Over the years, a number of antitumor agents have been developed and are now available for cancer chemotherapy. However, the search for new drugs with less undesired side effect from academic and industrial laboratories still remains critically important....[ Read more ]

Over the years, a number of antitumor agents have been developed and are now available for cancer chemotherapy. However, the search for new drugs with less undesired side effect from academic and industrial laboratories still remains critically important.

In this study, two classes of novel compounds, i.e. enediynes and propargylic sulfones, have been dealt with covering the aspects of molecular design, chemical synthesis, mechanism of action, and biological activity. These compounds are in the forms of prodrugs and need to be activated for delivering their activity through interaction with DNA via two distinct mechanisms. Enediynes are found in the naturally occurring antitumor antibiotics and are known to form 1,4-benzenoid diradical which abstracts hydrogen atoms from the deoxyribose of DNA and causes strand breakage. Propargylic sulfones are purely synthetic compounds and undergo a base-promoted isomerization to generate allenic sulfones which act on DNA through nucleic base alkylation.

For the first time, we have developed a novel prototype for synthesis of acyclic and cyclic enediyne compounds via allylic rearrangement under both SN2' and SN1' conditions, respectively. A systematic study has been carried out on the following aspects, including synthesis of the 1,5-diyne precursors, examination on the reaction conditions effecting the allylic rearrangement with high regioselectivity and diastereoselectivity, characterization of structures of the reactive intermediates and the products, kinetic studies on the acid-catalyzed allylic rearrangement, and formation and DNA cleavage of diradical species from acyclic enediynes. Based on this thesis study, a general and efficient methodology for preparation of enediyne compounds has been established. It provides a unique approach, different from the currently existing methods, toward design and synthesis of enediyne prodrugs. On the other hand, the gained knowledge in this thesis work on the allylic rearrangement should be helpful in understanding the activation of derivatives of maduropeptin chromophore, which is a naturally occurring enediyne having potent antitumor antibiotic activity.

Two series of novel propargylic sulfones and their conjugates with DNA intercalators have been synthesized and examined for DNA cleavage and anticancer activity. Reactions of propargylic sulfones with oxygen-, sulfur-, and nitrogen-containing nucleophiles were performed in order to understand the mode of action on DNA. Our results confirmed that nucleic base alkylation is the possible mechanism of DNA damage caused by propargylic sulfones. Interesting results on structural requirement for achieving high potency were obtained which should provide the foundation for further investigation on this class of synthetic molecules with promising DNA damage property.