Tuning Reactivity of Platinum(II) Complexes
Tuning Reactivity of Platinum(II) Complexes Tuning Reactivity of Platinum(II) Complexes
finally Pt2. The order of reactivity is in agreement with that of pKa1 values, although observed differences in the rates of substitution are purely of steric hindrance origin. Additionally, the HOMO-LUMO energy gap is wider for Pt3 compared to Pt2, suggesting a larger energy barrier and a slower substitution reaction inPt3. However, the pyridyl linker is relatively weak and was released from the Pt(II) centre by thiourea and related stronger nucleophiles in the second step. The results of temperature-dependence measurements performed with the diaqua complexes support an associative mode of activation that is characteristic of square- planar Pt(II) complexes. Because of the overall effect of charge neutralisation the values of the entropies of activation for the reaction with anions (SCN ¯, Br ¯) are less negative than that of thiourea and its derivatives. In Chapter 7, the role of the α,ω-alkanediamine linker in controlling reactivity of Pt(II) complexes was investigated. In previous studies more attention has been focused on polynuclear trans Pt(II) complexes such as BBR3464 that have promising anti-tumour activity. These complexes have proven to lose the bridging ligand soon after reacting with strong sulphur nucleophiles like thiourea. Investigations with thiourea and substituted thiourea on cis complexes of the type [{cis–Pt(NH3)2(H2O)}2–μ– NH2(CH2)nNH2] +4 ( n = 2, 3, 4, 6, 8, 10), were performed to get detailed information on the characteristic properties of these complexes at pH 2.0. The results of this investigation show that each of the aqua dinuclear complexes exhibited a single pKa value. The pKa values obtained clearly demonstrate that the σ- donor capacity of the bridging ligand increases with the elongation of aliphatic chain, resulting in higher pKa values. This causes a reduction in the electrophilicity of the Pt(II) centre. This leads to the observed order of the second-order rate constants, k2-values, for the simultaneous substitution of the aqua ligands, which progressively decreases from EnPt to DecPt. The corresponding diaqua complexes analysed in this study exhibited two substitution steps during the reaction with thiourea and its substituted derivatives. 1H and 195Pt NMR spectroscopy was applied to study the reaction of chloro HexPt with thiourea. This confirmed that the second reaction step, after the substitution 5
of water ligands, was the release of NH3 ligand due to the trans-effect of the strong labilising Pt–S bond from the first substitution. This provided an additional indicator that α,ω-alkanediamine linker remained coordinated to the metal centres probably due to their cis geometry to the incoming thiourea nucleophiles. And the final product of substitution reactions is [{cis–Pt(TU)2NH3}2–µ–NH2(CH2)nNH2] +4 . The current results demonstrate that the cis-dinuclear Pt(II) complexes with α,ω- alkanediamine linker are promising compounds for anti-tumour active drugs as they show higher stability to strong S-donor nucleophiles that are present in human cells and play an important role in biological reactions. Even if these complexes exhibited high levels of stability against the strong nucleophiles, it is expected that in presence of large amounts of the nucleophiles, they will substitute all the ligands and eventually destroy the bridging system. In conclusion, the most striking feature of the present study is the fact that the heterocyclic amines: diazine- and dipyridine-bridged Pt(II) complexes were degraded and released the linker. Whilst the aliphatic amine linkers remained attached interact to the metal centres. Ordinarily the tendency of an electron donor to bind to metal ions decreases with decreasing basicity. Therefore, the aliphatic amine centres are strongly basic and may act as σ-electron donors, which provides the Pt(II) centres with excess electron charge density that prevents attack by excess nucleophiles at the metal centres. On the hand, one may notice that the diazine and pyridine ligands can engage in “synergic σ–/π–bonding”. This type of bonding should be less dependent on the availability of σ-electrons, but here the flux of electrons is primarily directed from the metal centre to the ligand. This enhances the electrophilicity of the Pt(II) centre, allowing direct attack by the nucleophiles and eventual disintegration of the complex to release the linker as is the case in the present investigation. A great of deal remains to be studied about the effect of bridging ligands on drug design and development and on reaction rates of multinuclear complexes. The main focus should involve drugs that comprise better: • transport through the membranes 6
