In an effort to discover potential alternatives to the anti-cancer drug cisplatin, the synthesis of gold(III) polypyridyl coordination complexes was pursued. Specifically, this report describes the synthesis and characterization of a series of 2,9-dialkyl-1,10-phenanthroline (Rphen) gold(III) coordination complexes (R = n-butyl, sec-butyl, and tert-butyl). Due to the steric hindrance imparted by the alkyl substituents, these ligands do not react with HAuCl4 to form square-planar gold(III) dichloride complex ions, as is the case with 1,10-phenanthroline, but instead form salts comprised of [AuCl(4)](-) anions and protonated 2,9-dialkylphenanthroline cations (compounds 1 and 2). In an effort to facilitate direct binding between the substituted phenanthroline and the gold(iii) metal center, reactions were carried out between the ligand and NaAuCl4 in the presence of a Ag(I) salt. The precipitation of one equivalent of AgCl afforded the formation of neutral, distorted square-pyramidal gold(iii) trichloride complexes (compounds 3 and 4). Primary or secondary substitutions at the alpha carbon of the alkyl substituent allow direct metal-ligand coordination, whereas a tertiary substituent inhibits chelation and results only in the formation of a salt comprised of a protonated phenanthroline cation and a [AuCl2]- anion (compound 5). Compounds 1-4 have been characterized by 1H NMR, UV/vis, IR spectroscopy, and X-ray crystallography.

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Development of new, safe, and effective drugs or strategies targeting molecular events and pathways which are responsible for cancer initiation and progression is an urgent need to improve cancer patient care. In this study, we tested the antitumor effect of a novel agent, 2, 9-disecbutyl-1, 10-phenanthroline (dsBPT), a 1, 10-phenanthroline derivative. Both in vitro cell line and in vivo xenograft models were applied to study the antitumor efficacy and underlying mechanism of this compound. IC50s were initially determined using lung cancer cell lines: A549 (0.25 μM) and H1703 (0.1 μM), head and neck cancer cell lines: TU686 (0.08 μM) and TU212 (0.2 μM), and normal bronchial epithelial cells: BEAS-2B (2.0 μM), indicating that the growth inhibitory effect of dsBPT on cancer cell lines was about 10 times greater than that on normal human epithelial cells. Further studies demonstrated that dsBPT at a concentration of 1-2 μM induced autophagy and G1 cell cycle arrest. At higher doses between 4-8 μM, the compound further induced apoptosis (40-80%). Combination of dsBPT with the cytotoxic agent cisplatin synergistically inhibited cancer cell growth (combination index = 0.3) and induced apoptosis (80-90%) at a concentration of 1 μM for each drug. Two experiments were then performed to test dsBPT in vivo. First, xenografted mice implanted with TU212 cells were treated with three drug doses (2mg/kg, 5mg/kg, 10mg/kg). Compound was given by IV injection once per week for 3 weeks. We found that 10 mg/kg treatment significantly reduced tumor growth as compared with the control group (p = 0.004). Under the same treatment schedule, further study showed that the combination of dsBPT (2 mg/kg) with cisplatin (2 mg/kg) significantly reduced the tumor volume as compared with the untreated control (p = 0.0017), while each of the single drugs at the same concentration showed no significant inhibitory effect on tumor growth (p = 0.10 and 0.15 for cisplatin and dsBPT, respectively). Neither significant weight loss nor major organ damage was observed by histology examination in the experimental animals in this study. In summary, our study suggests that dsBPT is a novel, highly potent antitumor drug that warrants further preclinical and clinical development either as a single agent or in combination with known chemotherapy drugs such as cisplatin. (This study is supported by grants from DOD W81XWH-07-1-0306 Project 5, and GCC Distinguished Scholar Award to ZC). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 678. doi:10.1158/1538-7445.AM2011-678