This proposal describes a highly unified, enantioselective strategy to the complex, bioactive marine alkaloids palau'amine, axinellamine, and styloguanidine from a common cyclopentane intermediate bearing either a cyclic urea-hydantoin or bis-cyclic guanidines heterocycles. This strategy is suggestive of one possible biogenesis of these natural products and in order to study the various hypotheses posited in the literature, we propose the synthesis of 15N-labelled putative biosynthetic precursors to be subjected to cell-free acetone preparations from producing marine sponges in collaboration with Prof. Ted Moiinski (UCSD). A novel method for imidazolone annulation and amino-imidazoline annulation of alkenes will be further developed useful for heterocycle synthesis beyond the current targets. The synthetic strategies proposed and completed (in the case of gymnodimine and now agelastatins) will be """"""""put to work"""""""" to enable synthesis of appropriate conjugates of these natural products to enable a molecular level understanding of the bioacitivites exhibited by these anticancer agents and also begin to unravel the biosynthesis of higher order pyrrole-2-aminoimidazoIe alkaloids. In the case of gymnodimine, further SAR studies and mice toxicity will establish the potential of this natural product as both a cellular probe and as a public health hazard. The biomechanistic studies are enabled by continued productive collaborations with Prof. Jun Liu (Johns Hopkins).

Public Health Relevance

The natural products targeted in this proposal all possess potent biological effects including antibacterial, immunosuppressive, neuoronal, and antitumor effects thus having potential for the treatment of human disease including bacterial infection, inflammation, nervous system disorders, 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 and improve supply. 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 marine sponges that produce these complex natural products enabling alternative means to prepare these potential drug leads on scale.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37GM052964-20
Application #
8631384
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Fabian, Miles
Project Start
1995-08-01
Project End
2019-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
20
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Texas A&M University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
College Station
State
TX
Country
United States
Zip Code
77845
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
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
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
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
Stout, E Paige; Morinaka, Brandon I; Wang, Yong-Gang et al. (2012) De novo synthesis of benzosceptrin C and nagelamide H from 7-15N-oroidin: implications for pyrrole-aminoimidazole alkaloid biosynthesis. J Nat Prod 75:527-30
Reyes, Jeremy Chris P; Romo, Daniel (2012) Bioinspired total synthesis of agelastatin A. Angew Chem Int Ed Engl 51:6870-3
Kong, Ke; Moussa, Ziad; Lee, Changsuk et al. (2011) Total synthesis of the spirocyclic imine marine toxin (-)-gymnodimine and an unnatural C4-epimer. J Am Chem Soc 133:19844-56
Wang, Yong-Gang; Morinaka, Brandon I; Reyes, Jeremy Chris P et al. (2010) Synthesis of 7-(15)N-Oroidin and evaluation of utility for biosynthetic studies of pyrrole-imidazole alkaloids by microscale (1)H-(15)N HSQC and FTMS. J Nat Prod 73:428-34
Kuznetsov, Galina; Xu, Qunli; Rudolph-Owen, Lori et al. (2009) Potent in vitro and in vivo anticancer activities of des-methyl, des-amino pateamine A, a synthetic analogue of marine natural product pateamine A. Mol Cancer Ther :