Although many antitumor drugs have been created in order to lower side effect severity, a few of the drugs have efficiently been synthesized and given at smaller dosages to clearly show the lower side effects. The compound being synthesized in this research experiment consists of being a 9-aminoacridine derivative. These compounds undergo hydrolysis in all cells, causing a higher dosage to be given out in order for the compound to be effective. Since a cure that only targets cancer cells is yet to be created, one of the main goals stands as being lowering the dosage in order to have less side effects.
Based off Tewey, Chen, Nelson, and Liu’s research, it was found that the DNA Topoisomerase II is a cellular target for few drugs (Tewey et. al, 1984). The drugs were then recognized and established as “intercalative anti-tumor drugs [that] produce protein-associated DNA breaks (Peralta, Hackcbarth, Flatten, Kaufmann, Hiasa, Xing, Ferguson, 2009). The DNA Topoisomerase II was revealed, by Gálvez-Peralta, that compounds of this type were shown to catalytically inhibit topoisomerase II. They also found that other compounds may be non-lethal poisons of topoisomerase I (Peralta et. al, 2009). When the compounds act as non-lethal poisons of topoisomerase, it does not contribute to the drug-induced killing of cancer cells. On the other hand, when the compound catalytically inhibited topoisomerase II, this led the cell into programmed cell arrest, also known as apoptosis, which was tested on pancreatic cancer cells (Peralta et. al, 2009).
O-(4-methyl)-phenyl-N-(9'-acridinyl)-hydroxylamine is actually a derivative based off of O-phenyl-N-(9’-acridinyl)-hydroxylamine. When beginning the synthesis of O-phenyl-N-(9’-acridinyl)-hydroxylamine, instead of using an iodobenzene and a benzene ring, a methyl group will be attached to both compounds making them p-iodotoluene and toluene. The rest of the methods and procedure were then written based off the synthesis of O-phenyl-N-(9’-acridinyl)-hydroxylamine. The attached methyl group, an electron-donating group, will cause the compound to bind less strongly to the DNA base pairs. This is due to the change in the localization of the electrons in the electron cloud. The bond between the compound and the DNA would be less strong because the DNA phosphate groups have a negative charge, leading more cells into cell arrest and causing a smaller dosage to be given to patients (Bielawski, Zhu, Olofsson, 2007).
Due to O-(4-methyl)-phenyl-N-(9'-acridinyl)-hydroxylamine being a derivative of O-phenyl-N-(9’-acridinyl)-hydroxylamine, the procedure to produce the drug will be almost identical with a very few differences. The synthesis of the drug can be broken down into four steps. Several other research papers and articles lay out the foundation for the synthesis of the compound.
The first step includes the synthesis of diaryliodonium triflate. In this the reaction, the reactants will be p-iodotoluene and toluene. Due to O-(4-methyl)-phenyl-N-(9'-acridinyl)-hydroxylamine being a derivative of O-phenyl-N-(9’-acridinyl)-hydroxylamine, the synthesis of p-iodotoluene and toluene will be similar to the synthesis of iodobenze and benzene. Bielawski’s thesis shows several ways in which this synthesis is possible. His reactions resulted in having success at high yields as well (Ghosh, Olofsson, 2014). Ghosh and Olofsson show other types of ways in which this synthesis is possible (Ghosh et. al, 2014). One of these procedures will most likely be followed in order to finish step one of the reaction.
Step two of this reaction involves the synthesis of diaryliodonium triflate and N-hydroxyphthalimide to produce of N-(4-methyl)-phenyloxyphthalimide. A similar procedure that can be followed for this reaction is the synthesis of diaryliodonium triflate and hydroxyphthalimide to produce N-phenyloxyphthalimide. The only difference between N-(4-methyl)-phenyloxyphthalimide and N-phenyloxyphthalimide is that N-(4-methyl)-phenyloxyphthalimide has a methyl group attached to it. In a different thesis, Ghosh and Olofsson detail a clear procedure that is easy to follow to complete the reaction (Ghosh et. al, 2014).
The third step of this reaction is the hydrolysis of N-(4-methyl)-phenyloxyphthalimide to produce O-(4-methyl)-phenylhydroxylamine. This product can be purchased online, however the cost is not that feasible and it is more cost efficient to produce and synthesize the drug. The self-production of this drug in a lab setting would be the most simple and most feasible. This would also allow the mass production of the compound so that excess compound would be readily available if the compound is stable. One type of method to produce O-(4-methyl)-phenylhydroxylamine is explained by Carlson in his research paper (Carlson, 2015). Other methods to produce the compound have also been identified, however the one that will be followed is most likely the one that is explained by Carlson (Carlson, 2015).
Step four involves the synthesis of O-(4-methyl)-phenyl-N-(9'-acridinyl)-hydroxylamine with the reactants being 9-chloroacridine and O-(4-methyl)-phenylhydroxylamine. This synthesis is similar to the of O-phenyl-N-(9’-acridinyl)-hydroxylamine. Deselm has clearly written out a procedure for the synthesis of the compound in his research paper. He worked to synthesize O-phenyl-N-(9’-acridinyl)-hydroxylamine, however he does clearly give a procedure about the synthetization of O-(4-methyl)-phenyl-N-(9'-acridinyl)-hydroxylamine. His method will most likely be used to produce the compound (Bielawski et. al, 2007).
The side effects of cancer have gotten severe enough to a point in which a new drug that will readily be available for diagnosed use is necessary. O-(4-methyl)-phenyl-N-(9'-acridinyl)-hydroxylamine, if synthesis is successful, will allow for a smaller dosage and cause less side effects. The usage of the methyl group causing a stronger bond between DNA base pairs will pursue for the cell to undergo apoptosis. The production of O-(4-methyl)-phenyl-N-(9'-acridinyl)-hydroxylamine will hopefully pursue a better treatment for cancer, which pushes to ask whether it can successfully be synthesized with high yields.