- Page 376 and 377: H 3N NH 3 Pt NH 2 OH 2 n NH 3 NH 2
- Page 378 and 379: k obs2 , in s -1 -3 TU 1.2x10 DMTU
- Page 380 and 381: 7.3.4 Activation Parameters The tem
- Page 382 and 383: density is located on the metal cen
- Page 384 and 385: acetylmethionine, which reported th
- Page 386 and 387: References 1 (a) B. Rosenberg, L. V
- Page 388 and 389: 32 N. Summa, J. Maigut, R. Puchta a
- Page 390 and 391: Appendix 7 Table S7.1: Summary of s
- Page 392 and 393: k obs(2 nd ) , in s -1 0.00020 0.00
- Page 394 and 395: ln(k 2(2 nd ) /T) -8.5 -9.0 -9.5 -1
- Page 396 and 397: k obs(1 st ) , in s -1 0.06 TU DMTU
- Page 398 and 399: ln(k 2(1 st ) /T) -3.2 TU DMTU TMTU
- Page 400 and 401: Table S7.11: Summary of kobs(2 nd )
- Page 402 and 403: Table S7.13: Average observed rate
- Page 404 and 405: %T 22.0 20 18 16 14 12 10 8 6 4 2 0
- Page 406 and 407: k st obs(1 ) , in s-1 0.10 0.08 0.0
- Page 408 and 409: ln(k st 2(1 ) /T) -4.0 TU DMTU TMTU
- Page 410 and 411: Figure S7.23: Mass spectra for HexP
- Page 412 and 413: Table S21: Average observed rate co
- Page 414 and 415: Table S7.23: Summary of kobs(2 nd )
- Page 416 and 417: Table S7.25: Average observed rate
- Page 418 and 419: 90.0 80 70 60 50 40 30 20 %T 10 0 -
- Page 420 and 421: Figure S7.37: Mass spectrum for Hex
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<strong>of</strong> water ligands, was the release <strong>of</strong> NH3 ligand due to the trans-effect <strong>of</strong> the strong<br />
labilising Pt–S bond from the first substitution. This provided an additional indicator<br />
that α,ω-alkanediamine linker remained coordinated to the metal centres probably due<br />
to their cis geometry to the incoming thiourea nucleophiles. And the final product <strong>of</strong><br />
substitution reactions is [{cis–Pt(TU)2NH3}2–µ–NH2(CH2)nNH2] +4 .<br />
The current results demonstrate that the cis-dinuclear Pt(<strong>II</strong>) complexes with α,ω-<br />
alkanediamine linker are promising compounds for anti-tumour active drugs as they<br />
show higher stability to strong S-donor nucleophiles that are present in human cells and<br />
play an important role in biological reactions. Even if these complexes exhibited high<br />
levels <strong>of</strong> stability against the strong nucleophiles, it is expected that in presence <strong>of</strong> large<br />
amounts <strong>of</strong> the nucleophiles, they will substitute all the ligands and eventually destroy<br />
the bridging system.<br />
In conclusion, the most striking feature <strong>of</strong> the present study is the fact that the<br />
heterocyclic amines: diazine- and dipyridine-bridged Pt(<strong>II</strong>) complexes were degraded<br />
and released the linker. Whilst the aliphatic amine linkers remained attached interact to<br />
the metal centres. Ordinarily the tendency <strong>of</strong> an electron donor to bind to metal ions<br />
decreases with decreasing basicity. Therefore, the aliphatic amine centres are strongly<br />
basic and may act as σ-electron donors, which provides the Pt(<strong>II</strong>) centres with excess<br />
electron charge density that prevents attack by excess nucleophiles at the metal centres.<br />
On the hand, one may notice that the diazine and pyridine ligands can engage in<br />
“synergic σ–/π–bonding”. This type <strong>of</strong> bonding should be less dependent on the<br />
availability <strong>of</strong> σ-electrons, but here the flux <strong>of</strong> electrons is primarily directed from the<br />
metal centre to the ligand. This enhances the electrophilicity <strong>of</strong> the Pt(<strong>II</strong>) centre,<br />
allowing direct attack by the nucleophiles and eventual disintegration <strong>of</strong> the complex to<br />
release the linker as is the case in the present investigation.<br />
A great <strong>of</strong> deal remains to be studied about the effect <strong>of</strong> bridging ligands on drug design<br />
and development and on reaction rates <strong>of</strong> multinuclear complexes. The main focus<br />
should involve drugs that comprise better:<br />
• transport through the membranes<br />
6
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