106 Metal-Based Chemotherapy Drugs Kaitlyn Kasemodel Rogers State University, School of Arts and Sciences, Department of Mathematics and Physical Sciences, Claremore OK 74017 Katarzyna Roberts Rogers State University, School of Arts and Sciences, Department of Mathematics and Physical Sciences, Claremore OK 74017

Abstract: Metal-based compounds have been used to treat disease since as early as the 5th and 4th century B.C. Cisplatin, a -based chemotherapy drug, was one of the first metal-based compounds found to treat cancer. Other platinum drugs such as oxaliplatin and carboplatin have been the backbone of metal-based cancer treatment drugs as well. The potential therapeutic benefits of metal complexes, in particular, transition metals, has gained attention due to exhibiting unique characteristics including their capability to go through a redox reaction. Due to limitations like drug resistance and worsening side effects, ruthenium compounds have been developed that caused less severe and fewer side effects. complexes have been found to exhibit cytotoxic properties with distinct mechanisms of actions and even have the ability to competitively bind to sites occupied by different metals. It has been suggested that complexes have the potential to possess antitumor properties if cisplatin cannot be used as a form of treatment. complexes are another potential type of chemotherapeutic drug, found to exhibit greater selectivity against cancer cells and display better cytotoxic action than cisplatin with comparably low toxicity. The potential for metal-based chemotherapy drugs is continually expanding, and more research should be carried out in order to learn all of the benefits these unique drugs have to offer the world.

Introduction , which perform crucial roles in the natural functioning of organisms. Transition metals “Everything is poisonous, and nothing including , copper, and , among is harmless. The dose (amount) alone other transition metals, are involved in several defines whether something isn’t poison” biological mechanisms, from structural roles to Paracelsus, 1493-1541. catalysis to electron transfer, and are regularly associated with the active sites of enzymes. There is currently a broad scope of anticancer Dysregulation of several of these metals during agents that targets numerous biological and regular biochemical processes has been involved cellular characteristics across multiple tumor with the incidence of numerous pathological types. The evolution of anticancer drugs has disorders, including cancer. These cellular shifted away from traditional cytotoxicity and activities only need small, tightly regulated in the direction of selective agents which act amounts of “trace metals.” In comparison, other on particular cellular targets. Nonetheless, metals including , , , considerable challenges linger, and the link and are not as advantageous because between chemistry and structural biology those metals generate a broad range of severe may supply the most productive method for toxic side effects, such as carcinogenesis (Arita improving upon and discovering anticancer and Costa, 2009, Rahman and Singh, 2019). agents. Throughout history, numerous metal- In nature, numerous biological systems containing compounds have been used to treat a utilize metal ions, for instance, copper and broad array of disorders. In medicinal chemistry, Proc. Okla. Acad. Sci. 99: pp 106 - 113 (2019) Metal-Based Chemotherapy Drugs 107 which has generally been influenced by organic reactions (Haas and Franz, 2009). Due to these chemistry, metal-containing compounds properties of metals, the potential therapeutic have acquired favor as anticancer agents and use of medicinal inorganic chemistry in the diagnostic tools. The study of metal-containing construction of anticancer agents has recently anticancer agents began with the accidental gained significant interest. discovery of the anticancer properties of cisplatin, cis-[PtII(NH3)2Cl2]. The clinical use Throughout ancient history, metals have of cisplatin is limited as a result of resistance been used in various medical treatments. The along with a confined spectrum of activity earliest written account of metals being used for and dose-dependent toxicity. Because of these medical treatment dates back to 1500 BC when limitations, there has been an exploration for Ebers Papyrus wrote about how iron could be platinum-based complexes that demonstrate a used to treat anemia and how Copper could be wider spectrum of activity, higher selectivity, used to decrease inflammation (Dabrowiak, and lower toxicity; cisplatin and carboplatin 2012). Metals have the ability to treat cancer by emerged because of this research. Nonetheless, being able to collaborate precisely with DNA along with various platinum analogs, several and to specifically attack cancer cells. Since other metal compounds consisting of metal the phosphate backbone of DNA is negatively ions, for instance, copper chelating agents, charged, the positive charge of almost all metals gold, silver, copper(II), and zinc(II) have gained gives metals the ability to interact with DNA. abundant attention as possible anticancer agents. A number of drugs manufactured that contain In addition, the analysis of ruthenium-containing metals communicate precisely with separate complexes in clinical trials vouches for the vast