Developing glutathione-activated catechol-type diphenylpolyenes as small molecule-based and mitochondria-targeted prooxidative anticancer theranostic prodrugs

Developing concise theranostic prodrugs is highly desirable for personalized and precision cancer therapy. Herein we used the glutathione (GSH)-mediated conversion of 2,4-dinitrobenzenesulfonates to phenols to protect a catechol moiety and developed stable pro-catechol-type diphenylpolyenes as small...

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Bibliographic Details
Published in:Free radical biology & medicine 2019-04, Vol.134, p.406-418
Main Authors: Bao, Xia-Zhen, Dai, Fang, Wang, Qi, Jin, Xiao-Ling, Zhou, Bo
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Catechols - chemistry
Colonic Neoplasms - drug therapy
Colonic Neoplasms - metabolism
Colonic Neoplasms - pathology
Diphenylpolyenes
Glutathione
Glutathione - pharmacology
Humans
Mitochondria - drug effects
Mitochondria - pathology
Mitochondria-targeted
Oxidants - chemistry
Oxidants - pharmacology
Oxidation-Reduction
Polyenes - chemistry
Polyenes - pharmacology
Prodrugs - chemistry
Prodrugs - pharmacology
Prooxidant
Small Molecule Libraries - pharmacology
Theranostic Nanomedicine
Theranostic prodrug
Tumor Cells, Cultured
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Summary:Developing concise theranostic prodrugs is highly desirable for personalized and precision cancer therapy. Herein we used the glutathione (GSH)-mediated conversion of 2,4-dinitrobenzenesulfonates to phenols to protect a catechol moiety and developed stable pro-catechol-type diphenylpolyenes as small molecule-based prooxidative anticancer theranostic prodrugs. These molecules were synthesized via a modular route allowing creation of various pro-catechol-type diphenylpolyenes. As a typical representative, PDHH demonstrated three unique advantages: (1) capable of exploiting increased levels of GSH in cancer cells to in situ release a catechol moiety followed by its in situ oxidation to o-quinone, leading to preferential redox imbalance (including generation of H2O2 and depletion of GSH) and final selective killing of cancer cells over normal cells, and is also superior to 5-fluorouracil and doxorubicin, the widely used chemotherapy drugs, in terms of its ability to kill preferentially human colon cancer SW620 cells (IC50 = 4.3 μM) over human normal liver L02 cells (IC50 = 42.3 μM) with a favourable in vitro selectivity index of 9.8; (2) permitting a turn-on fluorescent monitoring for its release, targeting mitochondria and therapeutic efficacy without the need of introducing additional fluorophores after its activation by GSH in cancer cells; (3) efficiently targeting mitochondria without the need of introducing additional mitochondria-directed groups. [Display omitted] •Using the GSH-mediated conversion of DNBS to phenols to protect a catechol moiety.•Designing GSH-activated PDHH as a concise theranostic prodrug.•Monitoring for its release, targeting and therapeutic efficacy by a turn-on fluorescent.•Identifying PDHH as a potent prooxidative anticancer prodrug.•Identifying the diphenylpolyene skeletons as mitochondria-directed groups.
ISSN:0891-5849
1873-4596
DOI:10.1016/j.freeradbiomed.2019.01.033