So good afternoon everyone and welcome to the first graduate student seminar of while winter but moving into spring. But the first one of 2022 for sure. And it's my great pleasure to introduce Anthony Rice, who is a fifth year chemistry graduate, graduate student working in Joe Rosenthal lab. So so Anthony is from New Jersey, way far away. And and he attended Notre Dame high school and stuff honey University before joining us. Before joining us here, he has, his research interests include photodynamic cancer therapy. And since you've thrown down the gauntlet with your, with your seminar title, I'm going to attempt to read it as a challenge and we'll see how my, my chemistry pronunciation is. So he's here today to talk to us about, about photodynamic chemistry therapy. And his talk is entitled palladium by lagging complex is bearing aryl groups through organometallic cross couplings for sensitization of singlet oxygen and photodynamic cancer therapy. Well done. Thank you very much. Take it away. I'm looking forward to this. All right. Thank you. My screen. Okay. Can everyone see this well. Alright. Perfect. So thank you again. My name is Anthony Rice, graduate student working for Dr. Joe Rosenthal. Today I'm gonna be talking a little bit about the science that I do for developing and modifying new photo sensitizer drug candidates for photodynamic cancer therapy. So first off, I want to go into a little bit about what is photodynamic therapy. So it is a non-invasive treatment option for solid cancers tumors. How it works is that a photo sensitizer is injected into a patient over an extended period of time. The photo sensitizer disperses throughout the person's body, where the tumor site is then directly irradiated with light of any particular wavelength depending on what the photo sensitizer is. The photo sensitizer can absorb the energy from that light and use that to do an intermolecular energy transfer with local triplet ground-state oxygen. So this is oxygen that exists all around us in the world. And the energy that is transferred from the light to the oxygen promotes it into this excited state that we referred to. And what this means is that it can now interact with organic matter and what it will do is cause cellular damage and ultimately lead to cell death. And hopefully with the selective irradiation selectively killing the cancer cells. So this treatment option shows fewer side effects compared to that of traditional chemotherapies. And it can even elicit an anti-tumor immune response from the body on top of that therapy itself. So here I'm wanted to explain ij a block diagram of how this works. So basically I'm just going to walk through the electronics of how photodynamic therapy works with the photo sensitizer and the molecular oxygen. So once in the body, the photo sensitizer exist in a singlet ground state shown here as 0. It can absorb light at a particular wavelength and get excited into excited singlet states. So here the ground state is it as 0 and then the excited states, or S1 and S2 increasing in energy as you go up the y-axis here. The h new representation here is just energy of a particular wavelength. So our light of a particular way back, I'm sorry, which has different energies to promote the photo sensitizer two different states. Once in these excited states, the photo sensitizer can undergo internal conversion, which is going from S2 to S1, or vibrational relaxation, which is just going from these smaller energy levels, the vibrational energy levels down to the ground state ones, but still remaining in this excited singlet state that I mentioned previously. Once it is here, the photo sensitizer can then undergo fluorescence, which it just emits light. So think of like an LED. So it gets excited by either some sort of energy source like electricity or a battery, and then it can emit light, whether that be blue, green, red, so forth. So the photosynthetic can do that and release light that way. But what we need for our system is we need to have it, have the system undergo what is called inter system crossing. So the photo sensitizer goes from this excited singlet state. This excited triplet state here denoted T1. This just has to do with the electronics and the electrons present in the photo sensitizer. I'm not going to go into that right now. But when the photo sensitizer is in this excited triplet state, it can then undergo phosphorescence, which is just the exact same thing as fluorescence just occurring from the triplet state as opposed to the singlet state. But what we actually need is this intermolecular energy transfer that I mentioned previously. So when the photo sensitizer is in this triplet state, now, this triplet state can interact with the triplet state of the oxygen. And then so we get a relaxation effect back down to the ground state photo sensitizer year. We see a promotion of the ground state triplet oxygen to this excited singlet state. And again, as I mentioned previously, when the oxygen is promoted into the singlet state, it can then interact with the organic matter in cells and ultimately lead to cell death. So now that I've gone over how the electronics of photodynamic therapy works. I wanted to talk a little bit about the type of light that is best suited for these therapies. So the figure here on the left shows how deep light can penetrate into biological tissue depending on the actual wavelength of the light. So blue, green, and