metals that are already available at the protein potential of using non-platinum metal-based active sites. Other drugs developed have the complexes for cancer treatment (Dabrowiak ability to make metals communicate with amino 2012, Franklin and Costello 2009, Ajmal 2017). acids that have the largest reduction potential. This review examines the function of chosen Even though metals have been used since metals in biological mechanisms within cells as ancient times, the full potential of metal-based they relate to malignancy as well as feature the chemotherapy drugs was not realized until the medical uses of those metals and their structures discovery of cisplatin during the 1960s. It is well in the development and design of metallodrugs known that the existence of metals in cellular for cancer treatment. conditions is a heavily regulated process, Exceptional Features of Metal-Based therefore precise doses of drugs containing Complexes and Metal Ions metals need to be established in order to attain an optimum therapeutic response. If precise Medicinal inorganic chemistry is a promising administrations of metal-containing drugs are and constantly evolving field that involves not established, then a deficiency or excess of several processes including, but not limited to, metals could develop undesirable toxicity. the introduction (or expulsion) of an ionic metal into (or out of) an organism in order to diagnose In comparison to conventional carbon-based or to provide therapeutic effects. Because compounds, metal-containing compounds metals have the ability to become cations when present several benefits in the expansion of submerged in aqueous solution and bond to modern medicinal compounds. These benefits biological molecules with a negative charge, exist because of the metal-containing compounds charge manipulation can be achieved contingent capability to integrate ligands within a three- upon the coordination environment influencing dimensional configuration, which allows the the production of a cationic, ionic, or neutral functionalization of groups which can be tailor- biological molecule. Furthermore, metal ions made to carefully defined molecular targets displaying high electron affinity have the (Frezza et al., 2010). Metal-based compounds capability to polarize groups coordinated with present a well-supplied environment to assemble them, which allows the production of hydrolysis a wide range of specific molecular structures Proc. Okla. Acad. Sci. 99: pp 106 - 113 (2019) 108 K. Kasemodel and K. Roberts which deliberate an ample range of geometries cervical and ovarian cancers, and is often and coordination numbers, including kinetic employed in combination regimens (Kelland, properties, which could not be accomplished with 2007). The widespread clinical use of cisplatin traditional carbon-based compounds (Frezza et has been impeded by the presence of acquired al., 2010). Fascinating electronic features that and intrinsic resistance and increased toxicity. have the ability to act as applicable probes in In order to overcome these problems, there have the composition of anticancer agents are due to been 2nd and 3rd generation platinum drugs the partly filled d orbitals that occur in metals. developed, mainly oxaliplatin and carboplatin, When looking at the design of coordination which have the ability to maintain a much more compounds, it is essential to recognize the controllable toxicity profile (Alama et al., 2009). oxidation state of a metal due to the fact that Oxaliplatin has been clinically authorized as a it grants participation in the biological redox treatment for colorectal cancer, which has shown chemistry and has a significant function in the to be resistant to cisplatin, while carboplatin has optimum dosage and the bioavailability of agent been shown to be an effective treatment for head distribution. In addition, the capacity of metals and neck, lung, and ovarian carcinoma cancers to participate in ligand-exchanged reactions (Frezza et al., 2010). proposes endless opportunities for coordination and interaction to occur between metals and One of the main reasons platinum-based biological molecules, exhibited by the broad compounds have such a practical antitumor medicinal use of cisplatin. When constructing effect has to do with the platinum-based metal-based drugs, one is not confined to compounds ligand exchange kinetics. The choosing only certain metals; advantage ligand exchange behavior of platinum-based can be taken of the special characteristics of compounds is moderately slow, even though nonessential metals, along with other first and the platinum-ligand bond presents comparable second-row transition metals, including metals thermodynamic ability and is considerably that are not found naturally (Haas and Franz, weaker than classic coordination bonds, like C-O, 2009). Most momentous is the composition of C-N, or C-C double and single bonds. Due to the radiopharmaceuticals which have the ability ligand exchange behavior being rather slow, this to employ the radioactive features of metals gives platinum-based compounds a lofty kinetic and are frequently operated within diagnosing stability and grants exceptionally prolonged cancer and separate medicinal treatments. ligand exchange reactions to the point where it Platinum-based analogs in chemotherapy can take minutes to days to