Major
Chemistry
Anticipated Graduation Year
2021
Access Type
Restricted Access
Abstract
Matrix Metalloproteinases (MMPs) are a class of metalloenzymes integral to embryonic development, morphogenesis, and the maintenance and remodeling of the extracellular matrix. However, MMP upregulation is also characteristic of tumor growth and metastasis, in particular the gelatinases MMP-2 and MMP-9. Because of this, MMP inhibitors have been explored as promising antitumor targets. Separately, MMP inhibitor scaffolds have been used to target tumor cells. Currently, boron-neutron capture therapy (BNCT) is experiencing a renaissance, as it ideally involves targeting tumors with cellular-precision. BNCT involves the irradiation of 10B atoms with low-energy thermal neutrons, giving rise to an excited 11B atoms which then undergo fission. The high energy products of 11B fission only travel ~1 μm on average, which is roughly equivalent to the diameter of a single cell. This leads to the destruction of only the cell containing the boron atoms. The efficacy of BNCT is reliant on two conditions: cell-specific delivery of 10B atoms to the tumor, and achieving a sufficient cellular concentration of 10B-isotopes (20 μg/g). We hope to satisfy both of these conditions with hydroxamate MMP inhibitor 1 (Fig. 5), a sulfonamide-based MMP-inhibitor appended with an icosahedral carborane cluster. We will describe the successful synthesis of MMP inhibitor 1, based on known MMP inhibitor CGS-27023A (Fig. 5), a potent stromelysin inhibitor with affinity for gelatinases MMP-2 and -9. Compound 1 is currently undergoing testing as a new BNCT agent.
Faculty Mentors & Instructors
Daniel P. Becker, Ph.D., Professor; Sebastian Flieger, Graduate Student; Marlong Lutz, Ph.D., Post-Doctorate Fellow
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
SYNTHESIS OF A NOVEL, MMP-INHIBITOR-BASED BORON DELIVERY AGENT FOR USE IN BORON NEUTRON CAPTURE THERAPY (BNCT) FOR CANCER TREATMENT
Matrix Metalloproteinases (MMPs) are a class of metalloenzymes integral to embryonic development, morphogenesis, and the maintenance and remodeling of the extracellular matrix. However, MMP upregulation is also characteristic of tumor growth and metastasis, in particular the gelatinases MMP-2 and MMP-9. Because of this, MMP inhibitors have been explored as promising antitumor targets. Separately, MMP inhibitor scaffolds have been used to target tumor cells. Currently, boron-neutron capture therapy (BNCT) is experiencing a renaissance, as it ideally involves targeting tumors with cellular-precision. BNCT involves the irradiation of 10B atoms with low-energy thermal neutrons, giving rise to an excited 11B atoms which then undergo fission. The high energy products of 11B fission only travel ~1 μm on average, which is roughly equivalent to the diameter of a single cell. This leads to the destruction of only the cell containing the boron atoms. The efficacy of BNCT is reliant on two conditions: cell-specific delivery of 10B atoms to the tumor, and achieving a sufficient cellular concentration of 10B-isotopes (20 μg/g). We hope to satisfy both of these conditions with hydroxamate MMP inhibitor 1 (Fig. 5), a sulfonamide-based MMP-inhibitor appended with an icosahedral carborane cluster. We will describe the successful synthesis of MMP inhibitor 1, based on known MMP inhibitor CGS-27023A (Fig. 5), a potent stromelysin inhibitor with affinity for gelatinases MMP-2 and -9. Compound 1 is currently undergoing testing as a new BNCT agent.