yellow light are shorter nanometer. So shorter wavelength light. And what this means is that they have more energy, but they don't penetrate as deeply into the biological tissue. However, red light and near infrared light have a higher wavelengths to their lower energy and they penetrate deeper into that subcutaneous tissue. So for our photodynamic cancer therapy, if we're looking at deep tissue tumors, we want to be able to irradiate with red or near infrared light to get the deepest tissue penetration. This figure here on the right also illustrates this same phenomenon. So you could see that at 600 nanometers, below 600 nanometers, there's a lot of absorption between hemoglobin, which is present in your body as well as melanin, which is present in your skin. So all we all light of wavelength less than 600 gets pretty readily absorbed by these compounds, which is why the blue, green, and yellow light don't penetrate as deep. When you get out to about 900 to 1000 nanometers, you see that water actually starts absorbing this very strongly. So what this leaves us with is what we referred to as the photo therapeutic window. And that's between six hundred and nine hundred nanometers, which is the optimal range to get not only deep tissue penetration, but also still be able to activate the photo sensitizer to make that singlet oxygen that I mentioned in order to actually carry out the therapy. So for the optimal photo sensitizer, what we need is a compound that's the absorbs strongly in that photo therapeutic region that I just mentioned, between six hundred and nine hundred nanometers. We also need a photo sensitizer that has a high quantum yield for singlet oxygen. What this is referring to is that for every molecule that are every photon of light that this molecule absorbs, how efficient is it at taking that energy and using it to generate that singlet oxygen? The higher the better the more singlet oxygen that we can generate for this. For this therapy, the better. We also need a photo sensitizer that is water-soluble. So that way it can be administered to patients. We needed to have low inherent toxicities. So that way the compound can be easily tolerated inside cells. So that way we're not causing cellular depth just by administration of the drug, but rather by activation of it with the light. We also needed to clear rapidly from tissue so that patients don't remain photosensitive for long periods of time after their therapy. And lastly, we would like to see in preferential apoptotic cell death pathway. What this means is that the cells are dying via their own controlled cell death. The cells are realizing that there has been cellular damage and they take the measures necessary in order to Control Tab controlled cell death, as opposed to necrotic cell death, which is an uncontrolled cell death pathway which can lead to a variety of different side effects such as inflammation, hemorrhaging, and also can lead to the internals of those cells being dispersed out to other portions of the body, which can lead to secondary tumor sites popping up, which is not what we want. So here I have some photo sensitizer that are currently either approved or currently in clinical trials for PDT. So here we have photo friend, which is the first-generation photo sensitizer. So this compound here is kind of what everything has been based off of initially. So you see that this lambda max value refers to where it absorbs at. So you can see here that it absorbs in the photo therapeutic window at 630 nanometers. And this del, and this phi, phi delta symbol here refers to the singlet oxygen generation quantum yield. So what this is telling me is that it has an 89 percent quantum yield generation. So what this is saying is that for every, let's say every 100 photons that is absorbed, 89 of those is going to be used in generating the reactive oxygen species that I mentioned previously. These other compounds here all have similar. Structures which you can see. So the main thing to take away from these, that these are all tetra parole based structures. So a parole is this region here. So it's this little ring that has this n which is a nitrogen. And you can see that they're all cyclic. They're all completely cyclic and enclosed all the way around. They all have Lambda max values in that photo therapeutic window between six hundred and nine hundred nanometers. And they all have a singlet oxygen quantum yield of 50 percent or higher. Here I have 0 500 for this one book, that just simply means 50 percent, where pilots is 71% and then PFOS candidate 87 percent. And then these epsilon values just show how strongly these compounds absorb photo therapeutic window at that lambda max region. So you can see here photo friend, it absorbs pretty weakly only at 3 thousand AD, it's lambda max, whereas these compounds absorb much, much more strongly. 