complete instead of seconds (Reedijk, 2003). In addition, regarding The history of the first metal-based Pt(II) compounds, ligands that are located in the chemotherapy drug begins not in 1965 as many trans arrangement are substituted much more people believe, but in 1844, during which time quickly than ligands in the cis arrangement, it was originally developed by Michele Peyrone which plays an important part in the antitumor and known as Peyone’s chloride (Wheate and efficiency of these compounds(Frezza et al., Apps, 2015). The extraordinary breakthrough 2010). Cisplatin is known to go through ligand was made in 1965 was by Barnett Rosenberg, substitution reactions and rarely expands its a biophysical chemist, when he accidentally coordination number. Through active or passive discovered cisplatin could be used as a treatment transport, cisplatin is absorbed through cells and for cancer. The discovery of the therapeutic use its chloride ions will be replaced with molecules of cisplatin in cancer therapy encouraged efforts of water prior to interacting with DNA, thus to explore non-platinum and additional platinum making coordinative bonds to the nitrogen atoms metal-containing compounds that could in DNA (Fuertes et al., 2003). The resulting potentially be employed in cancer treatment. elevated chloride ion concentration in blood Cisplatin has been broadly utilized to treat an plasma allows cisplatin to be stable regarding assortment of tumors including testicular, non- hydrolysis, but the lower concentration of small cell lung carcinoma, head, and neck, intracellular chloride facilitates accelerated Proc. Okla. Acad. Sci. 99: pp 106 - 113 (2019) Metal-Based Chemotherapy Drugs 109 hydrolysis toward the activated cationic of innovative platinum-based coordination molecule that can bind DNA (Pizarro and compounds attention to oral administration Sadler, 2009). It has been found that carboplatin were low bioavailability and poor solubility of has a much more advantageous pharmacokinetic clinically accepted platinum compounds (Frezza profile due to its delayed conversion rate to the et al., 2013). While platinum(II) chemistry reactive species of carboplatin (Frezza et al., depends upon ligand exchange reactions, 2010). Carboplatin has a similar mechanism of platinum(IV) has octahedral geometry that offers actions when compared to cisplatin, therefore two excess ligand locations and the elevated problems remain when carboplatin is used kinetic inertness of platinum(IV) diminishes to treat tumors that are resistant to cisplatin. reactivity, which then has the ability to diminish Replacing the chloride group located on off-target effects (Hall et al., 2007). Most cisplatin by the cyclobutanedicarboxylate ligand evidence indicates platinum(IV) complexes located on carboplatin provides better stability are decreased in vivo to form platinum(II), and adequate aqueous solubility (Frezza et al., which is the compound that is accountable for 2010). This then induces decreasing side effects, its stimulation and can be treated as a pro-drug while maintaining a comparable degree of cross- (Frezza et al., 2010). Satraplatin, an octahedral resistance towards cisplatin and clinical activity. platinum(IV) compound that is given orally and is in progressive clinical stages for the medicinal At the time platinum-based compounds therapy of hormone refractory prostate cancer, is bind to cells in the body, miscellaneous signal the most distinguished example originating from transduction pathways undergo activation, this group (Frezza et al., 2010). Platinum(IV) which then acts to intervene with various compounds demonstrate benefits due to their cellular processes including DNA replication bioreductive activation and greater stability, and transcription, thereby causing apoptotic cell hence letting a large amount of drug to arrive at death. In comparison to cisplatin and carboplatin, its biological target. It has been shown that the the hefty diaminocyclohexane (DACH) carrier anti-tumor action of satraplatin works similarly ligand located on oxaliplatin has been thought to cisplatin due to the development of inter and to grant lower cross-resistance and a better intrastrand DNA cross-links (Choy et al., 2008). toxicity profile (Frezza et al., 2010). In 2002 the FDA approved oxaliplatin, often combined Powerful strides have been made regarding with chemotherapy, for treating advanced colon the field of platinum-based chemotherapy cancer. drugs, especially concerning mechanistic comprehension of these drug’s pharmacological Throughout the years, research into platinum- effects and design strategies. Advancing based medicine has been heavily influenced by our current knowledge of platinum-based the medicinal use of carboplatin, cisplatin, and compounds, including resistance mechanisms, recently oxaliplatin. Researchers have been tumor uptake, and structure-activity-relationship conducting innovative methods with the goal (SAR) can assist the progress of the medicinal of creating the next era of platinum-based installation of the next era of platinum-based drugs due to continual issues with resistant chemotherapy compounds. and toxicity in current platinum-based drugs. Zinc The fundamental information learned from platinum(II) compounds, along with resistance Zinc is known as a crucial trace element mechanisms and cellular