Designing of Pt(II/IV) and Ru(II) Complexes of Bioactive Ligands: Approaches to Enhance Selectivity Towards Cancer

Maji, Moumita (2021) Designing of Pt(II/IV) and Ru(II) Complexes of Bioactive Ligands: Approaches to Enhance Selectivity Towards Cancer. PhD thesis, Indian Institute of Science Education and Research Kolkata.

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Cancer affects billion of people and the growing drug resistance make the treatment more difficult. Nitrogen mustard is the first successful chemotherapeutic agent against cancer. More than 70 years of research gave a broad range of therapeutically active nitrogen mustard compounds as an anticancer agent. It acts by covalent transfer of alkyl group, in the first step intramolecular displacement of the chloride by the amine group leading to the formation of aziridinium intermediate. This electrophilic aziridinium ion is attacked by the N7 of guanine of DNA nucleobase to form intrastrand and/or interstrand crosslinks. This process stops the DNA replication process, which leads to cellular death or apoptosis unless the DNA is repaired. However, the electrophilic aziridinium intermediate is very reactive in nature, so it also binds with DNA of healthy cells and other potential nucleophiles which leads to severe side effects. Thus, controlling the reactivity of nitrogen mustard is required to reduce the activity of the lone pair. Researchers have tried different approaches, one of which is the formation of prodrugs of nitrogen mustard. Metal complexation is also one of the ways to control the activity of nitrogen mustard and the basic idea is to use the lone pair of nitrogen mustard by direct coordination with the metal center or keeping the nitrogen mustard as a part of the ligand framework. Chapter 1 of the thesis starts with a brief introduction to the origin of nitrogen mustards, their mechanism of action, clinical side effects and the acquired resistance. Then follows the discussion on various adapted approaches to control the reactivity of the nitrogen mustards, viz. by conjugation of the nitro group, quaternary salt and metal complex formation. Briefly, certain essential aspects of the metal complex of nitrogen mustards discussed with emphasis on the stability, lone pair deactivation and cytotoxicity. The discussion then flows into other Pt(II) complexes and discusses how the target specificity could be improved. The discussion brings in the change of oxidation state of Pt(II) complexes to Pt(IV) to generate six-coordinate complexes with increased inertness and targeting ability by use of the two additional coordination sites. A brief discussion on the alteration in the mechanistic pathway due to such design changes is provided followed by a discussion on Ru complexes which are known to be the excellent candidates especially against certain Pt-resistant and metastatic cancers. The brief discussion on Ru complexes start with the Ru(III/II) complexes in clinical trials and flows to the Ru(II) half-sandwich complexes which are relevant to the thesis work. The discussions end with a section on hypoxia active complexes since it is related to certain work in this thesis pertaining to Ru(II) complexes. Besides, each chapter also provides a brief introduction of its own to match the relevance. The work of chapter 2 was originated from three earlier studies on Pt(II) nitrogen mustard complexes performed by Karmakar et al. from our laboratory. The work of Karmakar et al. suggested that Pt(II) nitrogen mustard complexes successfully deactivated the lone pair responsible for aziridinium formation and activity towards alkylation upon coordination of the same nitrogen to the Pt(II/IV). The reactivity in solution showed that the Pt(II/IV) complexes were less reactive to thiols compared to cisplatin or oxaliplatin. However, a drawback was their cytotoxicity towards both cancerous and normal healthy cell lines. One important point to note here was that the more stable Pt(IV) mustard complex showed less toxicity to mouse fibroblasts. Thus, I started with the objective of changing the leaving group by a chelating one to render higher stability in physiological pH of 7.4 and find out if that further reduced the cytotoxicity towards normal cells. The Pt(II) complexes were synthesized with the change of the leaving groups by oxalato and cyclobutanedicarboxylato. Herein, four new Pt(II) complexes (1-4) of two carrier ligands, bis(2-hydroxyethyl)pyridylmethylamine (L1) and bis(2-chloroethyl)pyridylmethylamine (L2) with oxalato and cyclobutanedicarboxylato leaving groups were synthesized. Among the four new complexes (1-4) the