88 thousand for to get 30 thousand for early tin and then 35000 FAA scan. All these compounds have their own issues. To cat has lots of issues with water solubility and then products in it, phos can have issues with not readily clearing from biological tissue. So these con, so patients are having photosensitivity after their therapy. So in order to address that out all my God, I'm sorry. I don't know where this figure came from. I'm just going to abide by in order to address, address this. The Rosenthal group developed a non traditional tetrahedral. So we refer to this as our dimethyl Biola dine. So you can see here that it is a, another touch-up role-based structure we see for the Perola units, but this compound is non-cyclic and that is what we really want to take away from this. What this does is it completely changes the absorption capabilities as well as the singlet oxygen generation capabilities of these compounds. So here we have a crystal structure of the free base. So this just so you can get a full, an actual three-dimensional understanding of how the structure actually exists. So here we have the crystal structure of the Freebase. We have a compound that has a zinc metal center shown here, and then another with a copper metal center shown here. All of these compounds, however, don't display the absorption that we need in that photo therapeutic window. You can see here that the Freebase dimethyl by Li Dian only absorbs out slightly past 500 nanometers. Whereas the zinc and the copper absorb our only to about 600 nanometers on top of that, these compounds all have very, very low singlet oxygen generation capabilities with quantum yields at less than 3% or even lower, less than 0.2%. And that in the case of the copper. Oh jeez, sorry, I'm having a slight technical difficulties. So in order to address this by previous graduate student of ours, Dr. Andrew, Tony decided to invoke the heavy atom effect, and she did this by inserting a palladium center into the middle of our Freebase die map of iodine. So as I mentioned previously, we need to have these photo sensitizer is undergo inter system crossing to get into that triplet state. So what the heavy atom effect does is it enhances this inter system crossing steps just so that it's easier for the photo sensitizer king. Easier for the photo sensitizer to go from that excited singlet state into that excited triplet state. Here we have another crystal structure of this compound with the palladium center shown here. Here we have the absorption profile. So again, you can see that this, the methylated palladium by Luddite absorbs further towards that photo therapeutic window then the free base shown in blue. However, it still doesn't absorb out past 600 nanometers where we really needed to. But what was beneficial was that the heavy atom effect did what it needed to do in order in terms of the singlet oxygen generation capabilities for the parent palladium by Luddite, they singlet oxygen generation now at 54 percent as opposed to the 1.5% that was previously shown with the free base pyrimidine. Andrea then went on to perform cell studies with our collaborators in the Biomedical Engineering Department, dr. Emily day. So here we have some fluorescence imaging of triple-negative breast cancer cells that we did cellular studies with. The main thing to see here is that the portions of the image that are glowing red are actually our compound that has been water solubilize an inserted into these cells. So what you can take away here is that our compound is not only getting water solubilize, it is actually inserting itself into the cell where it can perform that photodynamic cancer therapy. We've actually determined that our compounds seems that allocate itself in the Golgi apparatus, which is interesting in itself, where the photo sensitizer localizes in cells and what type of organelles it is causing that cellular damage too, can have a large impact on how efficient that foot that cancer therapy is, as well as the apoptosis versus necrosis that I mentioned previously. So with these cell studies, we ran dark tests and. Irradiation tests in order to determine the LD 50 and the ED 50. So the LD50 here refers to the lethal dose required to kill 50 percent of the cells. So that is what was done during the dark and we were able to determine that with a concentration of 1.87 millimolar, that was the concentration required to kill 50 percent of the cells. So we see a decrease in cell viability down to about 50 percent at 1.87 millimolar. For a light or radiation studies we irradiated at for different amounts of time. So the longer you irradiate, the more singlet oxygen that you're going to make for the cancer therapy. The black bars are trials that had no light or radiation. The red bars are trials that had ten minutes of irradiation and the tan lines or 20 minutes of radiation and the blue lines are 30 minutes of radiation. So using this information, we were able to determine an ED 50, which is the effective dose required to kill 50 percent of cells. So these concentrations are much lower, but we're activating the photo sensitizer with light irradiation. So we were able to determine the effective dose required to kill 50 percent of cells at 0.354 micromolar. With these two values were able to determine what we referred to as a photo toxicity index. So this is the PI. What this is you're doing is you're taking your LD 50 and dividing it with the ED 50 in order to get this value here of approximately 5300. What this means is that our photo sensitizer is 5300 times more efficient at killing cells when activated with light, as opposed to just its inherent toxicity. So with all this in mind, we have, we see that we have a promising photo sensitizer framework for photodynamic cancer therapy. This compound has a high quantum yield for singlet oxygen. It has a low inherent dark toxicity with a high photo toxicity index. And we also saw preferential apoptotic cell death in our apoptosis necrosis assays with 