{"id":1310,"date":"2023-12-04T14:12:44","date_gmt":"2023-12-04T19:12:44","guid":{"rendered":"https:\/\/students.bowdoin.edu\/bowdoin-science-journal\/?p=1310"},"modified":"2023-12-04T14:12:44","modified_gmt":"2023-12-04T19:12:44","slug":"fine-tuning-of-chemotherapeutic-drug-reactions-through-ruthenium-organic-complexes","status":"publish","type":"post","link":"https:\/\/students.bowdoin.edu\/bowdoin-science-journal\/biology\/fine-tuning-of-chemotherapeutic-drug-reactions-through-ruthenium-organic-complexes\/","title":{"rendered":"Fine-tuning of Chemotherapeutic Drug Reactions through Ruthenium Organic Complexes"},"content":{"rendered":"\r\n

The development of cancer treatment reagents aims at optimizing the reactivity of the reagent with the cellular DNA while reducing the reactivity with other bodily sites. This is in order to maximize cytotoxicity to cancer cells while reducing the side effects associated with chemotherapy (W<\/span>ang, 2005).<\/p>\r\n

Organometallic complexes, organic compounds with one or more metallic central atoms, have been used to control the release of compounds involved in key biological reactions (Renfrew, 2014). In the context of cancer chemotherapy, cisplatin complexes have been successfully developed to react with guanosine 5\u2019 monoph<\/span>osphate, or GMP, as a potential binding site in the cell\u2019s DNA, while avoiding the reactions associated with side effects (Dasari, 2014 & Reedjik, 2003).<\/p>\r\n

The development of chemotherapeutic reagents requires the fine-tuning of the ligand substitution reactions that the organometallic complex can undergo. Ligand substitution reactions are reactions where one or more of the substituents bonded to the metal atom in the organometallic complex are replaced by a compound from the surrounding environment. An example is shown in the figure below.<\/span><\/p>\r\n

\"\"<\/span><\/p>\r\n

Fig 1. Example of an organometallic complex undergoing a ligand substitution reaction. When dissolved in pyridine, the chromium complex, [Cr(TPP)(Br)(H2O)], reacts with the solvent, and two of its ligands (Br and OH<\/span>2<\/span>) are replaced by pyridine compounds (Py) (Okada, 2012)<\/span>.\u00a0<\/span><\/em><\/p>\r\n

In a 2005 study, a group of chemists tested multiple ligand-substitution reactions of Ruthenium (Ru) complexes to test the possibility of the development of a competitor for cisplatin in chemotherapy (Wang, 2005). The Ruthenium complex studied have \u201cstool\u201d-like structures with an arene upper part and a tetrahedral Ruthenium compound which contains the leaving group. The researchers use X-ray crystallography and other characterization methods to identify the structure of every ruthenium complex involved in the study.<\/span><\/p>\r\n

\"\"<\/span><\/p>\r\n

Fig 2. The structure of the Ruthenium organometallic complexes tested in the study. The basic structure is shown on the upper left. The \u201carene\u201d can be any of the structures shown, while the leaving group, X, can be any of the structures shown as well as a halide or pseudohalide (Wang, 2005).\u00a0<\/span><\/em><\/p>\r\n

Given the high concentration of chloride anions in the bloodstream and the intercellular fluid, the substitution of X by chloride is a main mechanism by which the reagent is lost before it can attack cancer cells (Wang, 2005). Previous research has shown that hydrolysis (substitution of X by a water molecule) is an essential activation step in the reagent\u2019s reaction with GMP (Chen, 2003). The researchers thus investigated how the choice of the arene and the leaving group within the ruthenium complex can affect the reaction rates such that the reagent is cytotoxic but is inac<\/span>tive before reaching its target site.\u00a0<\/p>\r\n

The reaction rate with chloride was established by dissolving the complexes in a 104mM NaCl solution, mimicking the high-chloride media within the body, and monitoring the formation of the substitution reaction product using the same characterization methods involved in the identification of the complexes.<\/span><\/p>\r\n

The hydrolysis rate was established by allowing the aqueous solutions of the complexes to equilibrate for 24-48 hours at 37\u00b0C, mimicking body temperature. The formation of the hydrolysis product was monitored using the same characterization methods. The reaction equilibria were determined using high-performance liquid chromatography.\u00a0<\/span><\/p>\r\n

The reaction with GMP is believed to be the final step in the reagent\u2019s activity<\/span>against cancer cells. The reaction rate was established by dissolving 0.5mM of each complex in a 0.5mM aqueous GMP solution. The product formation rate was determined using the same methods as the other reactions.<\/p>\r\n

The researchers summarized their key resultsin the table below:<\/span><\/p>\r\n

\"\"<\/span><\/p>\r\n

The data show that complex 13, for example, has a faster reaction rate with chloride than GMP, and will, therefore, be lost before attacking cancer cells if it were to be used as a chemotherapy<\/span>reagent. Data shows that complexes 15 and 17, on the other hand, react faster with water and GMP than chloride, which makes them more suitable for chemotherapy. Complex 1 can undergo hydrolysis and react with GMP at a relatively high rate. A key finding in this research is that complex 21 can bind to GMP without undergoing hydrolysis, skipping a previously thought required first step.\u00a0<\/p>\r\n

The overall cytotoxicity of each complex was compared to cisplatin by determining the concentration of the complex which caused at least 50% inhibition in the growth of ovarian cancer cells, IC50 values. As previous research predicted, high hydrolysis rates correlated with high cytotoxicity (Chen, 2003). Cisplatin has IC50 = 0.6\u00b5M; chemotherapy reagents are considered to have good cytotoxic activity if they have IC50 < 18\u00b5M. Some of the same complexes discussed above, with the exception of complex 17 and 21 had IC50 values competitive with cisplatin (IC50 < 6\u00b5M). Furthermore, the studied Ru complexes exhibited cytotoxicity towards cisplatin-resistant ovarian cancer cells (Wang, 2005).<\/span><\/p>\r\n