Based off Tewey, Chen, Nelson, and Liu’s research, it was found that the DNA Topoisomerase II is a cellular target for few drugs (Tewey et. al, 1984). The drugs were then recognized and established as “intercalative anti-tumor drugs [that] produce protein-associated DNA breaks (Peralta, Hackcbarth, Flatten, Kaufmann, Hiasa, Xing, Ferguson, 2009). The DNA Topoisomerase II was revealed, by Gálvez-Peralta, that compounds of this type were shown to catalytically inhibit topoisomerase II. They also found that other compounds may be non-lethal poisons of topoisomerase I (Peralta et. al, 2009). When the compounds act as non-lethal poisons of topoisomerase, it does not contribute to the drug-induced killing of cancer cells. On the other hand, when the compound catalytically inhibited topoisomerase II, this led the cell into programmed cell arrest, also known as apoptosis, which was tested on pancreatic cancer cells (Peralta et. al, 2009).
O-(4-methyl)-phenyl-N-(9'-acridinyl)-hydroxylamine is actually a derivative based off of O-phenyl-N-(9’-acridinyl)-hydroxylamine. When beginning the synthesis of O-phenyl-N-(9’-acridinyl)-hydroxylamine, instead of using an iodobenzene and a benzene ring, a methyl group will be attached to both compounds making them p-iodotoluene and toluene. The rest of the methods and procedure were then written based off the synthesis of O-phenyl-N-(9’-acridinyl)-hydroxylamine. The attached methyl group, an electron-donating group, will cause the compound to bind less strongly to the DNA base pairs. This is due to the change in the localization of the electrons in the electron cloud. The bond between the compound and the DNA would be less strong because the DNA phosphate groups have a negative charge, leading more cells into cell arrest and causing a smaller dosage to be given to patients (Bielawski, Zhu, Olofsson, 2007).
Due to O-(4-methyl)-phenyl-N-(9'-acridinyl)-hydroxylamine being a derivative of O-phenyl-N-(9’-acridinyl)-hydroxylamine, the procedure to produce the drug will be almost identical with a very few differences. The synthesis of the drug can be broken down into four steps. Several other research papers and articles lay out the foundation for the synthesis of the compound.
The first step includes the synthesis of diaryliodonium triflate. In this the reaction, the reactants will be p-iodotoluene and toluene. Due to O-(4-methyl)-phenyl-N-(9'-acridinyl)-hydroxylamine being a derivative of O-phenyl-N-(9’-acridinyl)-hydroxylamine, the synthesis of p-iodotoluene and toluene will be similar to the synthesis of iodobenze and benzene. Bielawski’s thesis shows several ways in which this synthesis is possible. His reactions resulted in having success at high yields as well (Ghosh, Olofsson, 2014). Ghosh and Olofsson show other types of ways in which this synthesis is possible (Ghosh et. al, 2014). One of these procedures will most likely be followed in order to finish step one of the reaction.
Step two of this reaction involves the synthesis of diaryliodonium triflate and N-hydroxyphthalimide to produce of N-(4-methyl)-phenyloxyphthalimide. A similar procedure that can be followed for this reaction is the synthesis of diaryliodonium triflate and hydroxyphthalimide to produce N-phenyloxyphthalimide. The only difference between N-(4-methyl)-phenyloxyphthalimide and N-phenyloxyphthalimide is that N-(4-methyl)-phenyloxyphthalimide has a methyl group attached to it. In a different thesis, Ghosh and Olofsson detail a clear procedure that is easy to follow to complete the reaction (Ghosh et. al, 2014).
The third step of this reaction is the hydrolysis of N-(4-methyl)-phenyloxyphthalimide to produce O-(4-methyl)-phenylhydroxylamine. This product can be purchased online, however the cost is not that feasible and it is more cost efficient to produce and synthesize the drug. The self-production of this drug in a lab setting would be the most simple and most feasible. This would also allow the mass production of the compound so that excess compound would be readily available if the compound is stable. One type of method to produce O-(4-methyl)-phenylhydroxylamine is explained by Carlson in his research paper (Carlson, 2015). Other methods to produce the compound have also been identified, however the one that will be followed is most likely the one that is explained by Carlson (Carlson, 2015).
Step four involves the synthesis of O-(4-methyl)-phenyl-N-(9'-acridinyl)-hydroxylamine with the reactants being 9-chloroacridine and O-(4-methyl)-phenylhydroxylamine. This synthesis is similar to the of O-phenyl-N-(9’-acridinyl)-hydroxylamine. Deselm has clearly written out a procedure for the synthesis of the compound in his research paper. He worked to synthesize O-phenyl-N-(9’-acridinyl)-hydroxylamine, however he does clearly give a procedure about the synthetization of O-(4-methyl)-phenyl-N-(9'-acridinyl)-hydroxylamine. His method will most likely be used to produce the compound (Bielawski et. al, 2007).
The side effects of cancer have gotten severe enough to a point in which a new drug that will readily be available for diagnosed use is necessary. O-(4-methyl)-phenyl-N-(9'-acridinyl)-hydroxylamine, if synthesis is successful, will allow for a smaller dosage and cause less side effects. The usage of the methyl group causing a stronger bond between DNA base pairs will pursue for the cell to undergo apoptosis. The production of O-(4-methyl)-phenyl-N-(9'-acridinyl)-hydroxylamine will hopefully pursue a better treatment for cancer, which pushes to ask whether it can successfully be synthesized with high yields.