Date of Graduation
Summer 8-11-2026
Document Type
Thesis
Degree Name
Master of Science in Chemistry
College/School
College of Arts and Sciences
Department/Program
Chemistry
First Advisor
Herman Nikolayevskiy
Second Advisor
Janet Yang
Third Advisor
Jennifer Tripp
Abstract
Broad-range DNA damaging agents are still some of the most widely prescribed medications for cancer patients today. However, due to their lack of selectivity, off-target effects and collateral tissue damage are a serious concern with use of these therapies for both short-term and long-term patient health. Inspired by the ability of the DNA alkylator ficellomycin to selectively deactivate itself, we aimed to create a novel DNA alkylator with an “off-switching” mechanism reverse to a typical prodrug. A first generation-compound was synthesized and designed by two previous graduate students, who were able to successfully confirm the desired deprotection-cyclization sequence. However, when the compounds were deprotected in the presence of DNA under UV radiation, the deprotection process caused extraneous DNA damage, and the electrophilic warhead alone did not cause sufficient DNA damage.
To address this, a new compound was designed with a linked DNA intercalator as a means to improve DNA specificity and increase alkylation ability. The addition of the intercalator brought the compound to single-μM binding affinity in docking experiments. Convergent synthesis of the compound was successful until the last step, but the final epoxide formation step could not occur using established methods. This was likely due to the amine tail on the intercalator that oxidized significantly more readily than a terminal alkene and was potentially nucleophilic, causing the molecule to self-immolate. Early-stage assays showed some promise for the compound in isolated portions, with electrophilic warhead model compounds alkylating the guanine mimic NBP significantly more than known alkylator methyl methanesulfonate (MMS). However, other assays revealed insurmountable issues in near-full compound evaluations, including inadequate cell membrane permeability and inactive compound binding affinities being within only one scale of magnitude to the free intercalators. Future work on a different, intercalator-only deactivating scaffold is being continued in the Nikolayevskiy lab.
Recommended Citation
Albrecht, Christine Marie, "Design and early-stage evaluation of a novel DNA alkylating agent with an “off-switching” mechanism" (2026). Master's Theses. 1661.
https://repository.usfca.edu/thes/1661
Included in
Heterocyclic Compounds Commons, Medicinal and Pharmaceutical Chemistry Commons, Medicinal-Pharmaceutical Chemistry Commons, Nucleic Acids, Nucleotides, and Nucleosides Commons, Organic Chemicals Commons, Organic Chemistry Commons