processing, harnessed performs an integral function in a broad scope with an enhanced insight towards mechanisms of cellular processes especially with regards to of action might assist in translating the upcoming protection against free radicals, cell proliferation, generation of platinum-based medicinal and differentiation. Zinc operates as a crucial compounds into clinical practice. anatomical element in several enzymes and proteins, including DNA repair enzymes, Two big concerns that started the pursuit cellular signaling proteins, and transcription Proc. Okla. Acad. Sci. 99: pp 106 - 113 (2019) 110 K. Kasemodel and K. Roberts factors (Roohani et al., 2013). as a cofactor for redox reactions. In order to avoid unneeded binding to biomolecules, ensure It has been found that zinc performs a distribution and proper uptake, the procurement crucial function in regulating apoptosis within and dispersion of copper is a highly controlled mammalian cells, although it is not completely process. Notably, the coordination chemistry understood how it does this. In several cell types, associated with copper is usually distinct including ovarian epithelial cells, glial cells, dependent on its oxidation state: Cu+ displays prostate epithelial, and other cells, zinc has been favoritism towards sulfur donor ligands, for shown to activate apoptosis, while in Hela cells, example, methionine or cysteine, while Cu2+ macrophages, renal cells, lung epithelial cells, exhibits a preference for nitrogen donors, for and breast cells, zinc has been shown to have instance, histidine or oxygen donors including antiapoptotic effects (Franklin and Costello, aspartate or glutamate (Frezza et al., 2010). 2009). These conflicting developments have been subjected to extreme investigation and still, The relationship between copper and remain unanswered. carcinogenesis has been intensely investigated over the past two decades. The reason for this Since zinc plays a crucial role in countless was because it was discovered that tumor- biochemical systems, it is unsurprising that bearing humans and mice possess altered copper altered amounts of zinc are correlated with levels; studies found that elevated tissue and systemic anomalies, including the incidence serum levels of copper were present in several of cancer. Even though it has been found that human tumors including brain, lung, colon, concentrations of zinc are compromised in prostate, and breast, in comparison to healthy patients suffering from cancer in comparison to individuals (Frezza et al., 2010). The reason for healthy patients, the relation between zinc levels the elevated levels of copper has not yet been and tumor developments lacks recognizable fully understood and no conclusions have been conclusions and depends on the type of tumor made. (Frezza et al., 2010). Patients suffering from prostate, digestive tract, gallbladder, or liver The idea of antiangiogenic therapy utilizing cancer have been found to have reduced zinc copper chelators in the treatment of cancer levels, while patients suffering from breast has received abundant attention because of cancer exhibited elevated and decreased levels the discoveries concerning the significance of of zinc in malignant tissues and serum (Frezza copper and angiogenesis in tumor development et al., 2010). Emerging evidence has suggested (Frezza et al., 2010). Considerable clinical trials that the expression levels of zinc transports are have begun and have demonstrated encouraging related to cancer progression (Zhao and Eide, results (Redman et al., 2003). It is known 1996). Altered expression of zinc transporters that elevated copper concentration and raised could perform an important function in the proteasome activity are distinct characteristics incidence of cancer by interrupting function found in tumor-bearing humans. Frezza et and intracellular distribution. Along with the al. (2010) found that these particular aspects crucial duty, zinc has in biological systems, its associated with tumors cells have the ability unique characteristics have granted it to acquire to be utilized as distinct targets by previously approval as probable anticancer agents. clinically authorized drugs that perform as Copper effective tumor cell killers when those drugs form a complex with copper. Copper is a fundamental trace metal that is Ruthenium important in various biochemical processes including angiogenesis, development, cellular Because of limitations like drug resistance growth, and chemical redox reactions. In and worsening side effects to platinum-based biological systems, copper is found as both drugs in the treatment of cancer, the focus has (Cu+) or (Cu2+), which allows copper to act shifted toward the development and design of Proc. Okla. Acad. Sci. 99: pp 106 - 113 (2019) Metal-Based Chemotherapy Drugs 111 practical non-platinum-based drugs, including Saratale et al. (2017) made AgNPs from gold and ruthenium that are less harmful to Taraxacum officinale, also known as the normal cells, with less resistance and enhanced dandelion, and demonstrated its enhanced efficiency (Ajmal, 2017). Ruthenium-based cytotoxic impact against human liver cells compounds have distinct characteristics, such as stricken with cancer (HepG2). Biofunctionalized the ability to reside in a larger amount of spatial AgNps made within separate plant extracts