The objective of this submission is to develop the recently isolated natural product neaumycin B into a lead for glioblastoma therapy. Neaumycin B is highly toxic to glioblastoma cells while being significantly less toxic toward other cell lines, suggesting the potential for a unique biological target. The lethality of glioblastomas and the limited options for their treatment provide ample justification to explore and advance new hits. Hits can also serve as the basis for identifying new biological targets that will allow for new assay development for screening additional structures that could show anti-glioblastoma activity. The supply of neaumycin B is limited due to its instability during the prolonged cultivation period. The first Specific Aim, therefore is to develop an efficient, modular synthesis of neaumycin B that will provide suitable quantities for subsequent biological studies and will be sufficiently flexible to be applicable to analog synthesis. The second Specific Aim is to prepare several analogs that address limitations in the advancement of neaumycin B as a lead in glioblastoma therapy. These include accessibility, which will be addressed by synthesizing simplified analogs, and stability, which will be addressed through replacing a conjugated triene unit with stable isosteres. The capacity to prepare chimeric structures through cycloaddition chemistry will be advanced by preparing alkyne-containing analogs. All analogs will be evaluated for their potency toward U87 glioblastoma cells and other cancer cell lines to establish a structure- activity relationship, to validate the observed cell line selectivity, and to guide the preparation of agents for identifying the biological target. The proteomics-based approach to identifying the biological target will facilitate assay development, which will facilitate screening studies for identifying new anti-glioblastoma hits.
Specific Aim 3 is directed toward using the microenvironment around a glioma or in a neurodegenerative disease to release a biological effector from a blood-brain barrier transporter. This will allow for localization of the agent in the brain since the release from the transporter will prevent the agents from efflux through the blood-brain barrier. This synthesis-intensive project will involve contributions from experts in chemical biology and proteomics to deliver new approaches for treating glioblastomas and other neurological conditions.
Glioblastomas are death sentences with very few options for therapy that provides even modest enhancements to survival times. This proposal explores the potential for the recently isolated, glioblastoma selective cytotoxic natural product neaumycin B to serve as lead to glioblastoma therapy. This will proceed through the design of a synthetic pathway that delivers the natural product and analogs in sufficient quantities for biological studies, validating the selectivity, identifying the biological target, and developing an approach that uses the oxidative environment of the tumor to concentrate the cytotoxin in proximity to its target.
