Synthesis of Noscapinoids for Treatment of Lung Cancer

Lung cancer is the leading cause of smoking-related deaths in the United States, with non-small cell lung cancer (NSCLC) accounting for more than 80% of patient diagnoses. Moreover, as the disease has been shown to disproportionately affect lower socioeconomic communities, there is an increasing need for effective therapies to reduce the health and economic burden of NSCLC. Among the treatment options, the use of small molecule drugs constitutes a front-line medical treatment. While the effectiveness of these drugs has been validated, the emergence of drug resistance and unfavorable side effects has prompted the search for new and effective chemotherapeutic agents.

Noscapine is a naturally occurring molecule that exhibits anticancer activity and reduces the volume of NSCLC tumors in mice. Notably, noscapine does not display significant toxicity toward healthy cells and therefore holds significant promise as a milder chemotherapeutic drug. Strategies to increase the potency of noscapine are of significant interest to the medical community, spurring chemists to develop new methods to modify the structure of noscapine. While these efforts have led to derivatives at certain positions on noscapine, modification of the majority of sites of noscapine’s structure are beyond the capabilities of current semisynthetic approaches. A potential solution to this problem is synthesizing untested noscapine derivatives, or noscapinoids from simpler parts with site-specific alterations already in place. This proposal describes the development of a synthetic methodology that will allow for the rapid construction of such unexplored noscapinoids. Importantly, I will aim to modify specific sites that are inaccessible using current semisynthetic strategies and hypothesized to improve the anti-lung cancer activity of noscapine. Ultimately, these efforts will address the need to further evaluate noscapinoids as potential leads against non-small cell lung cancer.