• Background and rationale
Organometallic complexes are widely investigated in medicinal and pharmaceutical frameworks. Most studies on the biological activities of platinum, ruthenium, and iridium complexes have been useful in chemotherapy. One is the treatment of cancer, a major public health problem. It has been shown that cisplatin, cis-Pt(NH3)2Cl2, and other molecules in the platin family are effective anticancer drugs (Lyngdoh et al., 2019; Ronconi et al., 2008). However, Pt(II) in the platin family causes side effects to normal cells, including leukopenia, anemia, hepatotoxicity, cardiotoxicity, vomiting, diarrhea, stomatitis, and pain (Oun et al., 2018), etc.
Organometallic ruthenium and iridium compounds have been widely studied because they have some properties like various oxidation states, redox properties, various coordination numbers, and structural geometries modulated by coordinating ligands similar to platinum complexes. Ruthenium and iridium complexes are bringing forth a new generation of antitumor metallodrugs. Hence, there is an effort to synthesize other new complexes that are effective but with low toxicity to normal cells. Many works reported that ruthenium(II) and iridium(III) based metal complexes are promising anticancer agents with a greater extent of efficiency and negligible toxicity than that of cisplatin (Hearn et al., 2013; Kar et al., 2020; Lin et al., 2018; Pluim et al.).
Ruthenium(II)/(III) and Iridium(III) are interesting choices because of their low toxicity (Luck et al., 2012; Parveen et al., 2019). Ruthenium(II) behaves as iron mimicking which can bind to transferrin or albumin. Since transferrin is the primitive iron-binding protein, transferrin carries iron to our body tissues. Hemoglobin contains iron, an important protein in red blood cells which carries oxygen through the body to function normally; thereby, Ru(II) complexes reduce its toxicity. Besides, Ru(II) has ligand exchange kinetics similar to Pt(II) complexes which are important to their biological activity. The chloro ligands are labile for cisplatin, leading to DNA binding, causing damage that prevents protein synthesis and replication. That makes the cancer cell death.
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Some important Ru(II) and Ru(III) complexes exhibit cytotoxicity against cancer cells. Many Ru(II)/(III) complexes with several types of ligands, for example, amine (Gorle et al., 2014; Motswainyana et al., 2015), dimethylsulfoxide (Alagesan et al., 2014; Elsayed et al., 2020), imine (Chow et al., 2014; Lee et al., 2020), N- heterocyclic and polyaminopolycarboxylate (Adeniyi et al., 2016; Lee et al., 2020) ligands, have been reported to bind with DNA. The [trans-RuCl4(DMSO)Im][ImH], NAMI-A (Bergamo et al., 2000) is known as the most successful ruthenium-based anticancer compound without causing toxicity to normal cells (Huxham et al., 2003) and was approved for use in clinical trials. At present, Ru(II)-arene complexes are widely investigated. Some important complexes are RAPTA-C; [Ru(η6-arene)Cl2(pta)]
(PTA = 1,3,5-triaza-7-phosphaadamantane) (Chelopo et al., 2013). RAPTA-C displays effective inhibition of cancer cell growth by apoptosis (Babak et al., 2015; Chatterjee et al., 2008; Murray et al., 2016). It has been the prototype of other organometallic half- sandwich compounds, a potential anticancer agent for clinical application. RAPTA derivatives (RAPTA-T and RARTA-B; (Chelopo et al., 2013) containing two chloride ligands were susceptible to hydrolysis in a low chloride environment. The structure modification has been done by changing the PTA ancillary ligand to other types of ligands like O-donor (Rahman et al., 2018; Ude et al., 2016), N-donor (Clavel et al., 2015; Su et al., 2013), S-donor (Beckford et al., 2011; Rohini et al., 2018), and P- donor (Frik et al., 2014; Parveen et al., 2017) ligands.Apart from the benefit of cancer treatment, some ruthenium complexes are the active compounds in the anti-growth of bacteria, fungi, and viruses (Beckford et al., 2011; Dkhar et al., 2020; Karki et al., 2014) as well.
For decades, iridium(III) complexes have been studied for their stability (Jian et al., 2011; Lee et al., 2009; Tsuboyama et al., 2003), prospective luminous properties (Lin et al., 2011; Lowry et al., 2004; Tamayo et al., 2003), and therapeutic capabilities, particularly anticancer drugs (Hearn et al., 2018; Rubio et al., 2020; Xiao et al., 2018).