of positions in comparison to cisplatin, a larger clove and guava displayed the satisfactory anti- amount of probable accessory molecules which cancer impact against four separate cancer cell can be transported by the drug arrangement and lines including human chronic myelogenous, in particular, the likelihood to prevail in the human colorectal adenocarcinoma, concerning organic fluids of nearly all of the most crucial the human kidney, leukemia, human cervix and oxidation states ranging from oxidation state bone marrow (Abdel-Fattah and Ali, 2018). II to IV (Popolin et al., 2017). All of these Aydin et al. (2014) were able to demonstrate unique properties have made ruthenium-based that two silver-containing metal complexes, compounds encouraging antimetastatic and C16H34N8O5 Ag2 Cd (AN1) and C11H16N7O2 Ag3 antitumor candidates. Popolin et al. (2017) Ni (AN7), have the ability to act as effective discovered [Ru(CH3CO2)(dppb)(bipy)]PF6 anticancer drug candidates that demonstrate [where bipy = 2,2’-bipyridine and dppb = low cytotoxic, higher antiproliferative, 1,4-bis(diphenylphosphino)butane] as a possible strong apoptosis-inducing and efficient DNA treatment for triple-negative breast cancer topoisomerase inhibitory traits, although (TNBC) due to its ability to more efficiently additional in vivo and in vitro studies must be inhibit the proliferation of TNBC cells over carried out in order to verify the anticancer drug normal, non-tumor cells, inhibit TNBC cells potential of AN1 and AN7. migration and invasion, adhesion, and to cause Gold the death in TNBC cells, although this complex should be studied in vivo to establish its potential In order to attain a more advanced cytotoxicity to help improve the treatment for breast cancer. profile demonstrating a broader range of activity Silver in comparison to platinum-based compounds, the chemotherapeutic ability of gold coordination Since ancient times, it has been known that complexes has been investigated. Studies have silver is an effective antimicrobial agent against demonstrated that communications of DNA, the a wide range of microorganisms. Currently, favorable destination of platinum, with gold(III) silver is used to regulate bacterial growth in complexes failed to present an advantageous medical settings, including the mending of burn binding mode, accelerating the research into wounds, catheters, and dental work (Jung et al., gold and protein interactions (Frezza et al., 2008). Silver nanoparticles (AgNPs) comprise a 2010). In the beginning, studies concentrated on category of materials that range from 1-100nm. an array of artificial gold(III) diothiocarbamate Recently AgNps have been reported to adjust derivatives which were revealed to demonstrate Pgp activity and consequently improve the 1-to-4-fold more cytotoxicity than cisplatin chemotherapeutic efficiency against cancer and had the ability to substantially overcome cells that are multi-drug resistant (Abdel-Fattah acquired and intrinsic resistance (Ranconi et and Ali, 2018). Furthermore, the genotoxicity al., 2005). Still, these studies were unable to displayed by AgNPs is backed by the production demonstrate a molecular link among the gold of breaks in double-stranded DNA in addition to compounds and their chemotherapeutic activity. chromosomal instability which encourages the A study done by Frezza et al. (2010) featured the start of apoptotic execution (Abdel-Fattah and proteasome as a crucial molecular destination Ali, 2018). This acting mechanism indicates that of gold complexes but exhibited apparent AgNPs could be correlated with various DNA- mechanisms of action that are responsible for its targeting anticancer drugs. fundamental biological actions, which rely upon the metal’s oxidation state. Proc. Okla. Acad. Sci. 99: pp 106 - 113 (2019) 112 K. Kasemodel and K. Roberts Conclusion low toxicity. Because metals are equipped with unique characteristics that are not present in The crucial role metals perform in the common carbon-based medicines, the positive maintenance and functioning of life features the trend associated with the discovery of anticancer extensive role nature plays in managing these drugs can persist by advancing the fundamental essential components. The clinical achievements knowledge acquired from the study of medicinal of cisplatin paved the road for researching inorganic chemistry. The potential for metal- metals, nonessential or essential, and those based chemotherapy drugs is continually metals coordination complexes as possible expanding, and more research should be carried anticancer agents. Since the chemotherapeutic out in order to learn all of the benefits these effects of cisplatin were discovered, thousands unique drugs have to offer the world. of platinum-based compounds have been made, with only oxaliplatin and carboplatin References accomplishing widespread clinical use. Construction methods of novel platinum Abdel-Fattah, W., & Ali, G. (2018). On the anti- compounds have been intensely investigated in cancer activities of silver nanoparticles. J Appl order to focus on the defects of past generation Biotechnol Gioeng, 5(1), 43-46. platinum compounds. Ajmal, M. (2017). Review: electrochemical studies on some metal complexes having Cisplatin was the first widely used metal- anti-cancer activites. 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