82% of cells that died from this treatment. Doing so by apoptosis, which is beneficial because again, minimizing the amount of necrosis can help minimize the side effects from the therapy. But again, the main limitation for this compound is its absorption profile. So here you can see again that this compound does not absorb out past 600 nanometers in that photo therapeutic window. So in order to address this, we needed to actually modify the compound itself. So Dr. Max Martin, previous graduate student here with Dr. Joe Rosenthal, started by doing what is called a bromination and inserting these two bromide groups on our pilot IN framework here. Here we have another crystal structure. We can see those bromide groups present on the ligand scaffold as well as you can see a side on view where you can see that these compounds are not flat. The other photo sensitizer that I mentioned previously in the introduction, those compounds, they're all aromatic and they're all flat. These compounds, they're not flat so they're slightly puckered. And what we believe is that the flexibility of these systems can be beneficial for our compounds to. You could see here that the two arms of our Biola Dine or played out with an angle of about 34 degrees. Once we have this, what we referred to as an aryl bromide handle, we can then do various types of coupling reactions in order to lengthen our compounds, we are extending conjugation. And what that means is we are really just extending the system downwards. So we add the initial touch parole framework that ended at this Perola unit. But now we are extending it through this triple bond shown here via SONA give share a coupling and into an arrow ring, which is just another ring system like this at the bottom of our system. I'll get into that a little bit more as we progress further with the talk. So what Max found is that extending the conjugation. So I'm making this system longer had a drastic effect on the photo physics of these systems. So here we have what we're referring to as our phenol ester palladium by Luddite. This group here is a phenol ring, and this is a t-butyl ester. So that's where we get the name from the phenol ester. And what we found here is that the absorption for this compound, we see a slight decrease and how strong it absorbs at this main feature here. But what we do see is now drastically shifted further out into that photo therapeutic window and now absorbs out past 600 nanometers, which is what we want. Here we have a crystal structure of this compound. So again, you can kind of see how the conjugation of the system is being extended through the entire violet IS framework into this aryl system. And not only did we see a red shift of the absorption profile, we also saw a slight increase in the singlet oxygen generation capabilities for the system. That, remember, the parent palladium by Luddite had a singlet oxygen quantum yield of 54 percent. While this new phenol ester derivative, how to quantum yield a 59% We also were able to determine that there is a very important role that is played by the electronics of the system. So you can install and just kind of put different groups on that arrow ring that I mentioned previously. The one that I showed had a t-butyl ester, but you can install a variety of different types of functionalities. And what we have found is that the way that those functionalities Act have a drastic impact on the photo physics of our systems. So if you install an electron donating group on that arrow ring, what that does is it donates electrons into the, so it makes that ring system more electron rich. What this does is it redshifts are compound further out into that photo therapeutic window, but it shows a lower singlet oxygen generation quantum yield. So if you look at this phenol amine derivative here, you can see that it's quantum yield drastically decreased to 4%, but it absorbs out to almost 700 nanometers. If you go the other direction and you take an electron withdrawing group and you install that on the aryl ring. What it does is it pulls electrons out of that arrow ring and makes that ring system. Now electron poor. What this does is we don't see as significant as a redshift, but we see a much higher singlet oxygen quantum yield. So here we have this, this pink traces of pyridinium derivative. So you could see that it only absorbs out to about 600 nanometers. But we see an increase in the singlet oxygen quantum yield up to 83%, which is very, very promising. So this is where some of my work came into play. We wanted Max had previously shown that you can extend the conjugation of the system. It can get absorbed deeper out into the red while also increasing the singlet oxygen quantum yield. So what we wanted to see is if we make those ring systems bigger by installing either Nashville ester or an anthracene ester, what type of effect would that have? So here I have an overlaid absorption plot of all of these derivatives. So you could see here the phenol ester is shown in pink and the nap Lester has shown a maroon. These compounds aren't really shifted much from each other. You can see that they're absorbing both out to about 650 nanometers. But the Napal Esther showed a significant increase in how strongly it absorbs at the top of that feature. The anthracene Aster, however, showed the most significant redshift absorbing out to almost 700 nanometers here, while also still increasing how