RhodiumII complexes

Binuclear rhodium(II) complexes belong to the most promising anti-tumor complexes. Physicochemistry and reactivity of these complexes were very thoroughly investigated.20 Properties of many complexes containing less than four bridging ligands have also been characterized.20,21 The chemical structures of some of these complexes are presented in Figure 20.1.

In 1972 Bear and co-workers reported the anti-tumor activity of rhodium(II) carboxylates [Rh2(OOCR)4].22 These complexes were shown to be active against oral carcinoma, Ehrlich ascites, leukemia P388 and L1210 leukemia.22 30 Anti-tumor activity of [Rh2(OOCR)4] depends on the hydrophobic properties of the R group:

ch3 < ch3ch2 <ch3ch2ch2 < ch3ch2ch2ch2 >ch3ch2ch2ch2ch2.

Other rhodium(II) complexes with four bridges: [Rh2(OOCR)4L2] (L = isonicotinic acid, HSA),31,32 [Rh2{O(HN)CCF3}4],33,34 [Rh2(OOCCF3)4] and [Rh2(OOCCF3)4L2] (L = sulfadiazine),35 rhodium(II) citrate,36,37 rhodium(II) keto-gluconate and glucoronate and their adducts with cyclophosphamide38 have also

Rh c

O-XC

Figure 20.1 Structure of [Rh2(OOCR)4] (a) and [Rh2(OOCR)2(N-N)2L2]X2 (b) complexes. N-N = bipy, phen and their derivatives, L = Lewis base, X = RCOO~, BF4 , etc.

been investigated. The in vitro activity of [Rh2(OOCR)4L2] (R = Me, Et, Pr) adducts with isonicotinic acid against K562 human leukemic cell line and investigations of LD10 (poisoning with 10% lethality) of these complexes in vivo in mice indicate that, in the presence of cellular membrane or blood lipids, isonico-tinic acid adducts dissociate giving the parent complexes which therefore enter the cells more easily.31 Thus, adducts with isonicotinic acid can be used as carriers of rhodium(II) carboxylates to cells. The same was suggested in the case of the reaction products between HSA (human serum albumin) and [Rh2(OOCR)4] or [Rh2{O(HN)CCF3}4].32 Promising anti-tumor properties characterizes the amidate complex [Rh2{O(HN)CCF3}4] because it is more active than cis-[PtCl2(NH3)2], and LD50 values for these complexes are comparable.33,34 The activity of rhodium(II) trifluoroacetate and its adduct with sulfadiazine tested in mice against Ehrlich ascites carcinoma was much higher than that ofrhodium(II) acetate.35 Interesting anti-tumor properties also characterize rhodium(II) citrate, ketogluconate and glucoronate which are soluble in water.36 38 Their toxicity is low and their anti-tumor activity is comparable with that of cisplatin. They can form inclusion or association compounds with cyclodextrin and hydroxyapatite. The associates allow for the controlled release of pure rhodium complexes into tumor cells.37 Rhodium(II) complexes containing different bridging ligands are generally more reactive. This is caused by differences in the trans-influence of ligands. The formamidinato carboxylato complex [Rh2(form)2{O(HN)CCF3}2(H2O)2] (form = N,N'-di-p-tolylformamidinate, p-MeC6H4NCHNC6H4Me-p) shows activity against the Yoshida ascites sarcoma and the T8 sarcoma of Guerin.39 This complex reacts with 9-ethylguanine (9-EtGh) giving the complex [Rh2(form)2{9-EtGH}2](CF3COO)2 containing two 9-ethylguanine bridging ligands coordinated via O- and N7-atoms.40 The complexes [Rh2(RCOO)2(N-N)2L2](RCOO)2 and [Rh2Cl2(RCOO)2(N-N)2] (R = H, Me, Et, n-Pr, n-Bu, Ph, PhCHOH, MeCHOH, N-N = 2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthro-line, 4,7-diphenyl-1,10-phenanthroline) (Figure 20.1b) constitute another group of rhodium(II) complexes showing interesting biological activities.41 47 They are effective against the human carcinoma KB cell line,41,42 against bacteria43 45 and against the alga Chlorella vulgaris.46 Efficient cytostatic agents against the KB carcinoma, Hul703 (bladder cancer), SW707 (colon adenocarcinoma) and T47D (breast cancer) are acetato complexes containing bridging orthometallated meth-oxyphenylphosphine ligands:48 [Rh2(OAc)2{m-P(C6H3OMe-3)(C6H4OMe-3)2}2 (HOOCMe)(H2O)],48 [Rh2(OAc)3{m-P(C6H4O-2)(C6H4OMe-2)2}(HOOCMe)] and [Rh2(OAc)3{m-P(C6H3(OMe-6)O-2)(C6H3(OMe)2-2,6)2}(HOOCMe)] (Figure 20.2).49 Other acetato mono-orthometallated and di-orthometallated complexes, [Rh2(OAc)3{m-P(C6H3(OMe-3)(C6H4OMe-3)2}(HOOCMe)2], [Rh2(OAc)3 {m-P(C6H3OMe-4)(C6H4OMe-4)2}(HOOCMe)2] and [Rh2(OAc)3{m-P(C6H3SO3 Na-3) (C6H4SO3Na-3)2}(HOOCMe)2], exhibit lower anti-tumor activity or are biologically inactive. Thus cytostatic activity of these complexes strongly depends on structure and properties of the phosphine-bridging ligand.

