News & Events

When

Date - February 15, 2023
1:00 pm - 2:00 pm

What

Ph.D. Defense
Department of Chemistry & Biochemistry
UNC Greensboro
Croatt Research Group

Title: “Discovery of Medicinal Leads by the Semi-Synthesis of TAK-1 Inhibitors and Development of Novel Reactions of Allenamides”

Abstract:

Cancer continues to be one of the leading causes of death. In 2020, there were nearly 10 million deaths estimated by World Health Organization (WHO). Ovarian cancer is the 18^th most common cancer worldwide and the eighth most commonly occurring cancer in women, with approximately 314,000 new cases found in 2020 resulting in nearly 210,000 deaths according to the World Cancer Research Fund. Specifically targeting new mechanisms is the key to targeting current anticancer drug resistance. Hypothemycin, an epoxide analogue of 5Z-7-oxozeaenol, was used to make analogues through semisynthesis. The work here focused on C8-C9 diol functionalization and C5-C6 epoxidation. The traditional method focused on the selective functionalization of the more active site on the targeted molecule. Here, a non-selective functionalization was applied to the hypothemycin. Using this method, 35 analogues were made from only 12 reactions including esters, carbonates and sulfonate, providing in-depth knowledge about the role that C8-C9 diol plays in TAK-1 inhibition and cytotoxicity in breast and ovarian cancer cell lines. Monofunctionalized analogues presented moderated to good activities against TAK-1 and increased solubility. This shows the potential for modification of this section of the molecule to assist with solubility formulation and other desirable properties. Many analogues were cytotoxic, and three compounds had similar or increased potency with more than 100-fold improvements in solubility.

As the warhead of the hypothemycin, due to the cis-enone, the C5-position behaves electrophilic in the TAK-1 binding pocket for cysteine-175 to bind covalently. Experimental evidence shows that the cis-enone is prone to isomerization to the trans-enone, which then has greatly decreased activity. The epoxidation modification was proposed for C5-C6, to maintain or improve activity and substantially improve structural integrity. The work here is the route toward epoxidation of the C5-C6 alkene. To get a better understanding of the molecule, analogues including the C5-C6 alkene, cis-enone, and various epoxides were made to test for TAK-1 activity.

Allenes are an important building block for synthetic chemists in building crucial molecules including natural products and medicinal leads. In the past few decades, there has been a significant increase in attention to allenes and a curiosity for its unique structural properties. Similar to allenes, allenamides are nitrogen containing allene species and have been known for more than 40 years. The special π-donating ability of the nitrogen atom to switch the electrophilic center of the allene makes it suitable for alpha, gamma, or di-addition. In this work, regioselective intermolecular mono- or di-hydroalkoxylation of allenamides with alcohols using aluminum chloride as the catalyst is reported. The benefit of this novel transformation is it opens another alternative method for allenamide hydroalkoxylation. Hydroalkoxylation can be carried out regioselectively by using 1.1 equivalents of the respective alcohol at either at 50 °C for alpha addition product or at 80 °C for gamma addition. When treated with an excess of the alcohol (3 equivalents) at 50 °C, the 1,3-bis(alkoxy)propanamides are presented as the product. The reaction exhibited good functional group tolerance, efficiency, cost-effectiveness, and moderate to good yields.