Agelastatin A

Agelastatin A (AglA) is a marine natural product isolated from an axinellid sponge Agelas dendromorpha. As one of the most bioactive members of the pyrrole-aminoimidazole family, AglA features a compact tetracyclic (A-pyrrole, B-acylpiperazine, C-cyclopentane, and D imidazolone rings) structure bearing 4 stereogenic carbons with an overall staircase-like 3-dimensional structure. AglA demonstrated significant cytotoxicity against a panel of human cancer cell lines (with IC50 ranging from 0.097-0.703 L) 1 and has excellent blood-brain barrier penetration.2 In addition, AglA also inhibits glycogen synthase kinase-3 (GSK-3), a kinase that may be involved in the early stages of Alzheimer’s disease and type 2 diabetes mellitus.3 Its novel structure and potent biological activity have prompted considerable synthetic and biological studies.

Until recently, the mechanism of action responsible for the cancer cell cytotoxicity of AglA was unknown. In 2017, collaborators at Johns Hopkins University (groups of Prof. Jun O. Liu and Rachel Green) and the CNRS in France (Prof. Marat Yusupov), using the natural product and derivatives synthesized in the Romo Group, determined that AglA functions by disrupting protein synthesis at the elongation phase. 4,5 Using in vitro translation assays, molecular modeling, chemical footprinting, and subsequently X-ray crystallography, it was determined that AglA binds to the A site of the Peptidyl Transfer Center (PTC) of the yeast 80S ribosomal subunit preventing peptide bond formation and thus inhibiting protein synthesis.4 The AglA-80S crystal structure revealed key conformational changes that take place to nucleotides in the PTC upon AglA binding. Furthermore, the X-ray structure revealed key binding interactions between AglA and nucleotides that include -stacking, H-bonding (reminiscent of Watson-Crick pairing), and halogen–stacking.4

The results of this study laid the groundwork for the present efforts of the Baylor MiniPharma team in designing, modeling, and then synthesizing new derivatives of Agelastatin A followed by measuring their relative cytotoxic properties compared to the natural product. The Baylor Undergraduate MiniPharma Team is an interdisciplinary, collaborative effort including the Design and Synthesis Group working with Prof. Romo, the Molecular Modeling Group working with Prof. Shuford, and the Biological Assay team working with Prof. Taube to design, synthesize and test novel AglA derivatives.

1. Kumaraguru, T., Babita, P., Sheelu, G., Lavanya, K. & Fadnavis, N. W. Synthesis of Enantiomerically Pure 4-Hydroxy-2-cyclopentenones. Org. Process Res. Dev. 17, 1526–1530 (2013).
2. Al-Mourabit, A., Zancanella, M. A., Tilvi, S. & Romo, D. Biosynthesis, asymmetric synthesis, and pharmacology, including cellular targets, of the pyrrole-2-aminoimidazole marine alkaloids. Nat. Prod. Rep. 28, 1229–1260 (2011).
3. Dong, G. Recent advances in the total synthesis of agelastatins. Pure Appl. Chem. 82, 2231–2246 (2010).
4. McClary, B. et al. Inhibition of Eukaryotic Translation by the Antitumor Natural Product Agelastatin A. Cell Chem. Biol. 24, 605–613.e5 (2017).
5. Jouanneau, M. et al. Derivatization of agelastatin A leading to bioactive analogs and a trifunctional probe. Bioorg. Med. Chem. Lett. 26, 2092–2097 (2016).