar structure, was characterised using oscillatory rheology and confirmed using SEM and TEM imaging . The potential of this gel for drug delivery was explored in vitro using fluorescently labelled tracers. Cell viability assays were conducted using pancreatic cell lines which tolerated the gels well; whilst no adverse effects on the viability or proliferation of cells were observed for fibroblast cell lines.

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“…EGFR enhanced aerobic glycolysis in the triple negative breast cancer (TNBC) to promote tumor growth and immune escape, and targeting its signaling could offer an applicable strategy to treat TNBC [44]. Moreover, cisplatin and doxorubicin were reported to form adduct with human DNA, which in turn resulted in DNA damage of the cancer cell [45]. Thus, EGFR and human DNA were discovered as popular therapeutic targets inhibited by FDA approved combination products.…”

Section: Resultsmentioning

confidence: 99%

The Human Kinome Targeted by FDA Approved Multi-Target Drugs and Combination Products: A Comparative Study from the Drug-Target Interaction Network Perspective

Wang

et al. 2016

PLoS ONE

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The human kinome is one of the most productive classes of drug target, and there is emerging necessity for treating complex diseases by means of polypharmacology (multi-target drugs and combination products). However, the advantages of the multi-target drugs and the combination products are still under debate. A comparative analysis between FDA approved multi-target drugs and combination products, targeting the human kinome, was conducted by mapping targets onto the phylogenetic tree of the human kinome. The approach of network medicine illustrating the drug-target interactions was applied to identify popular targets of multi-target drugs and combination products. As identified, the multi-target drugs tended to inhibit target pairs in the human kinome, especially the receptor tyrosine kinase family, while the combination products were able to against targets of distant homology relationship. This finding asked for choosing the combination products as a better solution for designing drugs aiming at targets of distant homology relationship. Moreover, sub-networks of drug-target interactions in specific disease were generated, and mechanisms shared by multi-target drugs and combination products were identified. In conclusion, this study performed an analysis between approved multi-target drugs and combination products against the human kinome, which could assist the discovery of next generation polypharmacology.

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Antitumour benzothiazoles. Part 32: DNA adducts and double strand breaks correlate with activity; synthesis of 5F203 hydrogels for local delivery

Cited by 41 publications

References 41 publications

Development of novel apoferritin formulations for antitumour benzothiazoles

Development of novel apoferritin formulations for antitumour benzothiazoles

Developing a self-healing supramolecular nucleoside hydrogel

The Human Kinome Targeted by FDA Approved Multi-Target Drugs and Combination Products: A Comparative Study from the Drug-Target Interaction Network Perspective

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