CO N

C Me

Figure 20.2 Structure of [Rh2(OAc)2{m-P(C6H3OMe-3)(C6H4OMe-3)2}2(HOOCMe) (H2O)] (Rh-Rh: 2.4913(18)A)48 and [Rh2(OAc)3{m-P(C6H4O-2)(C6H4OMe-2)2}(NCMe)] (Rh-Rh: 2.421(1)A)49

CO N

C Me

Figure 20.2 Structure of [Rh2(OAc)2{m-P(C6H3OMe-3)(C6H4OMe-3)2}2(HOOCMe) (H2O)] (Rh-Rh: 2.4913(18)A)48 and [Rh2(OAc)3{m-P(C6H4O-2)(C6H4OMe-2)2}(NCMe)] (Rh-Rh: 2.421(1)A)49

Rhodium binuclear complexes can very easily coordinate ligands along the Rh-Rh axis. However, the substitution of equatorial carboxylato ligands is much more difficult. Thus, [Rh2(OOCR)4] complexes form labile axial adducts with N- and O-donors. Substitution of bridging RCOO ligands by other ligands including amino acids also occurs but this reaction is considerably slower, especially in the presence of strong acids.50 Thus, anti-tumor activity can follow both from formation of adducts with ligands coordinated in axial positions and coordination of ligands in equatorial coordination sites. The sulfhydryl (SH) compounds such as cysteine and glutathione can react to liberate carboxylate ligands and bind irreversibly to the rhodium.28 Rhodium(II) carboxylates in vivo inhibit synthesis of DNA, but minimal inhibition of RNA synthesis has been observed.25,27

Investigations of the influence of rhodium(II) carboxylates on the activity of enzymes revealed that all those having SH groups in or near their active site were irreversibly inhibited, while the enzymes without SH essential groups were not affected. The reaction of rhodium(II) carboxylates with enzymes containing SH groups closely parallels the toxicity and anti-tumor activity of these com-plexes.28 The rhodium(II) carboxylates bind to a variety of proteins and irreversibly inhibit those with cysteines in the active site. The mechanism of action of dirhodium(II) complexes can be similar to that of cisplatin. Recently, the ditolyl-formamidinato complex [Rh2{m-HC(NC6H4Me-4)2}2(9-EtGH)2(MeCN)][BF4]2 with bridging 9-ethylguanine ligands coordinated via O- and N7-atoms (head-to-head configuration) and the analogous 9-ethyladenine complex (head-to-tail configuration) have been prepared and structurally characterized40 (Figure 20.3). In the acetato complex containing 2,2'-bipyridine, 9-ethylguanine is coordinated as a terminal equatorial ligand51 (Figure 20.3).

