Chemistry and biology of topoisomerase I inhibitors: Indenoisoquinolines and camptothecins

Xiangshu Xiao, Purdue University

Abstract

Topoisomerase I (top1) inhibitors have been shown to possess promising anticancer responses in clinical trials. This dissertation is dealing with two classes of top1 inhibitors. The first class of top1 inhibitors studied is indenoisoquinolines. In order to design better indenoisoquinoline analogs as anticancer drugs, a hypothetical binding model of indenoisoquinoline in the DNA-top1 cleavage complex was proposed based on the structural similarity between indenoisoquinoline and camptothecin (CPT). This model was further confirmed by quantum mechanics calculation, X-ray crystallography, and biological results of a pair of indenoisoquinoline enantiomers. Using this model as the design scaffold, a series of 11-aminoalkenyl- and 11-diaminoalkenylindenoisoquinolines were designed and they showed potent top1 inhibition as well as cytotoxicity. The 11-substituents are proposed to project into the DNA minor groove in the DNA-top1 cleavage complexes. A potential DNA threading indenoisoquinoline with amino alkyl substituents at both C-11 and N-6 positions was also designed and synthesized. Although the threading agent demonstrated no top1 inhibition, a novel autoxidative cleavage reaction of 9-fluoredenes was discovered during the synthesis of this threading agent. Some indenoisoquinolines with modified 8,9-methylenedioxy moieties were also designed and synthesized based on the conformational differences in the nonscissile DNA strand between the DNA-top1 binary complex and DNA-top1-indenoisoquinoline ternary complex. Some of the indenoisoquinolines with aminoalkyl side chains displayed potent top1 inhibition, but generally they are not cytotoxic. The second class of top1 inhibitors investigated is CPTs, a classical type of top1 inhibitors. In order to understand the molecular forces dictating the binding orientation of CPT in the DNA-top1 cleavage complex, a quantum mechanics calculation was done by hypothesizing the π-π stacking interactions between CPT and its flanking base pairs are the predominant contribution to the binding interaction. The calculation results considering only the it-at stacking interactions can not only reproduce the experimental binding orientation of CPT, but also correlates very well with the experimentally observed DNA sequence selectivity in SV40 viral genome. Furthermore, the loss of biological activity of (R)-CPT and CPT-lactam is also due to the differences in π-π stacking. Based on the "π-stacking hypothesis", some aromathecins were designed and synthesized.

Degree

Ph.D.

Advisors

Cushman, Purdue University.

Subject Area

Pharmacology|Organic chemistry

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