The in vitro antitumor activity of arene-ruthenium(II) curcuminoid complexes improves when decreasing curcumin polarity.
The antitumor activity of ruthenium(II) arene (p-cymene, benzene, hexamethylbenzene) derivatives containing modified curcumin ligands (HCurcI=(1E,4Z,6E)-5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)hepta-1,4,6-trien-3-one and HCurcII=(1E,4Z,6E)-5-hydroxy-1,7-bis(4-methoxyphenyl)hepta-1,4,6-trien-3-one) is described. These have been characterized by IR, ESI-MS and NMR spectroscopy. The X-ray crystal structure of HCurcI has been determined and compared with its related Ru complex. Four complexes have been evaluated against five tumor cell lines, whose best activities [IC50(μM)] are: breast MCF7, 9.7; ovarian A2780, 9.4; glioblastoma U-87, 9.4; lung carcinoma A549, 13.7 and colon-rectal HCT116, 15.5; they are associated with apoptotic features. These activities are improved when compared to the already known corresponding curcumin complex, (p-cymene)Ru(curcuminato)Cl, about twice for the breast and ovarian cancer, 4.7 times stronger in the lung cancer and about 6.6 times stronger in the glioblastoma cell lines. In fact, the less active (p-cymene)Ru(curcuminato)Cl complex only shows similar activity to two novel complexes in the colon cancer cell line. Comparing antitumor activity between these novel complexes and their related curcuminoids, improvement of antiproliferative activity is seen for a complex containing CurcII in A2780, A549 and U87 cell lines, whose IC50are halved. Therefore, after replacing OH curcumin groups with OCH3, the obtained species HCurcI and its Ru complexes have increased antitumor activity compared to curcumin and its related complex. In contrast, HCurcII is less cytotoxic than curcumin but its related complex [(p-cymene)Ru(CurcII)Cl] is twice as active as HCurcII in 3 cell lines. Results from these novel arene-Ru curcuminoid species suggest that their increased cytotoxicity on tumor cells correlate with increase of curcuminoid lipophilicity.
Vassar College, Department of Chemistry, Poughkeepsie, NY 12604, USA. Electronic address: caruso@vassar.edu.
Francesco
F
Caruso
School of Science and Technology, Università di Camerino, via S. Agostino 1, 62032 Camerino, MC, Italy.
Riccardo
R
Pettinari
Vassar College, Department of Chemistry, Poughkeepsie, NY 12604, USA.
Miriam
M
Rossi
University of Insubria, Department of Structural and Functional Biology, Via A. da Giussano 10, 21052, Busto Arsizio, Varese, Italy.
Elena
E
Monti
University of Insubria, Department of Structural and Functional Biology, Via A. da Giussano 10, 21052, Busto Arsizio, Varese, Italy.
Marzia Bruna
MB
Gariboldi
School of Science and Technology, Università di Camerino, via S. Agostino 1, 62032 Camerino, MC, Italy.
Fabio
F
Marchetti
School of Pharmacy, Università di Camerino, via S. Agostino 1, 62032 Camerino, MC, Italy.
Claudio
C
Pettinari
Vassar College, Department of Chemistry, Poughkeepsie, NY 12604, USA.
Alessio
A
Caruso
Natsol Laboratories Private Limited, Commercial Hub, J.N. Pharma City, Visakhapatnam 531019, India.
Modukuri V
MV
Ramani
Natsol Laboratories Private Limited, Commercial Hub, J.N. Pharma City, Visakhapatnam 531019, India. Electronic address: subbarajugv@gmail.com.
Gottumukkala V
GV
Subbaraju
D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001554:Benzene / Q000737:chemistry*; D001555:Benzene Derivatives / Q000737:chemistry*; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000494:pharmacology; D003474:Curcumin / Q000737:chemistry*; D000081007:Cymenes; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D039821:Monoterpenes / Q000737:chemistry*; D009928:Organ Specificity; D012428:Ruthenium / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D056831:Coordination Complexes; D000081007:Cymenes; D039821:Monoterpenes; C007210:4-cymene; D012428:Ruthenium; D003474:Curcumin; D001554:Benzene; C091695:hexamethylbenzene
<Beta>-diketone; Antiproliferative activity; Apoptosis; Liposolubility; Modified curcumin; Ruthenium(II)