strongly it absorbs that feature compared to just the base phenol that I mentioned previously. We then did some singlet oxygen studies with these compounds, basically just seeing how fish, again, how efficiently they can make that reactive oxygen species. And what we found is that all three of these derivatives displayed increasing that oxygen generation capabilities compared to the parent palladium by Luddite, the phenol Esther showed a 59% quantum yield. The nap Lester showed the largest quantum yield of 73%. And then the anthracene and Esther showed another increased singlet oxygen generation quantum yield at 66 percent. So here I have some crystal structures of these derivatives. So for the naphtha Leicester, you can see there's two different orientations. Both of the Rings kind of pointing here to the left. For this orientation, they're displayed outwards. And this has had a pretty significant impact on how widely those arms splay that I mentioned previously. So when they're Orrin oriented in the same direction, you see a similar angle to what I meant for what I showed for the dibromo at 34 degrees. Whereas when they're all oriented in different directions, we see a much shorter angle at 20 degrees. For the Anthropocene, the Anthropocene is more symmetric, so there is no different orientations for this compound hat. But again, you can see that these aren't just splayed out again at an angle of approximately 35 degrees. So in summary, for these compounds, we were able to extend the conjugation of the systems with a phenol Leicester in naphtha, Lester and anthracene ester rang. We were able to successfully redshift the absorption into that photo therapeutic window, absorbing out past 600 nanometers. And we even increase the quantum yield for singlet oxygen generation for these compounds. So next we wanted to look at external cyclization of this, of these materials. So as I just previously said, we use the Sony to share a couple of things in order to extend our system here. And I mentioned previously had this compound is not cyclic, but a lot of the commercially available photo sensitizer is R. So what we ended up doing was doing an external cyclization of our system and having a conjugated bridge, which you can see here, that spans are two units. So these diapering units are just these section shown here. So what we have now done is we have made this compound a cyclic structure, but the actual touched her parole itself is still not cyclic because these two are Perola units are not connected. We did this externally. We have referred to this as r p 61 palladium bile at nine, just simply due to its physical resemblance to a P6 you on Black Widow aircraft. In the article and Yap, our x-ray crystallographer generated this image where you can see the actual crystal structure of our compounds superimposed on top of the piece 61 aircrafts. So that way you can count to get more of a visual understanding of why we refer to it the way that we do. So in order to synthesize this, we did the exact same chemistry, but we just had this dye Alkyne system. The dye Alkyne simply means that we have two of these triple bond regions here. And we were able to simply just click this compound near onto our dibromo palladium by Luddite. Here we have crystal structures of compounds. So again, you can see that the system is anthracene bridge. But the side on view still shows that even though this compound is now cyclic, it is still not flat and it still contorted. And we see an, a, a splaying angle between the two arms of the violet. I'm at approximately 29.6 degrees, so that's lower than the 34 and 35 them solve for the other derivatives, but it's still not 0, it's still not a flat structure. So here we have the absorption profile for the p 61 palladium by dying compared to our parent palladium by the Dine and the phenol ester that I just introduced. What you can see is that the piece 61 and the phenol ester both, Hello the same red shift out to about 650 nanometers. However, the piece 61 derivative shows slightly better abs or activity than the phenol ester. Singlet oxygen studies for this also showed that the p 61 displayed a much, much greater singlet oxygen generation compared to not only the parent palladium iodine, but also the phenol ester with a singlet oxygen quantity being determined of 84%. So this was the highest that we had found, that the highest that was reported when this manuscript was just recently published. So this is the strongest generating, strongest thing that oxygen generating palladium Melodyne that we have developed and published. So through this, we have increased the abs or activity. We have created a compound that absorbs in that photo therapeutic window that I mentioned. And we were also able to increase the singlet oxygen quantum yield. So now with this, we wanted to transition to a different linker. So we, as I showed, extending the conjugation of these systems does redshift the absorption. So we do see absorption further out into that photo therapeutic window. And we've also shown that the electronics of the system do have a drastic effect on the magnitude of how far that redshift goes, as well as it impacts the singlet oxygen quantum yields for these compounds. So all of these that I've shown you far, they don't absorb deep enough into that photo therapeutic window and they don't absorb strongly enough for them to be really promising photo sensitizer. So what we did