Pateamine A is a marine sponge-derived natural product that stabilizes human eukaryotic initiation factor 4A (eIF4A) onto mRNA. This ‘clamping’ results in translation inhibition and has expressed anti-cancer effects in vivo on pancreatic cancer and chronic lymphocytic leukemia cell lines. We are using Molecular Operating Environment (MOE) software to propose and dock novel derivatives which exhibit better mRNA selectivity, higher potency, and lower lipophilicity. Derivatives with favorable characteristics will be synthesized and tested for activity and selectivity.
Isolated from the marine sponge Spongionella gracilis and a member of the diterpene family, Gracilin A possesses a bisacetoxy tricyclic structure.1 Gracilin A is an inhibitor of cyclophilins A (CypA) and D (CypD) with IC50 values of 0.26 μM for CypD and 0.27 μM CypA, respectively. Inhibition of CypA has been shown to yield immunosuppression and inhibitors of CypD have been shown to provide neuroprotective effects.2,3 Gracilin’s novel structure and potent biological activity have prompted considerable synthetic and biological interest.
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.
Prototypical chemotherapeutic agents for cancer treatment are based on the concept of “one-drug, one-target, one-disease”, but most forms of cancer have the ability to develop resistance mutations or are able to up-regulate targeted proteins to elude treatment with a single therapeutic agent. Polypharmacology, previously considered undesirable for a drug, has re-emerged as an approach to cancer therapy by acting on multiple targets or cellular pathways.1 Anticancer drugs displaying polypharmacology are thought to evade drug resistance due to the need for cells to become resistant across multiple pathways through simultaneous protein/enzyme mutations.