Peptides, both linear and cyclic, have begun to emerge as a viable therapeutic for the treatment of various diseases. As such, synthesizing these linear and macrocyclic peptides as natural product targets or related structural analogs can help us to understand their biological importance. Reniochalistatin E is a proline-rich macrocyclic peptide natural product first synthesized in 2017 by our laboratory, and screening against various cancerous cell lines revealed moderate to low cytotoxicity as a sole agent. We next became interested in studying this compound as a potentiating agent to identify any synergistic effects. Indeed, reniochalistatin E was unveiled to show potential intramolecular pi-stacking that enhanced the cytotoxicity of clinically used anti-cancer agents. To exploit this unique characteristic, attention was directed towards the modification of the tryptophan residue to enhance the synergistic effect with additional cytotoxic agents. To this, a phenylalanine-tryptophan exchange was undertaken to probe this hypothesis and was found to possess no detectable cytotoxicity variation. Together, the data collected supports further exploration with drug conjugate handles en route towards a novel drug delivery platform.