was we did some literature review when we found a paper that was doing similar types of chemistry with these boat dP, dy, so that's just bow. Dp dt is just referring to this compound shown here. So they were extending the conjugation of their systems through SONA and cashier a coupling. So you could see here again you have that Alkyne triple bond with an arrow ring. But not only were they extended conjugation was shown to give shear coupling, they were also sending it with heck coupling. What this is is you're, you're extending through an alkene, which is this double bond into that arrow system. Coupling is actually developed by Dr. Haq here at the University of Delaware. So if you've gone to Brown lab, you might see some of the murals. And they have lots of lots of different structures that are kinda dedicated to the work that he has that he has done for the school and also published. He's done a lot of work on these types of couplings for the scientific community. And so what we've, what this manuscript is showing is that if you extend the conjugation of the system through this alkene as opposed to the alkyne, we see a more drastic redshift further out into the red. So these red traces here labeled three C, and that is referring to this heck, extended bow dP, dy, where the orange trace is 3D. So that's the SONA give Shira. And what you can see is that these red traces are absorbing further out, farther into the red than the orange traces. So what we wanted to do was implement this exact same science with our systems. So we found the a old manuscript that had that showed a type of McGhee she couplings is just another name for coupling. And what this was able to do was install that double bond that I just mentioned on to our actual palladium iodine. So we would take this bromide and now we're converting it to this double bond alkene shown here. This is referred to as a final group. But for this, I'll just keep calling this the double bond. Once we have here, I have a crystal structure for this as well. So you can see again, the conjugation is extending through the two Perola units and now into this double bond. So now that we have this die vinyl or guide double bond system, we can now do these HEC couplings to extend the conjugation of the systems through this double bond and then into that aryl ring. And then again, we can install different groups. So the ark and represent a whole bunch of different compounds or different functionalities. We can install onto that erroring. And so we have developed six different derivatives and we have crystal structures about six. So here we have one where this R group is just a proton, so it's not shown here. We have one where there's a CF three group. We have another structure here that has a CN group or a cyano group. We have this derivative here, which is a dimethyl means you have a nitrogen with two methyl groups attached here. You have this methoxy group, so you have an oxygen with a methyl. And then lastly, we have this total derivative. So it's just a CH3 methyl group at this position shown here. So here I have a comparison just kind of showing that, that the, how drastic that redshift is when you extend through the triple bond versus the double bond. So you see here that the red trace is our Sonya give shear a triple bond system which absorbs out to approximately 650 nanometers. Whereas the same derivative just extending through an alkene as opposed to an alkyne. So a double bond as opposed to a triple bond. We see it absorb out to almost 700 nanometers, which is much, much more drastic. So here we have the absorption profiles of those six derivatives plus the, the, the divine will die double bond species that I mentioned. And what you can see is that depending on what functionality you have on at this R group, it has a drastic impact on the absorption in the photo physics up with these systems. So in particular, I want to draw your attention to the dime methylamine derivative. So this compound showed the most drastic redshift absorbing way out past 700 nanometers, almost 800 nanometers. The issue with this compound, however, is that like what I showed with Max's work previously, the amine derivatives do not generate a lot of singlet oxygen, so it absorbs the strongest, but it also has the smallest thing that oxygen generation. But from this table you can take away a nice trend. And that is that the electronic studies that Macs performed on his derivatives hold true for these compounds that I have synthesized as well. So these groups up here are the electron poor. So these are electron withdrawing groups that are taking electron density out of that aryl ring. And you see that their lease redshifted. They have lower absorption values at 650 nanometers, but they had the highest singlet oxygen generation, the nitrile at 85% and then the CF three derivative at 94%. Whereas the electron rich derivatives like this dimethyl amine and the anisole, which is that OCH3 that I mentioned. They have better abs or activity. So you can see here and eleven thousand and twenty four thousand, which is drastically higher, but they also display much lower singlet oxygen generation capabilities. So in summary, from these compounds, you were able to continue to successfully redshift the absorption of the palladium dimethyl Melodyne. We were able to increase the singlet oxygen quantum yield from that of the palladium iodine, as well as fine tune the