Synthesis of 4,5-dihydro-1H-pyrazole derivatives as BRAF inhibitors
Session Title
Other Abstracts
Faculty Mentor
T. Christian Grattan, Ph.D.
College
College of Arts and Sciences
Department
Chemistry, Physics, Geology, & the Environment
Abstract
BRAF is a human gene that encodes the BRAF protein which stimulates cell growth. BRAF mutations are found in several types of cancer, most notably in 50-70% of melanoma cell lines and tumors. 90% of activating BRAF mutations in cancer cells are a glutamic acid to valine substitution at position 600 (BRAFV600E), which is approximately 500 times more active than the wild-type protein. A study in 2006 revealed a 4,5-dihydropyrazole derivative as a potent inhibitor of KSN (kinesin spindle protein) to treat human cancers with good potency, pharmacokinetics, and water solubility. Another study in 2009 at the National Cancer Institute corroborated the anti-cancer activity of 4,5-dihydropyrazole derivatives with positive results on leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate and breast cancer cell lines. Nicotinic acid amide also acts as a chemo- and radio-sensitizing agent, and can be used with intravenous vitamin C therapy. Compound 27e* in the literature on which this research was based has a half inhibitory concentration of 0.20 µM and the concentration causing 50% of cell growth inhibition is 0.89µM. These values are promising for cancer treatment, however only one constitutional isomer of anisaldehyde was used in the synthesis of the compound sent for analysis. The purpose of this research is to synthesize 4,5-dihydro-1H-pyrazole derivatives. This study focuses on comparing the effectiveness of para-anisaldehyde, meta-anisaldehyde, and ortho-anisaldehyde in synthesizing the derivatives. All three compounds both yielded the chalcone derivatives. Para-anisaldehyde and meta-anisaldehyde both yielded the 4,5-dihydropyrazole derivatives, however the ortho-anisaldehyde has yet to be optimized for purified results. Future goals include further synthesis and purification of the chalcone derivatives, further synthesis and purification of 4,5-dihydropyrazole derivatives, and completion of the reaction optimization to form the desired BRAF (V600E) inhibitors. The final compounds will be purified and submitted for bioassay testing.
Grant Support?
Supported by an SC-INBRE grant from the National Institute for General Medical Sciences (P20GM103499).
Start Date
15-4-2023 12:00 PM
Synthesis of 4,5-dihydro-1H-pyrazole derivatives as BRAF inhibitors
BRAF is a human gene that encodes the BRAF protein which stimulates cell growth. BRAF mutations are found in several types of cancer, most notably in 50-70% of melanoma cell lines and tumors. 90% of activating BRAF mutations in cancer cells are a glutamic acid to valine substitution at position 600 (BRAFV600E), which is approximately 500 times more active than the wild-type protein. A study in 2006 revealed a 4,5-dihydropyrazole derivative as a potent inhibitor of KSN (kinesin spindle protein) to treat human cancers with good potency, pharmacokinetics, and water solubility. Another study in 2009 at the National Cancer Institute corroborated the anti-cancer activity of 4,5-dihydropyrazole derivatives with positive results on leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate and breast cancer cell lines. Nicotinic acid amide also acts as a chemo- and radio-sensitizing agent, and can be used with intravenous vitamin C therapy. Compound 27e* in the literature on which this research was based has a half inhibitory concentration of 0.20 µM and the concentration causing 50% of cell growth inhibition is 0.89µM. These values are promising for cancer treatment, however only one constitutional isomer of anisaldehyde was used in the synthesis of the compound sent for analysis. The purpose of this research is to synthesize 4,5-dihydro-1H-pyrazole derivatives. This study focuses on comparing the effectiveness of para-anisaldehyde, meta-anisaldehyde, and ortho-anisaldehyde in synthesizing the derivatives. All three compounds both yielded the chalcone derivatives. Para-anisaldehyde and meta-anisaldehyde both yielded the 4,5-dihydropyrazole derivatives, however the ortho-anisaldehyde has yet to be optimized for purified results. Future goals include further synthesis and purification of the chalcone derivatives, further synthesis and purification of 4,5-dihydropyrazole derivatives, and completion of the reaction optimization to form the desired BRAF (V600E) inhibitors. The final compounds will be purified and submitted for bioassay testing.
