Natural products that interfere in a specific and potent manner with cellular processes have proven to be useful probes in cell biology research. In particular, agents that exhibit specific cellular effects have served as powerful biochemical tools for dissecting molecular mechanisms of signal transduction pathways involved in various cellular functions. This proposal seeks to further exploit the rich potential of marine natural products in this regard building on our previous success with the marine alkaloid pateamine A, a novel eukaryotic protein synthesis inhibitor, in collaboration with Prof. Jun Liu (Johns Hopkins). Principal aims include a highly unified, enantioselective strategy to the complex, bioactive marine alkaloids palau'amine, axinellamine, and styloguanidine from a common cyclopentane intermediate bearing either cyclic urea-hydantoin or bis-cyclic guanidine heterocycles. This strategy is suggestive of one possible biogenesis of these natural products and as a means to study the various hypotheses posited in the literature, we propose the synthesis of singly- and doubly-15N-labelled oroidin and sceptrin for biosynthetic feeding experiments in collaboration with Prof. Ted Molinski (UCSD). A novel and concise cascade process will be studied for the synthesis of the antimetastatic agent agelastatin A enabling cellular receptor isolation studies in collaboration with Prof. Coran Watanabe (TAMU) building on known SAR data. Employing our synthesis of gymnodimine, we propose synthesis of haptens for eventual development of an ELISA assay for this marine toxin in collaboration with Prof. Chris Elliott (UK). The synthetic strategies proposed and completed (in the case of gymnodimine and phakellstatin) will be """"""""put to work"""""""" to enable synthesis of biotin and fluorophore conjugates of palau'amine, phakellstatin, and agelastatin A to enable a molecular level understanding of the immunosuppressive and antitumor activities exhibited by these agents and also to begin unraveling the biosynthesis of the oroidin alkaloids. The biomechanistic and biosynthetic studies are enabled by continued, productive collaborations with Prof. Liu and new collaborations with Profs. Watanabe and Molinski. Innovative aspects of this proposal include: (1) Proposed controlled, oxidative cyclizations from the common cyclopentane intermediate providing a highly unified strategy to several complex, oroidin dimers. (2) A novel N-acyliminium cascade process for a concise and versatile synthesis of agelastatin A and congeners further demonstrating the nucleophilic character of imidazolones. (3) Synthesis of `committed,'complex 15N-labelled precursors to provide the first direct data regarding intermediates in the proposed biogenetic pathways to more complex oroidin-alkaloids. (3) Hypothesis-driven biomechanistic studies of spirocyclic imine marine toxins building on our total synthesis of gymnodimine. The end results of these studies will be identification of further useful biochemical tools and potential leads for drug development as demonstrated with pateamine A.
The natural products targeted in this proposal all possess potent biological effects including antibacterial, immunosuppressive, and antitumor effects thus having potential for the treatment of human disease including bacterial infection, inflammation, and cancer. We propose unique, concise synthetic strategies to prepare these natural products and derivatives to address questions regarding the molecular details of their interactions in cells. Subsequent mode of action studies of these compounds including cellular target elucidation will contribute to fundamental studies in cell biology and define the potential of these natural products as drug leads. In addition, the studies proposed will begin to shed light on the biosynthetic pathways used by the producing marine sponges that produce these complex natural products.
|McClary, Brandon; Zinshteyn, Boris; Meyer, Mélanie et al. (2017) Inhibition of Eukaryotic Translation by the Antitumor Natural Product Agelastatin A. Cell Chem Biol 24:605-613.e5|
|Abbasov, Mikail E; Hudson, Brandi M; Kong, Weixu et al. (2017) Enantioselective Diels-Alder-lactamization organocascades employing a furan-based diene. Org Biomol Chem 15:3179-3183|
|Zhu, Mingzhao; Harshbarger, Wayne D; Robles, Omar et al. (2017) A strategy for dual inhibition of the proteasome and fatty acid synthase with belactosin C-orlistat hybrids. Bioorg Med Chem 25:2901-2916|
|Jouanneau, Morgan; McClary, Brandon; Reyes, Jeremy Chris P et al. (2016) Derivatization of agelastatin A leading to bioactive analogs and a trifunctional probe. Bioorg Med Chem Lett 26:2092-7|
|Vellalath, Sreekumar; Romo, Daniel (2016) Asymmetric Organocatalysis: The Emerging Utility of ?,?-Unsaturated Acylammonium Salts. Angew Chem Int Ed Engl 55:13934-13943|
|He, Qing-Li; Titov, Denis V; Li, Jing et al. (2015) Covalent modification of a cysteine residue in the XPB subunit of the general transcription factor TFIIH through single epoxide cleavage of the transcription inhibitor triptolide. Angew Chem Int Ed Engl 54:1859-63|
|Abbasov, Mikail E; Romo, Daniel (2014) The ever-expanding role of asymmetric covalent organocatalysis in scalable, natural product synthesis. Nat Prod Rep 31:1318-27|
|Low, Woon-Kai; Li, Jing; Zhu, Mingzhao et al. (2014) Second-generation derivatives of the eukaryotic translation initiation inhibitor pateamine A targeting eIF4A as potential anticancer agents. Bioorg Med Chem 22:116-25|
|Liu, Gang; Shirley, Morgan E; Van, Khoi N et al. (2013) Rapid assembly of complex cyclopentanes employing chiral, ?,?-unsaturated acylammonium intermediates. Nat Chem 5:1049-57|
|Stout, E Paige; Wang, Yong-Gang; Romo, Daniel et al. (2012) Pyrrole aminoimidazole alkaloid metabiosynthesis with marine sponges Agelas conifera and Stylissa caribica. Angew Chem Int Ed Engl 51:4877-81|
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