A variety of complexes containing iridium(III) or (IV) ions as the metal center has been extensively investigated; the complexes have a wide range of prospective applications owing to their biological activity (Pérez-Arnaiz et al., 2018), capability as photoactive compounds in LEDs (Chi et al., 2010) and their sensing units in optical
3 and/or electroanalytical sensors (Wang et al., 2017). Phosphorescent iridium(III) complexes can attain a high quantum efficiency, which brings to the promising materials for light-emitting diodes. (You et al., 2009) Cyclometalated iridium(III) complexes with 2-phenylpyridine and other auxiliary groups typically have a distorted octahedral molecular geometry (Chao et al., 2017; Liu et al., 2017). The strong spin- orbit coupling in iridium(III) complexes is the lowest triplet excited states population with a long luminescence lifetime, large Stokes shifts, and a high quantum efficiency.
(Ma et al., 2017) Many cyclometalated iridium(III) complexes have been investigated for their anticancer activities (Du et al., 2019; Song et al., 2017; Xiao et al., 2018; Yang et al., 2019) regarding the hydrolysis mechanism on a chloride ligand created a monohydrated complex. Then, it reacts with DNA. (Bacac et al., 2004) Iridium(III) complexes predominantly target apoptosis leading to cancer cell death (Hearn et al., 2013). Generally, the iridium(III) complexes that were studied possess chelating ligands. The intercalation or penetration to cancer cells has been usually observed (Carrasco et al., 2020; Geldmacher et al., 2012; Mukhopadhyay et al., 2015; Ng et al., 2008). Bis-complexes are often designed with an octahedral geometry as the primary backbone, and varied their ancillary ligands. Because of the strong interaction of borderline acid metal and primary ligand, the majority of them are N-donor ligands (Chi et al., 2010; Goldsmith et al., 2005; Lin et al., 2011). However, P^P-donor ancillary ligands have been rarely studied (Hao et al., 2019; Li et al., 2018; Liu et al., 2019).
As explained earlier, the phosphine derivatives (Biancalana et al., 2017), especially in the RAPTA family, have been qualified to inhibit breast cancer cells' growth. Diphosphine derivatives have also been proved to be effective ligands in the design of anticancer agents for over a decade (Herry et al., 2019; Li et al., 2018).
Mostly, ruthenium(II) and iridium(III) complexes with bidentate PP binding mode give mononuclear structures. Just a few P^P ligands present bimetallic Ru(II) complexes (Herry et al., 2019). Nevertheless, reports on the geometries and antiproliferative activity of the cancer cell growth of ruthenium(II) and iridium(III) complexes with monodentate binding mode of diphosphine ligands have not been presented to date. From the literature review, the [(ɳ6-p-cymene)Ru(P^P)Cl]PF6
complex, in which P is 2,20-bis-(diphenylphosphino)-1,10-binaphthyl (BINAP), shows
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high anticancer activity against A549 and HeLa cells, up to 15 and 7.5 times than that of cisplatin (Karakaş et al., 2018; Li et al., 2018), Half-sandwich of Ru(II)-arene complexes [CpRu(PPh3)2Cl] also exhibit antimicrobial properties (Lyngdoh et al., 2019). Complexes containing monodentate P-donor ligands CpRu(PPh3)-(CO)SR (R = 2-mercapto benzimidazolyl (a), 2-mercaptobenzothiazolyl (b), and 2- mercaptobenzoxazolyl (c)) have been shown to inhibit microbial growth (bacteria and fungi) (El-khateeb, 2001), but there are no reports on diphosphine derivatives.
In this thesis dissertation, Synthesis of the three distorted tetrahedral of piano stool half-sandwich p-cymene-ruthenium(II) (1-3) and four octahedral bis-complexes of iridium(III) metal center (4-7) was reported. The main ancillary ligands are different P^P diphosphine derivatives of dppm, dppp, dpppe, and dppbe. The Ru(II) complexes are [Ru2(p-cymene)2(dppp)Cl4] (1), [Ru2(p-cymene)2(dpppe)Cl4] (2), and [Ru2(p- cymene)(dppbe) Cl4] (3) while the iridium(III) complexes are three monomeric complexes of Ir(ppy)2(L1)Cl (4) and [Ir(ppy)2(L5,7)]Cl (5, 7) and a dimeric structure of Ir2(ppy)4(L4)Cl2 (6) where L4 = bis-(diphenylphosphino)methane (dppm), L5 = bis- (diphenylphosphino)propane (dppp), L6 = bis-(diphenylphosphino)pentane (dpppe) and L7 = bis-(diphenylphosphino)benzene (dppbe). Their geometries were studied by single crystal X-ray diffraction and spectroscopic data. Density functional theory (DFT) and time-dependent density functional theory (TD-DFT) were used to explain the electronic transitions of studied complexes. The inhibition on 3 human breast cancer cells growth and their antimicrobial activity were explored. Luminescence property of iridium(III) complexes were also reported.
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Figure 1 The structure of Ru(II) and Ir(III) complexes studied in this work Objectives
• To synthesize and characterize the ruthenium (II) and iridium (III) complexes based on diphosphine derivatives.
• To study photophysical properties, theoretical calculation, and applications in biological activities of the studied complexes.
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