Pt(II) complex of L2 with oxalato leaving group (3, termed as, “oxamusplatin”) is cytotoxic. Oxamusplatin demonstrates better selectivity than oxaliplatin towards cancerous cells. It is more resistant than cisplatin or oxaliplatin towards hydrolysis, thiol binding and sequestration by ATP7B. It targets cellular DNA and can disrupt the microtubule network in the cytoskeleton and induces apoptosis by mitochondria-mediated pathway. The Chapter 3 of the thesis deals with the change of the bis(2-chloroethylamine) motif to chloroethylamine since this was known to happen for two existing clinical drugs (cyclophosphamide and ifosfamide) used against cancer. This chapter brings in Ru(II) halfsandwich complex. It compares the activity differences between the Pt(II) and Ru(II) while using the same bidentate ligand for both the Pt(II) and Ru(II) along with other necessary auxiliary ligands. Herein, we have synthesized two Ru(II) complexes having fromulations [RuII(L)(η⁶-p-cymene)Cl] (5-6) and two Pt(II) complexes having fromulations [PtII(L)(DMSO)Cl] (7-8), where L is a chelate imine ligand derived from chloroethylamine and salicylaldehyde (HL3) or o-vanillin (HL4). The complexes start forming the aquated complex within an hour. They bind to the N⁷ of the model nucleobase 9-ethylguanine (9-EtG). Interaction with Calf Thymus (CT) DNA shows moderate binding interactions. The complexes exhibit significant anti-proliferative activity against various cancer cells tested. The in vitro potency of all the complexes towards pancreatic cancer cell line MIA PaCa-2 are more than cisplatin (CDDP). The studies show that with the same ligand the Pt(II) complexes are more potent than the Ru(II) complexes. Moreover, the Pt(II) complexes also differ from the Ru(II) complexes in terms of mechanism of cell killing pathway. The literature studies during the work of chapter 2 and 3 led to knowledge on a metabolic by-product orotic acid (OA), which is mostly metabolized in the liver and can act as a chelating leaving group for Pt complexes. Thus, we have prepared OA conjugated Pt(II) complexes 9 and 10 from cisplatin and cis-[Pt(DACH)Cl₂] (DACH = transdiaminocyclohexane). 9 and 10 were then oxidized with H2O2 to obtained the Pt(IV) dihydroxido complexes (c,t,c-[PtIV(NH₃)₂(OH)₂(OA)] and c,t,c-[PtIV(DACH)(OH)₂(OA)]) respectively. The Pt(IV) dihydroxido complexes were then reacted with the anhydride of the axial ligands to form the corresponding acetate (9a & 10a) and dichloroacetate (DCA) derivates (9b & 10b). The DCA derivates (9b & 10b) show selective toxicity towards liver cancer (Hep G2 and Huh7) without affecting the growth of other cancer and normal cells. They show 8-9 times greater accumulation in Hep G2 compared to the breast cancer cells MDA-MB-231. The data suggest that OAT2 receptor may be responsible for their selective uptake inside the liver cancer specifically. The complexes are resistant to sequestration by cellular tripeptide glutathione and copper transporter ATP7B. Both the complexes induce apoptosis and arrest the The idea of hypoxia and the literature studies during this work suggested that carbonic anhydrase-IX a membrane-based enzyme that helps maintain the interstitial pH of the tumor cells may be a good target. Certain sulphonamides happened to inhibit this transmembrane enzyme. Thus, Chapter 5 of the thesis was initiated on certain sulphonamide ligand-based Ru(II) complexes. Herein, we have prepared five RuII-p-cymene complexes (11-15) of Schiff base ligands (L5-L8) containing the sulphonamide moiety. All the complexes are hydrolytically stable up to an observed period of 24 h except 11, which starts to hydrolyzed within 1 h. Among the five complexes, the imidazole derivates (11 & 12) are only cytotoxic. cell cycle in G2/M phase. They show lower toxicity towards the normal cells and better efficacy in cancer cells. The cellular accumulation data show increased accumulation of complex 11 & 12 compared to nontoxic 15. Both the complexes (11 & 12) bind with model nucleobase 9-ethylguanine, but they possess slower reactivity towards cellular tripeptide glutathione. They induce apoptosis, depolarize mitochondrial membrane potential and arrest the cell cycle in SubG1 phase.

Item Type: Thesis (PhD)
Additional Information: Supervisor: Prof. Arindam Mukherjee
Uncontrolled Keywords: Bioactive Ligands; Cancer; Nitrogen Mustard; Pt(II/IV) Complexes; Ru(II) Complexes
Subjects: Q Science > QD Chemistry
Divisions: Department of Chemical Sciences
Depositing User: IISER Kolkata Librarian
Date Deposited: 26 Oct 2021 10:10
Last Modified: 02 Dec 2021 06:04

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