Induced-fit recognition of DNA by organometallic complexes with dynamic stereogenic centers

Abstract

Organometallic chemistry offers novel concepts in structural diversity and molecular recognition that can be used in drug design. Here, we consider DNA recognition by 6 -arene Ru(II) anticancer complexes by an induced-fit mechanism. The stereochemistry of the dinuclear complex [(( 6 -biphenyl)RuCl(en)) 2 -(CH2)6] 2؉ (3, en ‫؍‬ ethylenediamine) was elucidated by studies of the half unit [( 6 -biphenyl)RuCl(Et-en)] ؉ (2, where Et-en is Et(H)NCH2CH2NH2). The structures of the separated R* RuR * N and S* RuR * N diastereomers of 2 were determined by x-ray crystallography; their slow interconversion in water (t1/2 Ϸ 2 h, 298 K, pH 6.2) was observed by NMR spectroscopy. For 2 and 3 the R* RuR * N configurations are more stable than S* RuR * N (73:27). X-ray and NMR studies showed that reactions of 2 and 3 with 9-ethylguanine gave rise selectively to S* RuR * N diastereomers. Dynamic chiral recognition of guanine can lead to high diastereoselectivity of DNA binding. The dinuclear complex 3 induced a large unwinding (31°) of plasmid DNA, twice that of mononuclear 2 (14°), and effectively inhibited DNA-directed RNA synthesis in vitro. This dinuclear complex gave rise to interstrand cross-links on a 213-bp plasmid fragment with efficiency similar to bifunctional cisplatin, and to 1,3-GG interstrand and 1,2-GG and 1,3-GTG intrastrand cross-links on site-specifically ruthenated 20-mers. Complex 3 blocked intercalation of ethidium considerably more than mononuclear 2. The concept of induced-fit recognition of DNA by organometallic complexes containing dynamic stereogenic centers via dynamic epimerization, intercalation, and cross-linking may be useful in the design of anticancer drugs.

Controlling ligand substitution reactions of organometallic complexes: Tuning cancer cell cytotoxicity

“…The synthesis and characterization of the ruthenium arene complexes studied here, [( 6 -arene)Ru(en)X][PF 6 ] n , arene ϭ hmb, X ϭ Cl (1), Br (5), I (9), N 3 (14), and thiophenolate (SPh) (21), n ϭ 1; X ϭ py (16), 3,5-dichloropyridine (dcp) (17), 3,5-difluoropyridine (dfp) (18), p-cyanopyridine (pcp) (19), and 3-picoline (pic) (20), n ϭ 2; arene ϭ bip, X ϭ Cl (2), Br (6), I (10), and N 3 (15), n ϭ 1; arene ϭ ind, X ϭ Cl (3), Br (7), and I (11); arene ϭ bz, X ϭ Cl (4), Br (8), I (12); arene ϭ p-cym, X ϭ I (13), n ϭ 1, are described in Supporting Text, which is published as supporting information on the PNAS web site. CF 3 COOH (TFAH) was purchased from Acros (Geel, Belgium), and GMP disodium salt hydrate was purchased from Aldrich.…”

“…The syntheses followed previously described routes (12,(22)(23)(24). The x-ray crystal structures of complexes 2, 13, 22, and 23 have already been reported (12,13 6 ] n [X ϭ Cl (1), Br (5), I (9), N 3 (14), dcp (17), dfp (18), pcp (19), and pic (20)] were allowed to equilibrate for 24-48 h at ambient temperature and were then analyzed by HPLC. Two well separated peaks were observed for each complex corresponding to the aqua adduct and the respective parent cation (Fig.…”

“…These complexes can exhibit cytotoxicity toward cancer cells, including cisplatin-resistant cells (11,12). In nucleotide adducts, {( 6 -arene)Ru(en)} 2ϩ exhibits a high selectivity for N7 of guanine and, in contrast to cisplatin, shows little interaction with adenine (13,14). Reactions of these chloro Ru II arene complexes with nucleotides appear to involve initial aquation, and Ru-OH 2 bonds appear to be more reactive than Ru-OH bonds (15), a behavior parallel to that of Pt II diam(m)ine anticancer complexes (16).…”

Anticancer activity of multinuclear arene ruthenium complexes coordinated to dendritic polypyridyl scaffolds

“…The first complex evaluated of this kind was [Ru(benzene)(metronidazole)Cl 2 ] which presented a higher activity compared to the antitumour drug metronidazole itself [13]. More recently the hydrophilic phosphine-containing [Ru(p-cymene)(pta)Cl 2 ] (pta = 1,3,5-triaza-7-phosphatricyclo [3.3.1.1] [16] and ethylendiamine [17] ligands were found to be relatively inactive in vitro, whereas pyrone-derived dinuclear complexes have demonstrated in vitro anticancer activity in the low lM range [18][19][20]. The in vitro anticancer activity of the latter compounds are determined to some extent by their lipophilicity [20], and their mononuclear analogues are not active in cell cultures [21] 2+ [23] have been studied in vitro or in vivo for their activity, and some show promise against cisplatin-resistant cell lines.…”

Cytotoxicity of ruthenium(II) piano-stool complexes with imidazole-based PN ligands

“…[16] These compounds coordinate to guanine N7 of DNA, which can be complemented by intercalative binding of an extended arene, as well as specific hydrogen-bonding interactions. [20,21] For example, increasing the size of the coordinated arene is accompanied by an increase in activity in human ovarian cancer cell lines [16] and the nature of the chelating ligand YZ and leaving group X seems influence their kinetics and even can change their nucleobase selectivity. [22] The RAPTA family of organometallic Ru(II) compounds contain the water-soluble phosphine ligand phosphaadamantane (pta) or derivatives thereof.…”