Triphenyltin Ortho-Aminophenyl- and 2-Pyridyl-Thiolates: Synthesis and In Vitro Antitumour Activity

The synthesis, spectroscopic characterization and in vitro antitumour activity of two triorganotin compounds, triphenyltin ortho-aminophenylthiolate (1) and triphenyltin 2-pyridylthiolate, compound (2) are reported. The structure of 1 is confirmed by X-ray diffraction, with the tin atom in a distorted tetrahedral geometry because of monodentate coordination, as a thiolate (Sn-S 2.431(2) Å), of the ortho-aminophenylthiolate ligand. The in vitro antitumour activities of 1 and 2, against a number of cell lines, are comparable to those exhibited by methotrexate and doxorubicin, and higher than those of carboplatin and cisplatin.

Because triphenyltin compounds are usually more active than di-n-butyltin derivatives [2], the most active of the diorganotin compounds, we synthesized triphenyltin ortho-aminophenyl-and 2pyridyl-thiolates and screened their the antitumour properties in vitro.
X-ray structure of compound 1 Single crystals suitable for X-ray structure determination were obtained for compound 1, but a full analysis for compound 2 was not obtained (see Experimental). The molecular structure of 1, shown in Fig. 1, with the main interatomic parameters listed in the caption, is in agreement with a previous report [3]. The Sn atom exists in a distorted tetrahedral geometry defined by the three phenyl substituents and the S atom derived from a monodentate ortho-aminophenylthiolate ligand; Sn-S 2.431 (2) .N o evidence was found for a significant interaction between the Sn and N(1) atoms and this accounts for the relatively narrow range of angles about the Sn atom. The amino group forms two weak interactions with thoe S(1) atom, namely an intramolecular S(1)...H(lb) interaction of 2.58 . . (S(1)...N(1) is 3.o018(4) A) as well as an interrnolecular S(1)...H(la)' interaction of 2.84 (S(1)...N(1)' is 3.736(4) A., symmetry operation: x, 0.5-y, -0.5+z). It is of interest to -'nmpare this structure with that of the dimethylated analogue [Ph3Sn(SC6H4NMe2)] [4] for which Sn-S(1) is 2.429(1) ,&, and S(1)-C(2)is 1.774 (5) ,&, (cf. 1.776 (4) ,& in the present study). In the latter structure there is a close intramolecular Sn...N contact of 2.893(3) A which is responsible for the opening of a S(1)-Sn-C angle to 121.7(1) . Clearly, the orientation of the amino group away from the Sn atom in 1 occurs to facilitate the formation .of hydrogen bonding contacts, a situation that can not occur for the dimethylated analogueA full structure determination could not be achieved for2 because of crystal disorder. The analysis confirmed nevertheless the generation of the desired compound and showed that the triorganotin center is coordinated by the S atom, leading to a distorted tetrahedral geometry; a weak intramolecular interaction with the pyridine-N atom is evident.
Spectroscopic characterization of compounds I and 2 13 119 119 The compounds were characterized bylH, C, Sn NMR and Sn MSssbauer spectroscopy (see 13 Experimental Section). 13C assignments were achieved from the comparison of C{ H} standard and DEPT spectra as well as from aromatic chemical shift increment calculations [6].
For compound 1, somewhat lower 1J(13C-119/llFSn) coupling constants (558/533 Hz) are observed, but a quite different 119Sn chemical shift (-68.0 ppm). These NMR data confirm the data from the solid state that the intramolecular N-->Sn interaction is stronger in the 2-pyridylthiolate ) than in the orthoaminophenylthiolate.
(1). Thus in solution likewise both the low frequency shift of the 119Sn chemical 13 119/1 shift and the higher J( C-17Sn) coupling are indicative of a stronger distortion of the tetrahedral geometry towards five-coordination as a consequence of the weak N->Sn interaction. In contrast, the MSssbauer data, especially the very close QS values, do not discriminate between slight but significant differences in coordination spheres revealed by the NMR and X-ray data.
Antitumour activities of compounds 1 and 2 The in vitro antitumour activities of compounds 1 and 2 were determined against a panel of six human tumour cell lines, MCF-7 and EVSA-T, two breast cancers, WiDr, a colon cancer, IGROV, an ovarian cancer, M19 MEL, a melanoma, andA498, a renal cancer; the results are shown inTable 1.
M. Gielen The in vitro results show that the two compounds are as active or more active than methotrexate, and doxorubicin, and significantly more active than carboplatin, cisplatin and even 5-fluorouracil against all cell lines.

Syntheses
Compounds 1 and 2 were prepared by adding 5 mmole of triphenyltin hydroxide to a solution of 5 mmole of respectively ortho-aminothiophenol or 2-thiopyridine in 150 cm 3 toluene and 50 cm 3 ethanol. After refluxing for 6 h, distilling off the ternary azeotrope water/toluene/ethanol witll a Dean-Stark funnel and half of the remaining solvent, the resulting mixture was cooled down to room temperature, filtered and evaporated under vacuum. The residue was recrystallized from chloroform/n-hexane.

Characterization
MEssbauer data: QS: quadrupole splitting; IS: isomer shift; r'l and F2: line widths, all in mm/s. NMR data" all spectra were acquired from CDCl3 solutions and referenced to the residual C lHCI3 resonance at 7.24 ppm for the 1H spectrum, to the central 13CDCl3 resonance at 77.0 ppm for the 13C spectrum and to (119Sn) 37.290665 for the 119Sn spectra [5].
Abbreviations for coupling patterns: dd doublet of doublets; ddd doublet of doublets of doublets; m complex pattern; b broad; coupling constants are given in Hz in parentheses for nj(H-H) for H spectra. Other coupling constants are indicated explicitly. Calculated chemical shifts, using incremental rules [6], are given in parentheses.

Instruments
All NMR spectra were recorded on a Bruker AC250 instrument, using a QNP probe tuned at 250.13, 62.93 and 93.28 MHz for 1H, 13C and 119Sn nuclei, respectively. MEssbauer spectra were obtained as described previously [8]. The in vitro antitumour screenings were performed as described earlier [9].  [11] and refined by a full-matrix least squares procedure based on F [12]. Non-H atoms were refined with anisotropic thermal parameters and H atoms were included in the model at their calculated positions (N-H 0.95 ./x. and C-H 0.97 .&,). At convergence R 0.027 and Rw 0.030 (sigma weights); the maximum peak in the final difference map was 0.28 e-3. The molecular structure is represented in Fig. (drawn with ORTEP [13] at 35% probability ellipsoids). Supplementary material (fractional atomic coordinates, thermal parameters, all interatomic parameters and structure factor tables) are available on request from ERTT. 2: A total of five data sets for different samples of 2 were collected at both room temperature and at -70C, however, only unsatisfactory analyses were obtained. Whereas the gross structural were determined (R ca 12%), reliable geometric parameters were not; see text. Crystal data: monoclinic, space group Cc, a 17.179(5), b 15.256(1), c= 8.142 (5) ,/k, [ 109.55(2) , V= 2010(1) ,/,3, Z'-4.