Stable and potent analogues derived from the modification of the dicarbonyl moiety of curcumin.
Curcumin has shown promising therapeutic utilities for many diseases, including cancer; however, its clinical application is severely limited because of its poor stability under physiological conditions. Here we find that curcumin also loses its activity instantaneously in a reducing environment. Curcumin can exist in solution as a tautomeric mixture of keto and enol forms, and the enol form was found to be responsible for the rapid degradation of the compound. To increase the stability of curcumin, several analogues were synthesized in which the diketone moiety of curcumin was replaced by isoxazole (compound 2) and pyrazole (compound 3) groups. Isoxazole and pyrazole curcumins were found to be extremely stable at physiological pH, in addition to reducing atmosphere, and they can kill cancer cells under serum-depleted condition. Using molecular modeling, we found that both compounds 2 and 3 could dock to the same site of tubulin as the parent molecule, curcumin. Interestingly, compounds 2 and 3 also show better free radical scavenging activity than curcumin. Altogether, these results strongly suggest that compounds 2 and 3 could be good replacements for curcumin in future drug development.
Department of Biochemistry, Bose Institute , P-1/12 CIT Scheme VIIM, Kolkata 700054, India.
Soumyananda
S
Chakraborti
Gopa
G
Dhar
Vishnu
V
Dwivedi
Amlan
A
Das
Asim
A
Poddar
Gopal
G
Chakraborti
Gautam
G
Basu
Pinak
P
Chakrabarti
Avadhesha
A
Surolia
Bhabatarak
B
Bhattacharyya
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D005434:Flow Cytometry; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry*; D007659:Ketones / Q000737:chemistry*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D011720:Pyrazoles / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D016166:Free Radical Scavengers; D007555:Isoxazoles; D007659:Ketones; D011720:Pyrazoles; D014404:Tubulin; C031280:pyrazole; D003474:Curcumin