electronics of these systems and analyze the trends that we see. So one kind of direction that we want to take with this compound is that we want to do nanoparticle encapsulation in order to install it, in order to run our cell studies. So I mentioned previously how we did water stabilization and then we ran cell studies on the triple-negative breast cancer cells with just the parent palladium pilot IN I was Andrew's work where we got the LD 50 to 80 50 and are very high photo toxicity index. We cannot do that same science on this compound. These alkenes just make it too difficult. So what we can do is we can take our, our structure here when it is dissolved and we can encapsulate it in PAGA, which is just a polymer that's water-soluble. What it does is it basically just traps those compounds denoted here as just a green dot. It traps them inside of the polymer. And then what this enables it to do is then be able to be dissolved in water. And so then when it's in water, we can then do that same photodynamic therapy in order to generate that single box. And then what else is next? One other future work that we had is taking that key 61 palladium iodine that I mentioned previously. And taking what we learned from the heck derivatives that I just showed and applying that. So extending the conjugation through the double bonds as opposed to the triple bonds. And then also installing different groups onto this anthracene bridge in order to test how far we can get that redshift to go, as well as how strongly these compounds can generate that singlet oxygen. So with that, that's the end of my talk. I would like to thank everyone in my group, Dr. Joe Rosenthal, my PI, Dr. Andrea petitioning, Dr. Max Martin kind of headed up this project where I've taken it over now. Caitlin word is a first-year graduate student in our group who's going to be, I'm going to be handing the reigns for this project over to her. And then Molly worn door, Sabrina Bill Anthony, Nate Renner, and lean dresser. All undergraduate students that have common worked in our lab and gotten first-hand experience. Not only gender synthesizing these compounds, but then actually seeing how that can be applied. I would also like to thank Dr. SHE by any NMR facility, Dr. Glenn Yap in the x-ray lab, pop any in the mass spec facility. And then John moist cell and Gary for all their help with facilities. And so with that, I'd like to open the floor to any questions if anybody has. Well, I can I can lead off with ones. So I'm not, I'm not a chemist, I'm a mathematician. But I, so, so just in terms of the thought process when you do things like this. So you reference some known, some known bond groups that you took advantage of. The head, like the Heck reaction head group. But is there, is, there are computational modeling before you do this or are there just well-known processes? And you look at the literature and say, okay, I can add this subgroup to my molecule or yes, So actually It's kind of a little bit of both. So you can do literature review and see how these different things applied to other systems. And then we in particular don't really do as much computation, but we have collaborators that can help us with computation. And so we've actually published some things that kind of help explain why we're seeing what we're seeing. But then we can also use it to kind of say, okay, if we put this group on our aryl ring, how far would that get us? And we can do some computations to see that. But for the most part, B, you do, there's, it's not always just a 100 percent overlap between what you compute and the actual experimental results that you get. Still, we try to take some things that are mostly promising and then actually physically make them in order to test it. So like all those absorption curves, those are experimental then those are all experimental values. Yes, I see. So there's no known technique to like if I, if I give you the, you know, the structure of this big molecule, you can't. That's hard to compute. I guess. You could. We particularly don't do that. But you a 100 percent could do that. And there are a lot of groups that use that method in order to try to narrow down their paths for the different types of compounds that they're making. Hey, Other questions for Anthony. Most of the people on the call work with you down by fly that most of most of my very best, not everyone is here for this talk. Yes. Okay. So so then what yeah. So then what happens next like that. So I take it this isn't quite ready for. I put, you know, give a mouse a tumor and hunt and do this to the mouse. But is that where this goes? So I guess that when you have something that reaches a certain threshold, does that Yes. So then what is the ultimate goal? Initially, the next steps will be taking the most whenever, whenever we continue to develop, finding which one would be the most promising. And then, first off, we need to get it to be able to dissolve in water so that way we can do cell studies. And then secondly, we'll do initial like cell line test as opposed to animal studies just to see how efficient it is on that scale before it actually gets administered into animal testing. We have, we have a lot of weight, a lot of ways to go before we before we get to those. Any other questions? All right. Well, then, Anthony, thank you so much for coming and giving giving a great talk. Thank you very much. I appreciate it. All right. Take care.
