| Summary: |
We propose to develop and synthetize novel antitumor drugs based on the scaffold of Coelenterazine (CLZ), a marine chemiluminescent (CL) substrate. These drugs will be applied ina groundbreaking broad-spectrum cancer therapy with enhanced tumor-selectivity and activity. CL consists on the conversion of thermal energy into excitation energy with light-emission, due to a chemical reaction. The original feature of this project is the development of single-molecule CLZ mimetics that act as inactive prodrugs until intracellular self-activation by a cancer marker (overexpressed superoxide anion). This will trigger the CL reaction of this system, which instead of emitting light, will use its excitation energy toproduce the highly cytotoxic singlet oxygen. These mimetics are tumor-selective as they are only triggered by a cancer marker, while being broad-spectrum as singlet oxygen candestroy tumors by several pathways. In fact, preliminary data showed that the mimetics led to significant toxicity toward several cancer types (even for ones with poor prognosis, aslung and gastric cancer), while not affecting healthy cells. This new technology is already patent pending (PCT/IB2019/053642). This project is the next step of a previous FCT-funded project (PTDC/QEQ-QFI/0289/2014), in which the PI was a Team Member and the Co-PI was the PI.
Cancer is the second-highest global cause of death, and several cancer types still present dismal prognosis. Also, while more broad-scope therapies (as chemotherapy) can causeserious side-effects, more targeted therapies are limited to few patients/tumor types that possess the therapy target and are more susceptible to therapeutic resistance. So, there isa growing demand for more efficient anticancer drugs.
We will use the radical-induced CLZ CL system to tackle this problem. CLZ can produce CL excited states due to oxidation by superoxide anion. We intend to use this process as aself-activation and tumor-selective mechanism, as this radica  |
Summary
We propose to develop and synthetize novel antitumor drugs based on the scaffold of Coelenterazine (CLZ), a marine chemiluminescent (CL) substrate. These drugs will be applied ina groundbreaking broad-spectrum cancer therapy with enhanced tumor-selectivity and activity. CL consists on the conversion of thermal energy into excitation energy with light-emission, due to a chemical reaction. The original feature of this project is the development of single-molecule CLZ mimetics that act as inactive prodrugs until intracellular self-activation by a cancer marker (overexpressed superoxide anion). This will trigger the CL reaction of this system, which instead of emitting light, will use its excitation energy toproduce the highly cytotoxic singlet oxygen. These mimetics are tumor-selective as they are only triggered by a cancer marker, while being broad-spectrum as singlet oxygen candestroy tumors by several pathways. In fact, preliminary data showed that the mimetics led to significant toxicity toward several cancer types (even for ones with poor prognosis, aslung and gastric cancer), while not affecting healthy cells. This new technology is already patent pending (PCT/IB2019/053642). This project is the next step of a previous FCT-funded project (PTDC/QEQ-QFI/0289/2014), in which the PI was a Team Member and the Co-PI was the PI.
Cancer is the second-highest global cause of death, and several cancer types still present dismal prognosis. Also, while more broad-scope therapies (as chemotherapy) can causeserious side-effects, more targeted therapies are limited to few patients/tumor types that possess the therapy target and are more susceptible to therapeutic resistance. So, there isa growing demand for more efficient anticancer drugs.
We will use the radical-induced CLZ CL system to tackle this problem. CLZ can produce CL excited states due to oxidation by superoxide anion. We intend to use this process as aself-activation and tumor-selective mechanism, as this radical is characteristically overexpressed in tumor cells. This process will be modulated to produce directly and efficientlytriplet states that generate the highly cytotoxic singlet oxygen, in a Type II reaction with triplet oxygen. We propose that this exchange of superoxide anion for singlet oxygen canlead to tumor cell destruction. Singlet oxygen has proven to be a much stronger oxidant than superoxide, with considerable reactivity toward nucleic acids, proteins and lipids.Moreover, superoxide is a major target of the cell antioxidant defenses while singlet oxygen is not. Thus, this exchange is able to produce oxidative damage that can bypass the celldefenses.
In order to develop efficient self-excited CLZ mimetics, able to generate singlet oxygen in a reaction with triplet oxygen, the CL of CLZ must be characterized with frontier andmultidisciplinary techniques. State-of-the-art quantum-mechanical modelling will be used to determine the chemical space of CLZs and related reactivity trends, allowing for thetarget-oriented synthesis of a broad-availability of target molecules. Fast access to these molecular targets will be provided by known and reliable synthetic routes, already optimizedby our team. The thermodynamic/kinetic CL and singlet oxygen sensitization profiles of these derivatives will be obtained by an in-depth luminescence spectroscopic analysis. Use ofhigh-performance liquid chromatography (HPLC), luminescence, UV-Vis and mass spectroscopy will be needed to identify and quantify all reaction components. Singlet/tripletchemiexcitation yields will be measured by energy- |