Doctor of Philosophy

dissertationDuring the past decade, palladium-catalyzed alkene functionalization reactions that intercept the Pd-alkyl intermediate for further functionalization has attracted significant interest because of its ability to generate diverse C-O, C-N and C-C bond connections. However, developments of these reactions are considered to be challenging due to the propensity of the Pd-alkyl intermediate for ?-hydride elimination. The Sigman group has been involved in developing methods to stabilize the Pd-alkyl intermediate that is formed at the benzylic or allylic positions to generate interesting product. Herein, we describe the discovery of new efficient methods to stabilize these intermediates to achieve difunctionalization and hydrofunctionalization products. First, a highly cationic PdII-catalyzed alkene difunctionalization of terminal olefins using organostannanes is developed in which a conjugated alkene can lead to a 1,2-addition product. However, electron withdrawing styrenes gave a mixture of 1,2- and 1,1-addition products. Based on an observed linear free energy relationship, it was found that electronic nature of the styrene determines the ratio of the 1,2- vs 1,1-diarylation product. This study ultimately lead us to develop a 1,1-diarylartion reaction using simple olefins. The mechanistic experiments suggested that the electrophilic nature of the palladium catalyst is necessary to stabilize the resultant ?-benzyl species, that yields the alkene difunctionalization product

Zebrafish screen identifies novel compound with selective toxicity against leukemia

To detect targeted antileukemia agents we have designed a novel, high-content in vivo screen using genetically engineered, T-cell reporting zebrafish. We exploited the developmental similarities between normal and malignant T lymphoblasts to screen a small molecule library for activity against immature T cells with a simple visual readout in zebrafish larvae. After screening 26 400 molecules, we identified Lenaldekar (LDK), a compound that eliminates immature T cells in developing zebrafish without affecting the cell cycle in other cell types. LDK is well tolerated in vertebrates and induces long-term remission in adult zebrafish with cMYC-induced T-cell acute lymphoblastic leukemia (T-ALL). LDK causes dephosphorylation of members of the PI3 kinase/AKT/mTOR pathway and delays sensitive cells in late mitosis. Among human cancers, LDK selectively affects survival of hematopoietic malignancy lines and primary leukemias, including therapy-refractory B-ALL and chronic myelogenous leukemia samples, and inhibits growth of human T-ALL xenografts. This work demonstrates the utility of our method using zebrafish for antineoplastic candidate drug identification and suggests a new approach for targeted leukemia therapy. Although our efforts focused on leukemia therapy, this screening approach has broad implications as it can be translated to other cancer types involving malignant degeneration of developmentally arrested cells