Abstract

Scheme 2. 2 Proposed direct nucleophilic attack and solvotic pathways of associative substitution reaction of square planar complexes

3.0 Abstract

75 CHAPTER 3

Tuning the Reactivity of Palladium(II) Complexes of Pyrazolyl-based Terpyridyl Type of Ligands through Electronic and Steric effects. Crystal Structures

76 3.1 Introduction

Palladium is one of the metals belonging to the platinum group of metals, whose members include ruthenium, rhodium, osmium, iridium, and platinum which are characteristically square planar d⁸ complexes.¹ Platinum group metal complexes have increasingly shown great potential for anti-tumour activity making them useful in chemotherapy.^2-7 For example, Pt(II) complexes such as carboplatin, oxaliplatin and cisplatin have been used in chemotherapy for the treatment of ovarian and testicular cancer.^{2, 8-13} Some of these drugs have shown serious side effects such as nausea, vomiting, nephrotoxicity, neurotoxicity and ototoxicity among others^{11, 14-16} creating a continuous need for the search for alternative non-platinum drugs with high efficacy, less side effects and easy administration.

Pd(II) among other transition metals^17-24 are promising alternatives as some of them showed activity on tumours which had developed resistance to cisplatin or in which cisplatin was inactive.²⁵ Pd(II) complexes having antitumor activity have been demonstrated.^26-29 In general, the synthetic design of these Pd(II) antitumor agents follows the same strategies that have been used to design potential Pt(II) antitumor drugs.³⁰ Pt(II) and Pd(II) complexes are very similar in their chemical equilibrium and structural activities, their mechanistic and kinetic studies have so far indicated that Pd(II) complexes are 10³ –10⁵ more labile than Pt(II). ^{1, 31-34}

The use of Pd(II) complexes as an antitumour agent has been neglected because of the serious effects caused by rapid hydrolysis of the leaving groups (e.g., Cl^- ) in the cell medium, producing highly reactive species which hinders them from reaching their targeted DNA^{17, 35} This implies that Pd(II) complexes will undergo side reactions with biomolecules other than DNA and dissociate before reaching the DNA target. Another draw-back is that some of them undergo rapid cis–trans isomerism kinetics.^35-37 For instance, cispalladium complex (cis-[Pd(NH3)2Cl2]), an analogue of cisplatin complex (cis-[Pt(NH3)2Cl2]) do not show any antitumour activity, which

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is also similar for cis-[Pd(DACH)Cl2]; (DACH: (1R,2R)-(–)-1,2-diamine-cyclohexane). This is because the former undergoes cis-trans isomerization to form an inactive trans-conformer whose hydrolysis is very fast,^{30, 38} leading to in vivo interactions with other non-targeted biomolecules thus compromising their antitumor activity. Therefore, a good antitumor active Pd(II) complexes, should be stabilised by a strongly coordinated N-donor multidentate spectator ligands and a reasonably non-leaving group is required to enable the drug maintain its structure in vivo long enough so as to reach its DNA target and perform its therapeutic function.^{35, 39} Furthermore, the Pd(II) complexes can also be stabilized and side reactions prevented by introducing inert sterically hindered ligands into the Pd(II) complex coordination sphere. These structural modifications on the ligand framework can offer a thermodynamically stable and kinetically inert Pd(II) complexes with improved cytotoxic ability towards the cancer cells.2-5, 40, 41

It has been shown that the terpy ligand and its derivatives coordinated to Pd(II) and Pt(II) complexes affects the lability of their leaving group through electronic and steric effects as well as influence their interaction with bio-relevant nucleophiles and DNA fragments.⁴² The [Pt(terpy)Cl]⁺ and [Pd(terpy)Cl]⁺ complexes are known to be highly labile.^43-46 The high lability is attributed to the ability of terpy ligand to accept electrons from the metal leading to the stabilization of the five coordinate intermediate compared to ground state.^{47, 48} The lability was doubled when the ligand was modified to 2-(2’-pyridyl)-1,10-phenanthroline^{49, 50} due to extended π-conjugation as a result of the fused ring enhancing π-back bonding making the metal centre more electrophilic. However, the presence of substituents at the 4’-position of the terpyridyl system^{49, 51} and electron donating groups at 4, 4' and 4" positions lowers the rate of lability by diminishing the π-back bonding ability of the ligand.^{52, 53}

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Substitution reactions of Pd(II) complexes with tridentate N-donor ligands such as terpy, bpma [(2-pyridylmethyl)-amine], dien (diethylenetriamine), Me4-dien and Et4-dien, having varied steric and electronic effects, have provided good basic substrates for ligand exchange studies of square-planar d⁸ complexes13, 33, 34, 43-45, 49, 54-56 and DNA interaction.⁵⁷ For instance, van Eldik and his coworkers showed that the introduction of substituents such as ethyl and methyl on a tridentate R5dien chelate decreased the substitution rate of a series of [Pd(R5dien)Cl]⁺ complexes by several orders of magnitude without the steric hindrance introduced affecting the associative mechanistic nature across the series of the complexes.^58-62

The rate of substitution from Pt(II) complexes coordinated with tridentate N^N^N and N^C^N of a terpyridine ligand framework was decelerated when the cis-pyridyl rings were replacement with pyrazolyl and its derivatives due to the presence of the pyrrolic-N π-donor within the chelate ring.^{63, 64} The effect of the pyrazole ligand coordinated to Pd(II) complex, particularly on the cis-position to the leaving group remains unknown. Given the good π/σ-donor properties of pyrazole and in anticipation to control the highly reactive Pd metal from the already known labile [Pd(terp)Cl]⁺ complex as a reference, the role of cis-pyrazole is investigated. Therefore, the rate of substitution of the chloride ligand from the complexes in Figure 3.1 by bio-relevant thiourea nucleophiles, Tu, Dmtu and Tmtu, was measured using stopped-flow methods. The thiourea nucleophiles was used because of their high solubility, good nucleophilicity and appropriate model compounds representing thioether (σ-donor, π-acceptor) and thiolate (σ- donor) groups^65-67 in the human cell. Density function theory (DFT) calculations was performed to give insights into understanding the experimental reactivity trends. The X-ray crystal structures of PdL2, PdL3 and PdL4 are also reported.

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PdL1 PdL2 PdL3 PdL4 Figure 3. 1 Structures of the studied Pd(II) complexes (counter ions omitted to enable clarity)

3.2 Experimental Section