Synthesis and structure-activity relationship studies of the calothrixins and other redox-active compounds

Abstract

Calothrixin A and B are novel pentacycIic qui nones that have been isolated from the Calothrix cyanobacteria. The calothrixins exhibit anti proliferative activity against chloroquine resistant strains of Plasmodium falciparum, the deadliest causative agent of malaria. Furthermore, these compounds have potent and selective activity against a range of human cancer cell lines. These biological properties have led to the identification of the calothrixins as lead compounds for drug development. A brief review of the calothrixins and other quinones, as well as an overview of Structure Activity (SAR) and Quantitative SAR studies is presented in Chapter 1. ... The ability of calothrixin A to undergo one-electron reduction to the semiquinone radical anion led to the hypothesis that calothrixin A may accumulate in cells. This mechanism of redox-driven accumulation of compounds was first observed in our SAR and QSAR studies of the epidithiopiperazine-2,5-diones (ETP compounds). These studies have led to the proposal that there is a relationship between the reduction potential of ETP compounds and the intracellular concentration of these toxins leading to redox-driven biological accumulation of the ETP compounds. To determine if the cellular accumulation of calothrixin A is driven by a similar process, uptake studies were carried out. This work is described in detail in Chapter 5. The details of the procedures for experiments carried out in Chapters 2 to 5 are given in Chapter 6, along with the relevant data used to characterize the synthetic compounds.