Part I. Design, synthesis, and evaluation of functional analogues of the potent antitumor antibiotic CC-1065. Part II. Diels-Alder reactions of heterocyclic azadienes. Part III. Total synthesis of the antineoplastic agent combretastatin D-2

Subas Man Sakya, Purdue University

Abstract

Full details of the total synthesis of the aborted and the extended CC-1065 functional analogues (+)- and ($-$)-CPI-PDE-I$\sb1$ ((+)- and ($-$)-2), (+)- and ($-$)-CPI-CDPI$\sb1$ ((+)- and ($-$)-3), and ($\pm$)-, (+)- and ($-$)-CPI-CDPI$\sb3$ (($\pm$), (+)-, and (+)-5) are described. Comparative DNA binding studies of the agents versus (+)-N-BOC-CPI (6), (+)-N-acetyl-CPI (7), (+)-CC-1065 (1), and (+)-/($-$)-CPI-CDPI$\sb2$ (4) are presented in efforts to establish the structural and functional features of CC-1065 responsible for its sequence-selective B-DNA minor groove association and the resulting potent cytotoxic activity. The results of the comparative study suggests that the noncovalent binding selectivity of the agent contributes to the DNA covalent alkylation selectivity and stabilizes the DNA-agent covalent complex formation. The results of the study suggest that it is the simple event of DNA covalent complex stabilization that potentiates the cytotoxic activity of the agents. The synthesis and comparative evaluation of (+)-CBI-indole$\sb2$ (18) are detailed in efforts that further substantiate a direct relationship between the chemical stability of the agents and their biological potency/DNA alkylation intensity. The inverse relationship between the cytotoxic potency and improved in vivo antitumor activity of the agents and their solvolytic reactivity suggests that an agent's relative stability may constitute the relevant feature for design of improved functional analogs. The preparation and DNA binding properties of ACDPI$\sb{\rm n}$ (25-28, n = 1-4) and TACDPI$\sb{\rm n}$ (29-31, n = 1-3) are detailed. Comparable to observations made with CDPI$\sb{\rm n}$ (n = 1-5), the examination of ACDPI$\sb{\rm n}$ revealed that ACDPI$\sb3$ is the optimal minor groove binding agent within the series and that the agents exhibit a selectivity for AT vs GC rich DNA which is most pronounced with ACDPI$\sb3$. Similarly, TACDPI$\sb{\rm n}$ (n = 1-3) exhibited a substantial AT vs GC DNA binding selectivity. The direct comparison of the parent CDPI$\sb{\rm n}$ with ACDPI$\sb{\rm n}$ illustrates that the introduction of a C-5 amino substituent onto the peripheral face of the agent reduces the binding affinity, presumably through introduction of destabilizing electrostatic interactions. In contrast, the comparison with TACDPI$\sb{\rm n}$ revealed that the introduction of a C-5 quaternary amine substantially enhanced the binding affinity, presumably through introduction for stabilizing electrostatic interactions. A full investigation of the scope of the participation of 3,6-bis(methylthio)-1,2,4,5-tetrazine (42) in (4+2) cycloaddition reactions is detailed. The use of the resulting 3,6-bis(methylthio)-1,2-diazine cycloadducts as direct precursors to the parent 4,5-substituted-1,2-diazines as well as alkyne/allene 1,2-diazines suitable for use in subsequent intramolecular Diels-Alder reactions are described. The latter application constitutes the direct implementation of a divergent indoline/indole Diels-Alder strategy. The total synthesis of combretastatin D-2, a cytotoxic constituent of Combretum caffrum (combretaceae), is detailed and is based on the implementation of a key intramolecular Ullmann macrocyclization reaction for formation of the cyclic 15-membered caffrane biaryl ether.

Degree

Ph.D.

Advisors

Boger, Purdue University.

Subject Area

Organic chemistry|Pharmacology

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