Os N3CO

Os N3CO

Figure 20.3 Structure of [Rh2{m-HC(NC6H4Me-4)2}2(9-EtAH)2(MeCN)][BF4]2 (Rh-Rh: 2.510(3) A) and [Rh2(m-OOCMe)2(bpy)(9-EtGH)(H2O)2(O3SOMe)](O3SOMe)-H2O (Rh-Rh: 2.5112(7) A)

These complexes were prepared from dirhodium(II) complexes containing two or three bridging ligands. The structure and the Rh-Rh distances in these complexes suggest that compounds containing both bridging and terminal purine nucleotide ligands can be formed in vivo from [Rh2(OOCR)4] or other tetrabridged complexes. The complexes of this type can be responsible for the anti-tumor activity of the binuclear rhodium(II) complexes. These data indicate that dirhodium complexes can coordinate not only to guanine but also to adenine, while cisplatin forms bonds mainly with guanine. This was confirmed by a combination of matrix-assisted laser desorption ionization mass spectro-metry (MALDI MS) and enzymatic digestion experiments of Rh2(m-OOC-Me)2(TCTCTAATCTC) and Rh2(m-OOCMe)2(CCTCTGGTCTCC). It has been established that the Rh2(m-OOCMe)2 unit forms an adduct with AA and GG sites.52 In the presence of oxygen, the dimers [Rh2(m-OOCMe)2(bpy)2-(MeCN)2][BF4]2 and [Rh2(m-OOCMe)2(phen)2(MeCN)2][BF4]2 react with 2-aminothiophenol giving rhodium(III) octahedral complexes: [Rh{C6H4S (NH2)-N,S}{C6H4S(NH2)-S}2(phen)], ^{m-CaHSCNH^SMC^HSCNH:,) -S}2(bpy)2]2+ and [Rh{C6H4S(NH2)-N,S}2(bpy)].53 In the reaction of [Rh2(m-OOCMe)2(bpy)2(MeCN)2][BF4]2 with PhSH in the absence of O2, a new binuc-lear rhodium(II) complex with two bridging and two terminal C6H5S ligands is formed: [Rh2(m-C6H5S)2(C6H5S)2(bpy)2].54 Thus, sulfido ligands are capable of stabilizing Rh(II) complexes. However, the complexes [Rh2(m-OOCMe)2(N-N)2(H2O)2](CH3COO)2 in alcohols and water immediately react with SH compounds (glutathione, cysteine, coenzyme A) giving polynuclear complexes with (Rh2+)„ chains.55 Formation of complexes with rhodium in non-integral mean oxidation states +1.25, +1.33, +1.5 and +1.75 is also possible because [Rh2(u-OOCMe)2(N-N)2(H2O)2]2+ complexes, even in water-alcohol solutions, are readily reduced giving rhodium wires containing infinite chains of Rh-Rh bonds.56 59 Recently, the structure of the complex {[Rh4(m-OOCH)4(b-py)4](BF4)}n-0.5nC4H8O2 with a Rh5+ core has been determined. The mass spectra of [Rh2(m-OOCR)2(N-N)2(H2O)2](RCOO)2 in different alcohol matrices revealed their reduction to the di-, tetra-, hexa- and even octanuclear rhodium complexes in which the mean oxidation states of rhodium change in the range of 1.25-1.75. In solution, rhodium wires dissociate with the formation of mainly tetranuclear (and probably octanuclear) complexes. The latter have 30 and 31 d electrons and are isoelectronic with platinum blues60 which show promising antitumor activity.61 Thus, during the cellular reactions of [Rh2(m-OOCR)2(N-N)2(H2O)2]2+, species similar to the platinum blues can be probably formed. The binding of the [Rh2(m-OOCMe)4(H2O)2] and [Rh2(m-OOCMe)2(phen)2(H2O)2]2+ complexes to DNA has been investigated. The binding constants of these complexes to calf-thymus DNA were determined from electronic spectra recorded during titrations. The equilibrium constants are equal to 4.6 x 102M^1 and 1.7 x 104M^1 for [Rh2(m-OOCMe)4(H2O)2] and [Rh2(m-OOCMe)2(phen)2(H2O)2]2+, respectively.62 The electronic spectra indicate that DNA is coordinated in the axial coordination site immediately upon mixing. Both Rh(II) complexes inhibit transcription more effectively than cisplatin, plausibly owing to their binding to the enzyme T7-RNA polymerase.

Interaction of rhodium(II) complexes with HSA has also been investigated. The spectrophotometric titration of HSA with [Rh2(OOCR)4] has shown that albumin binds eight equivalents of rhodium dimer.32,47,63 65 The complex is bound to histydyl imidazole groups and is influencing the conformation of HSA.

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