Chapter 1. Synthesis and Evaluation of a Series of C5'-Substituted Duocarmycin SA Analogs; Chapter 2. Progress Towards the Synthesis and Biological Characterization of a Novel Symmetric DNA Bis-Alkylating Agent; Chapter 3. Selected Cytoxicity Studies

The duocarmycins are potent antitumor natural products that exert their biological properties through a sequence selective alkylation of duplex DNA. Substantial work has defined the mechanism of activation of these agents to involve a binding-induced conformational change around the linking amide, disrupting the stabilizing cross-conjugation between the cyclopropane and the vinylogous amide. This disruption increases the cyclopropane electrophilicity, activating it for attack by a proximal adenine. Additionally, a direct relationship between chemical reactivity of the alkylation subunit and biological potency has been defined. The potency of each analogue requires the alkylation subunit to be stable enough to reach its biological target (DNA) intact, but reactive enough to undergo activation once it reaches DNA.;The synthesis of analogues containing deep-seated structural changes has been central to our studies of such compounds and has provided insights not accessible through examination of the natural products themselves. Following our synthesis of CBI and, more recently, related alkylation subunits with an extended aromatic skeleton (CNI and iso-CNI) we report progress toward the synthesis of the novel symmetric DNA bis-alkylating agents in Chapter 2.;The development and use of cytotoxicity assays in our laboratories has played an essential role in our ongoing efforts to identify key structural features within selected classes of compounds that modulate cytotoxic potency against a variety of cancer cell lines. These studies have led to the development and discovery of new, structurally-modified analogs of natural products that exhibit cytotoxic activity against several cancer cell lines. Chapter 3 describes and summarizes the use of these assays in the determination of cytotoxic potency of a variety of natural product analogues, including those of the duocarmycin SA and yatakemycin family, and vinca alkaloid family (vinblastine, vincristine).;It has been shown that the substituent at the C5' position of the indole DNA binding subunit of duocarmycin SA is of predominant importance, and that it can alone provide a fully active agent with little or no contribution derived from the C6' and C7' substituents found in duocarmycin A and duocarmycin SA. Additionally, and as first systematically explored with CBI derivatives, the nature of the C5' substituent proved to have pronounced impact that correlated with its presence, size, rigidity and length, but not electronic properties. In Chapter 1 we systematically explore the importance of the C5' substituent within duocarmycin SA analogs that also bear the minor groove imbedded C6 methyl ester.