Anthony Rice: Palladium Biladiene Complexes Bearing Aryl Groups Through Organometallic Cross-Couplings for Sensitization of Singlet Oxygen and Photodynamic Cancer Therapy
From Timothy Nelson January 20, 2022
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Photodynamic therapy (PDT), which involves the photoinduced sensitization of singlet oxygen (1O2) is an attractive treatment for certain types of cancer. The development of new photochemotherapeutic agents remains an important area of research. Macrocyclic tetrapyrrole compounds including porphyrins, phthalocyanines, chlorins and bacteriochlorins have been pursued as sensitizers of singlet oxygen for PDT applications but historically are difficult to prepare/purify and can also suffer from high non-specific dark toxicity, poor solubility in biological media and/or slow clearance from biological tissues. In response to these shortcomings, we have developed a series of novel linear tetrapyrrole architectures complexed to late transition metals as potential PDT agents. We find that these dimethylbiladiene (DMBil1) tetrapyrrole complexes can efficiently photosensitize generation of 1O2 oxygen upon irradiation with visible light, when metalated with palladium (Pd[DMBil1]). To extend the absorption profile of the Pd[DMBil1] platform, alkynyl-aryl groups have been conjugated to the periphery of the tetrapyrrole using Sonogashira methods. Derivatives of this type containing ancillary phenyl (PdDMBil–PE), naphthyl (PdDMBil–NE) and anthracenyl (DMBil–AE) groups have been prepared and characterized. A second derivative was synthesized utilizing an anthracene bridge to link the two dipyrrin units of the biladiene framework (Pd[DMBil2-AE). A third suite of derivatives was prepared using Heck coupling to extend conjugation through alkenes, rather than alkynes, while also altering the electronics of the aryl system to affect the photochemical properties of the biladiene platform (Pd[DMBil3–R]). Extension of the tetrapyrroles conjugation successfully redshifts the absorption of the Pd[DMBilX–Ar] family of biladienes further into the phototherapeutic window (i.e., 650–850 nm), which is the spectral range that most deeply penetrates epithelial tissues. Photochemical sensitization studies demonstrate that our series of new palladium biladiene complexes (Pd[DMBilX–Ar]) can sensitize the formation of 1O2 with quantum yields ranging from FD = 0.01 – 0.94 upon irradiation with light of l > 600 nm. The improved absorption properties of the Pd[DMBilX–Ar] complexes in the phototherapeutic window, together with their high 1O2 quantum yields highlight the promise of these compounds as potential agents for PDT and other photomedicine applications.
Anthony Rice is a fifth-year graduate student working in Joel Rosenthal’s lab and pursuing a doctorate in chemistry. Rice is from New Jersey and attended Notre Dame High School and Susquehanna University for undergraduate studies. At Susquehanna, Rice received a B.S. in chemistry while also being a four-year letter recipient for the men’s lacrosse team. Between undergraduate and graduate school, he worked in industry for nine months as a lab technician for a bioanalytical lab in Princeton, New Jersey. Rice has been a TA at UD and is working on a project developing and modifying molecular candidates for photosensitizers for photodynamic cancer therapies. Additionally, he is an author of two manuscripts published in “Inorganic Chemistry” with a few more manuscripts currently submitted or in preparation. After graduation, he is looking to get back into industry working in pharmaceuticals and the “business of science” realm in industry.
Anthony Rice is a fifth-year graduate student working in Joel Rosenthal’s lab and pursuing a doctorate in chemistry. Rice is from New Jersey and attended Notre Dame High School and Susquehanna University for undergraduate studies. At Susquehanna, Rice received a B.S. in chemistry while also being a four-year letter recipient for the men’s lacrosse team. Between undergraduate and graduate school, he worked in industry for nine months as a lab technician for a bioanalytical lab in Princeton, New Jersey. Rice has been a TA at UD and is working on a project developing and modifying molecular candidates for photosensitizers for photodynamic cancer therapies. Additionally, he is an author of two manuscripts published in “Inorganic Chemistry” with a few more manuscripts currently submitted or in preparation. After graduation, he is looking to get back into industry working in pharmaceuticals and the “business of science” realm in industry.
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- Graduate College
- Date Established
- January 20, 2022
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