Discipline: Chemistry and Chemical Sciences
Subcategory: Cancer Research
Nkiruka Oragwam - California State University, Bakersfield
Co-Author(s): Haley Hashim, California State University Bakersfield, Bakersfield, CA
Lysyl oxidase (LOX) is a protein that plays a role in the spread of cancer within the body when upregulated by tumor cells. There have been findings that demonstrate that the inhibition of LOX can prevent the spread of cancer. β- Aminopropionitrile (BAPN) has been known to be an effective inhibitor of LOX. However, due to its highly reactive and toxic nature, it needs to be selectively carried to the hypoxic environment of tumor cells without affecting the LOX in healthy cells. Otherwise, since LOX also strengthens collagen and elastin, this could cause serious repercussions such as weakening of connective tissues and even paralysis as a result of lathyrism. Because of this, our project focuses on the attachment of BAPN to a small carrier molecule that could selectively release the inhibitor when exposed to hypoxic conditions, such as the environment of the tumors we are specifically targeting. Other derivatives of BAPN will also be tested in this project in order to further determine which structures are optimal for LOX inhibition. We hypothesized that BAPN and its derivatives will be successfully synthesized and inhibit LOX when introduced to a hypoxic environment containing LOX.
To accomplish this, aromatic compounds will be utilized for the synthesis of small molecule inhibitors of LOX. These cyclic compounds will incorporate the usage of an electron withdrawing group, such as a nitro group. We predict that in the hypoxic environment of the tumor, it will be reduced to a donating group (hydroxylamine) which can release the BAPN. BAPN, and its derivatives, can be attached via a reaction with carbonyl group to form a small molecule carrier that could selectively release the inhibitor when exposed to hypoxic conditions. Also, as we synthesize these compounds, a collaborating biochemistry research group will screen our products using LOX in order to determine which structures actually work. So far, our optimized synthetic scheme using BAPN works effectively with aldehydes and ketones. We should expect to see some results soon for the derivatives of BAPN. Further research questions will have to do with exploring whether the effects of manipulating other features on the small molecule carriers would have a better or worse effect on inhibition. For example, changing the carbonyl, withdrawing group, or aromatic structure. These results will hopefully provide us with an insight as to what works and help improve our understanding to design a more effective drug.
Funder Acknowledgement(s): NSF grant HRD-0331537 / LSAMP/ NSF grant MRI 1229301 – CSUB Student Research Scholars Program
Faculty Advisor: Danielle Solano,