Synthesis, Properties and Biological Activity of Organotitanium Substituted Heteropolytungstates

Six new compounds [(CpTi)X, Cp=ϋ∇-c∇H∇, X=Ge, Ga, B) have been prepared and their Keggin structures determined by elementary analysis, IR, UV, ∞H NMR and ∞∀∊WNMR spectrometry. The results show that the complexes retain Keggin structure. The complexes exhibit antitumoral activity in vitro as shown by MTT experiment.


INTRODUCTION
Our recent work involves studies in both the antitumoral activity and catalytic activity of substituted heteropolyorganometallic complexes. Polyoxometalates (POMs) have attracted much attention because of their potential applications in catalysis, medicine and material science I--l. Hill has pointed out that the versatility of the POMs and grafting organic and organometallic groups on to the polyoxometalate surface can significantly increase their catalytic or medical applications. POMs containing a [CpTi]group show high anti-HIV activity I41 but, to the best of our acknowledge, there is no report on the antitumoral activity of organotitanium substituted heteropoly complexes. As part of our continuing investigat!on of POMs containing organometallic groups, we have systematically synthesized the [CpTi]"substituted heteropolytungstates and investigated their antitumoral activity in vitro.
The title complexes [(CpTi)XWO39]" (X Ge, Ga, B) are attractive targets for three reasons" first, CpzTiCI2 is a more potent antiviral agent than other organotitanium compounds, but its insolubility in water makes it less useful in chemotherapy. So modifying Cp2TiCI2 into soluble complexes is a ve,'y attractive topic. Second, POMs containing titanium exhibit high antitumoral activity I5.61, so their investigation is very useful for determining the influence of the organometallic group on antitumoral or antiviral activity.

Antitumoral activiO,
The antitumoral activity of POMs on two types of the human cancer cells was tested by the MTT experiment as described in ref. [9].

Physical measurements
H NMR spectra were recorded on a Brucker AC-80 spectrometer. S3W NMR were recorded on a Unity-Jingfu Liu et al.
Synthesis, Properties and Biological Activity of Organotitanium Substituted Heteropolytungstates 400 spectrometer. IR spectra were recorded on an Alpha Centauri FTIR spectrometer (4000-200cm range) as KBr pellets. UV spectra were recorded on a Beckman Du-8D spectrometer (solvent H20). Polarograms were obtained using a 384B polarographic analyser. W, Ti, Si, Ge were determined by a Leeman Corporation inductively coupled plasma (ICP) emission spectrograph. C, N, H were determined using a PE-2400 analyzer. Water content was determined by thermogravimetry. The IR spectra display a single, sharp absorption at 1469cm in the 1300-1500cm region. This feature is characteristic of the C-C stretch for a :rls-CH5 ligand bonded to Ti I01. At 3032, 3038cm in the 3030-3040cm region, the C-H stretches shows the existence ofrl-cyclopentadienyl ligand.

C6'mp0unds
The title anions absorb at ca. 200+2 nm and 260+2 nm. The first band at higher energy has been assigned to the Ob/-->W charge transfer band. The second band at lower energy is characteristic of 12heteropolytungstates and has been attributed to the O0->W charge-transfer band.

An'ions
Anions Table 2 The,, IR (cm") and UV(,nm) data of comp0unds, In the well-known T Keggin structure all the tungsten atoms are identical, as shown by a singlet in the 83W NMR spectra. imposed by Cs point symmetry, and the expected six lnes are obtmned m the W NMR spectra .The W NMR spectra of(CpTi)XWl confirm that the substituted [CpTi] 3+ group occupies an empty octahedral site of a XW anion and forms a polyanion with a Keggin structure.

Electrochemistry
The redox proprieties of (CpTi)XWI were investigated by polarography. The half-wave potentials in different pH values are listed in Table 4. It can be seen that: (1) The reduction process of (CpTi)XW anions involve the reduction of titanium and tungsten. The first peak is assigned to the conversion of Ti (IV) to Ti (III) t21. (2) The latter two polarographic peaks are assigned to the conversion of W (VI) to W (V), showing that the title anions undergo a two-step tungsten reduction process. They are pH-dependent reduction waves. And straight lines are obtained by logarithmic analysis of the polarographic wave. The number of electrons involve in the reduction can be calculated from the slope of the straight lines, showing that (CpTi)XWI has undergone a two-step, two-electron tungsten reduction. (3)E/2 shifts to negative potentials with increasing pH of the solution, implying that the reduction of polyanions is accompanied by protonation. From the slope of E/2 versus pH, it can be calculated that when n 2, m 2 (n and m stand for the electron and proton number, respectively) for the reduction of tungsten, two protons must be added to gain two electrons while the polyanion is reduced; this prevents charge build-up on the anion, which would otherwise be destabilized.

Antitumoral activity
The data summarized in Table 5 show that the title complexes display inhibitory action to two types of human cancer cells Hela and SSMC-7721 tumor cells.
3.6 The stability of the POMs at the physiological condition In order to assess the stability of the complexes, they were treated in the same MTT experimental conditions but without adding cancer cells. After evaporation to dryness, IR and H NMR spectra showed that the complexes retained the Keggin structure and the [CpTi] 3+ group was not eliminated from the XW moiety demonstrating that they are stable under the evaluation conditions.