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(6_Suppl):Abstract nr A025.