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.