Photoswitchable anticancer activity via trans-cis isomerization of a combretastatin A-4 analog.
Combretastatin A-4 (CA4) is highly potent anticancer drug that acts as an inhibitor of tubulin polymerization. The core of the CA4 structure contains a cis-stilbene, and it is known that the trans isomer is significantly less potent. We prepared an azobenzene analog of CA4 (Azo-CA4) that shows 13-35 fold enhancement in potency upon illumination. EC50 values in the light were in the mid nM range. Due to its ability to thermally revert to less toxic trans form, Azo-CA4 also has the ability to automatically turn its activity off with time. Azo-CA4 is less potent than CA-4 because it degrades in the presence of glutathione as evidenced by UV-Vis spectroscopy and ESI-MS. Nevertheless, Azo-CA4 represents a promising strategy for switchable potency for treatment of cancer.
Department of Chemistry, Virginia Commonwealth University, 1001 W. Main St., Richmond, VA 23284-2006, USA. mchartman@vcu.edu.
Jonathon E
JE
Sheldon
M Michael
MM
Dcona
Charles E
CE
Lyons
John C
JC
Hackett
Matthew C T
MC
Hartman
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D055668:Photochemical Processes; D058105:Polymerization / Q000187:drug effects; D013237:Stereoisomerism; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism
D000970:Antineoplastic Agents; D013267:Stilbenes; D014404:Tubulin; C058728:fosbretabulin