Final Report Summary - TBKO (Synthesis and Biological Evaluation of a Potent Antituberculosis Natural Product and Analogues)
Summary description: The aim of this project was the total synthesis, full structural characterization of the natural product epidithiodiketopiperazine 1 and the design and synthesis of analogues thereof aiming at optimization of its properties and development of useful tool compounds. Epidithiodiketopiperazine 1 exhibits potent antimycobacterial activity with an MIC value of 0.15 ng/mL and is directly relevant to studies on developing novel therapies for tuberculosis (TB). The construction of a small library of analogues of epidithiodiketopiperazine and subsequent SAR studies are expected to lead to the design of compounds with improved biological and pharmacological properties.
Figure 1. Structure of epidithiodiketopiperazine 1
Description of the work: During the first year of the project, a multiple-step procedure was applied towards the synthesis of the parent diketopiperazine 3 starting from N-Boc-L-Tyrosine 2. During the shortened return phase, the biological evaluation of synthesized compounds was performed, revealing important information about the structure of the compounds.
Scheme 1. Synthesis of parent compound 3
Description of the main results: The initially proposed strategy for the synthesis of 3 starting from the monomeric oxepine compound 5 appeared to be problematic. The step for the oxepine ring formation was significantly low yielding and the quantities of 5 isolated were insufficient for further use. As such, a different approach was proposed which included the synthesis of the dimeric unit 6 first and then the attempt for the double oxepine ring formation at the end which failed to give any of the desired product and instead led to total decomposition of the starting material (Scheme 2).
Scheme 2. Initially proposed and alternative synthetic strategy
In parallel, few diketopiperazine analogues were synthesized and underwent biological evaluation (for structures see figure 2).
Figure 2. Structures of analogues synthesized
Results and impact: The biological evaluation of the compounds showed no significant activity against Tuberculosis in its non-replicating form but both compounds inhibited TB in its replicating form. The fact that the compounds were efficacious on the replicating vs non-replicating form suggested a broader cytotoxicity. These results give a better understanding of the biological activity of the family of epidithiodiketopiperazines and opens up opportunities for future structure modifications.
Figure 1. Structure of epidithiodiketopiperazine 1
Description of the work: During the first year of the project, a multiple-step procedure was applied towards the synthesis of the parent diketopiperazine 3 starting from N-Boc-L-Tyrosine 2. During the shortened return phase, the biological evaluation of synthesized compounds was performed, revealing important information about the structure of the compounds.
Scheme 1. Synthesis of parent compound 3
Description of the main results: The initially proposed strategy for the synthesis of 3 starting from the monomeric oxepine compound 5 appeared to be problematic. The step for the oxepine ring formation was significantly low yielding and the quantities of 5 isolated were insufficient for further use. As such, a different approach was proposed which included the synthesis of the dimeric unit 6 first and then the attempt for the double oxepine ring formation at the end which failed to give any of the desired product and instead led to total decomposition of the starting material (Scheme 2).
Scheme 2. Initially proposed and alternative synthetic strategy
In parallel, few diketopiperazine analogues were synthesized and underwent biological evaluation (for structures see figure 2).
Figure 2. Structures of analogues synthesized
Results and impact: The biological evaluation of the compounds showed no significant activity against Tuberculosis in its non-replicating form but both compounds inhibited TB in its replicating form. The fact that the compounds were efficacious on the replicating vs non-replicating form suggested a broader cytotoxicity. These results give a better understanding of the biological activity of the family of epidithiodiketopiperazines and opens up opportunities for future structure modifications.
