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Developing glutathione-activated catechol-type diphenylpolyenes as small molecule-based and mitochondria-targeted prooxidative anticancer theranostic prodrugs.
- Source :
-
Free Radical Biology & Medicine . Apr2019, Vol. 134, p406-418. 13p. - Publication Year :
- 2019
-
Abstract
- 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 H 2 O 2 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 (IC 50 = 4.3 μM) over human normal liver L02 cells (IC 50 = 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. Image 1 • 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *CATECHOL
*CANCER cells
*LIVER cells
*CARCINOMA in situ
*COLON cancer
*PRODRUGS
Subjects
Details
- Language :
- English
- ISSN :
- 08915849
- Volume :
- 134
- Database :
- Academic Search Index
- Journal :
- Free Radical Biology & Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 137030691
- Full Text :
- https://doi.org/10.1016/j.freeradbiomed.2019.01.033