Overall, the results show that the rates of the reactions involved in chemotherapy can be fine tuned by the choice of the ligand within the ruthenium complex. These results can be used in the future development of novel chemotherapy reagents.\u00a0\u00a0<\/span><\/p>\r\n

Work Cited:<\/span><\/p>\r\n

Chen, H., Parkinson, J. A., Morris, R. E., & Sadler, P. J. (2003). <\/span>Highly selective binding of organometallic ruthenium ethylenediamine complexes to nucleic acids: novel recognition mechanisms<\/span><\/i><\/a>. <\/span>Journal of the American Chemical Society<\/span><\/i>, <\/span>125<\/span><\/i>(1), 173-186.<\/span><\/p>\r\n

Dasari, S., & Tchounwou, P. B. (2014). <\/span>Cisplatin in cancer therapy: molecular mechanisms of action. European journal of pharmacology<\/span><\/i><\/a>, <\/span>740<\/span><\/i>, 364-378.<\/span><\/p>\r\n

Okada, K., Sumida, A., Inagaki, R., & Inamo, M. (2012). <\/span>Effect of the axial halogen ligand on the substitution reactions of chromium (III) porphyrin complex.<\/span><\/i><\/a> Inorganica Chimica Acta<\/span><\/i>, <\/span>392<\/span><\/i>, 473-477.<\/span><\/p>\r\n

Reedijk, J. (2003). <\/span>New clues for platinum antitumor chemistry: kinetically controlled metal binding to DNA. Proceedings of the National Academy of Sciences<\/span><\/i><\/a>, <\/span>100<\/span><\/i>(7), 3611-3616.<\/span><\/p>\r\n

Renfrew, A. K. (2014). <\/span>Transition metal complexes with bioactive ligands: mechanisms for selective ligand release and applications for drug delivery.<\/span><\/a> Metallomics<\/span><\/i>, <\/span>6<\/span><\/i>(8), 1324-1335.<\/span><\/p>\r\n

Wang, F., Habtemariam, A., van der Geer, E. P., Fern\u00e1ndez, R., Melchart, M., Deeth, R. J., … & Sadler, P. J. (2005). <\/span>Controlling ligand substitution reactions of organometallic complexes: Tuning cancer cell cytotoxicity.<\/span><\/a> Proceedings of the National Academy of Sciences<\/span><\/i>, <\/span>102<\/span><\/i>(51), 18269-18274.<\/span><\/p>\r\n","protected":false},"excerpt":{"rendered":"

The development of cancer treatment reagents aims at optimizing the reactivity of the reagent with the cellular DNA while reducing the reactivity with other bodily sites. This is in order to maximize cytotoxicity to cancer cells while reducing the side effects associated with chemotherapy (Wang, 2005). Organometallic complexes, organic compounds with one or more metallic […]<\/p>\n","protected":false},"author":683,"featured_media":1335,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_genesis_hide_title":false,"_genesis_hide_breadcrumbs":false,"_genesis_hide_singular_image":false,"_genesis_hide_footer_widgets":false,"_genesis_custom_body_class":"","_genesis_custom_post_class":"","_genesis_layout":"","footnotes":""},"categories":[63,64],"tags":[59,69],"class_list":{"0":"post-1310","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-biology","8":"category-chem-biochem","9":"tag-chem-biochem","10":"tag-medicine","11":"entry"},"featured_image_src":"https:\/\/students.bowdoin.edu\/bowdoin-science-journal\/wp-content\/uploads\/sites\/35\/2023\/12\/Screenshot-2023-12-04-at-2.10.23\u202fPM-600x400.png","featured_image_src_square":"https:\/\/students.bowdoin.edu\/bowdoin-science-journal\/wp-content\/uploads\/sites\/35\/2023\/12\/Screenshot-2023-12-04-at-2.10.23\u202fPM-600x600.png","author_info":{"display_name":"Ahmad Harb '25","author_link":"https:\/\/students.bowdoin.edu\/bowdoin-science-journal\/author\/aharb\/"},"_links":{"self":[{"href":"https:\/\/students.bowdoin.edu\/bowdoin-science-journal\/wp-json\/wp\/v2\/posts\/1310","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/students.bowdoin.edu\/bowdoin-science-journal\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/students.bowdoin.edu\/bowdoin-science-journal\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/students.bowdoin.edu\/bowdoin-science-journal\/wp-json\/wp\/v2\/users\/683"}],"replies":[{"embeddable":true,"href":"https:\/\/students.bowdoin.edu\/bowdoin-science-journal\/wp-json\/wp\/v2\/comments?post=1310"}],"version-history":[{"count":0,"href":"https:\/\/students.bowdoin.edu\/bowdoin-science-journal\/wp-json\/wp\/v2\/posts\/1310\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/students.bowdoin.edu\/bowdoin-science-journal\/wp-json\/wp\/v2\/media\/1335"}],"wp:attachment":[{"href":"https:\/\/students.bowdoin.edu\/bowdoin-science-journal\/wp-json\/wp\/v2\/media?parent=1310"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/students.bowdoin.edu\/bowdoin-science-journal\/wp-json\/wp\/v2\/categories?post=1310"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/students.bowdoin.edu\/bowdoin-science-journal\/wp-json\/wp\/v2\/tags?post=1310"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}