Synthesis and characterization of dual function vanadyl, gallium and indium curcumin complexes for medicinal applications Khosro Mohammadi a,1 , Katherine H. Thompson a, * , Brian O. Patrick a , Tim Storr a , Candice Martins a , Elena Polishchuk a , Violet G. Yuen b , John H. McNeill b , Chris Orvig a, * a Medicinal Inorganic Chemistry Group, Chemistry Department, University of British Columbia, Vancouver, BC, Canada V6T 1Z1 b Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada V6T 1Z3 Received 6 June 2005; received in revised form 19 July 2005; accepted 8 August 2005 Available online 19 September 2005 Abstract Novel bis[4-hydroxy-3-methoxyphenyl]-1,6-heptadiene-3,5-dione (curcumin) complexes with the formula, ML 3 , where M is Ga(III) or In(III), or of the formula, ML 2 where M is [VO] 2+ , have been synthesized and characterized by mass spectrometry, infra- red and absorption spectroscopies, and elemental analysis. A new ligand, bis[4-acetyl-3-hydroxyphenyl]-1,6-heptadiene-3,5-dione (diacetylbisdemethoxycurcumin, DABC) was similarly characterized; an X-ray structure analysis was performed. Vanadyl com- plexes tested in an acute i.p. testing protocol in STZ-diabetic rats showed a lack of insulin enhancing potential. Vanadyl complexes were, however, more cytotoxic than were the ligands alone in standard MTT (3-[4,5-dimethylthiazole-2-yl]ate, -2,5-diphenyl-tetra- zolium bromide) cytotoxicity testing, using mouse lymphoma cells. With the exception of DABC, that was not different from VO(DABC) 2 , the complexes were not significantly different from one another, with IC 50 values in the 5–10 lM range. Gallium and indium curcumin complexes had IC 50 values in the same 5–10 lM range; whereas Ga(DAC) 3 and In(DAC) 3 (where DAC = diacetylcurcumin) were much less cytotoxic (IC 50 = 20–30 lM). Antioxidant capacity was decreased in VO(DAC) 2 , Ga(DAC) 3 , and In(DAC) 3 , compared to vanadyl, gallium and indium curcumin, corroborating the importance of curcuminÕs free phenolic OH groups for scavenging oxidants, and correlated with reduced cytotoxic potential. Ó 2005 Elsevier Inc. All rights reserved. Keywords: Vanadium; Gallium; Indium; Curcumin; Diacetylcurcumin; Cytotoxicity; Antioxidant capacity 1. Introduction Curcumin, a naturally occurring extract of the spice, turmeric (Curcuma longa L.) has a long history of ther- apeutic use. It has been used as an antioxidant, an anti- tumour agent, and an anti-inflammatant [1–4], and has completed a Phase I trial in 15 colorectal cancer patients in the United Kingdom [5]. Evaluation of curcumin and structural derivatives in cancer chemoprevention model systems has demonstrated a range of potencies depen- dent upon particular substituents on the aromatic moi- ety [6]. Vanadyl curcumin (VO(cur) 2 ) was recently synthesized and characterized in our laboratory [7]. It was more effective as an anti-cancer agent and as an inhibitor of synoviocyte proliferation, compared to uncomplexed curcumin or vanadyl ion alone; it also proved to be exceptionally non-toxic in vivo, with no evidence of negative symptomatology during a month- long treatment period, at doses up to and including 2.0 mmol kg 1 d 1 [7]. 0162-0134/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.jinorgbio.2005.08.001 * Corresponding authors. Tel.: +1 604 822 4449/1776; fax: +1 604 822 2847. E-mail addresses: kthompso@chem.ubc.ca (K.H. Thompson), orvig@chem.ubc.ca (C. Orvig). 1 Current address: Chemistry Department, University of Shiraz, Shiraz 71454, Iran. www.elsevier.com/locate/jinorgbio Journal of Inorganic Biochemistry 99 (2005) 2217–2225 JOURNAL OF Inorganic Biochemistry