Abstract A025: Design and synthesis of a novel DNA alkylating agent as a potential treatment for glioblastoma

Abstract Amongst all brain cancers, glioblastoma (GB) is the most frequently diagnosed in adults and has the highest mortality rate 1. The dismally short survival period after diagnosis (8–15 months) is due to the challenges of rapid disease progression, development of drug resistance, and capability for self-renewal of GB cancer stem cells 2. The current front-line treatments for GB are a small set of DNA alkylating agents, but their activity is constrained by low permeability through the blood-brain barrier (BBB) 3. Thus, there is an urgent need to develop effective DNA-targeted chemotherapeutics that have enhanced BBB permeability. Preliminary studies by the Hunter research group found that phenazine derivatives containing twin aziridine moieties are cytotoxic towards a range of cancer cell lines, including GB, in the single-digit nanomolar range 4. The phenazine intercalates DNA while the aziridines form covalent bonds to bases within each of the two DNA strands. However, these potent first-generation cytotoxins were not BBB-permeable 4. In this work, we designed and realized the synthesis of a second-generation agent (see below) that is computationally predicted to be more BBB-permeable. Notably, the synthesis encompassed the first total synthesis of a C2-symmetric natural product from Bravibacterium sp. 5, which then underwent further functionalisation to give our novel designed molecule. Current work is focused on measuring the BBB permeability, DNA-binding properties, and cytotoxic activity. Citation Format: Ramsha Iftikhar. Design and synthesis of a novel DNA alkylating agent as a potential treatment for glioblastoma abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (6Suppl): Abstract nr A025.