The purpose of this application is to continue the development of cascade guanidine hydroamination sequences, developed in our laboratory, to prepare highly substituted 2-aminoimidazoles and polyclic guanidine scaffolds and study their rich and diverse biological activities. Specifically, this proposal targets three important structures: (1) We have identified a new class of N2-acyl-2-aminoimidazoles as Zn2+ ionophores that selectively kill breast cancer cells. These compounds cause the active uptake of Zn2+ by cells, leading to Zn2+- dyshomeostasis. Studies will optimize our lead structure (named ZNA) to achieve a complex balance of pKa and pZn (?log [Zn2+]free) which underpins this scaffold's activity of inducing zinc dyshomeostasis and lysosomal membrane depolarization. These compounds are active in vivo and are well tolerated, providing an important therapeutic lead for the treatment of breast cancer. Since this mechanism of action is not receptor mediated, these compounds are active against the major breast cancer subtypes including ER?, HER2? and PR? or triple negative cells. (2) We have developed a powerful cascade hydroamination sequence to construct the bis- guanidine core of (+)-saxitoxin. An extension of this strategy will target the synthesis of zetekitoxin AB (ZTX) a more complex and potent member of the voltage gated sodium channel (Nav) inhibitors that shares this bis- guanidine core. ZTX represents a powerful tool to study ion channel physiology, however, only 0.3 mg of the purified compound exists in human hands. The frog that produces this compound is critically endangered and protected by the Panamanian government. Thus the extreme rarity of this natural product dictates that only total chemical synthesis can provide this compound to the community. (3) Lastly, we will target guadinomine B, a unique carbamoylguanidine containing natural product that we believe is actually the same as NA22598A1, as they are structurally similar and both isolated from Streptomyces spp.. If they are indeed the same, their ascribed activities as an inhibitor of type 3 secretion system mediated pathogenesis (guadinomine B) and inhibition of anchorage independent growth / metastasis (NA22598A1) suggests an overlapping biological target. We advance the hypothesis that this common target is a matrix metalloproteinase (MMP), and that their inhibitory activity relies on Zn2+ chelation by the carbamoylguanidine. If guadinomine B's target is indeed an MMP, this offers a new therapeutic strategy to prevent bacterial pathogenesis, critical to the treatment of human disease (e.g. meningitis, cholera, the plague), either with compounds inspired by these natural products or the abundance of well-developed MMP inhibitors.

Public Health Relevance

The purpose of this application is to develop new chemistry to access important and medicinally relevant natural product architectures. This chemistry permits conceptually new approaches to nitrogen rich heterocycles poised to better human health. Specifically, this chemistry will be deployed to construct molecules as therapeutic leads for the treatment of breast cancer, as tools to study the physiology of ion channels and as leads for the inhibition of bacterial pathogenesis / infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM090082-06A1
Application #
9177653
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Lees, Robert G
Project Start
2010-05-01
Project End
2020-04-30
Budget Start
2016-09-01
Budget End
2017-04-30
Support Year
6
Fiscal Year
2016
Total Cost
$199,773
Indirect Cost
$67,473
Name
University of Utah
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Salvant, Justin M; Edwards, Anne V; Kurek, Daniel Z et al. (2017) Regioselective Base-Mediated Cyclizations of Mono-N-acylpropargylguanidines. J Org Chem 82:6958-6967
Kwon, Ki-Hyeok; Edwards, Anne V; Yang, Miao et al. (2017) Exploring hydroamination-cycloaddition-fragmentation sequences to access polycyclicguanidines and vinyl-2-aminoimidazoles. Tetrahedron 73:6067-6079
Paladugu, Srinivas R; Looper, Ryan E (2015) Preparation of a 1,2-isoxazolidine synthon for the synthesis of zetekitoxin AB. Tetrahedron Lett 56:6332-6334
Basham, Kaitlin J; Leonard, Christopher J; Kieffer, Collin et al. (2015) Dioxin exposure blocks lactation through a direct effect on mammary epithelial cells mediated by the aryl hydrocarbon receptor repressor. Toxicol Sci 143:36-45
Gibbons, Joseph B; Salvant, Justin M; Vaden, Rachel M et al. (2015) Synthesis of Naamidine A and Selective Access to N(2)-Acyl-2-aminoimidazole Analogues. J Org Chem 80:10076-85
Kwon, Kihyeok; Haussener, Travis J; Looper, Ryan E (2015) Preparation of Mono-Cbz Protected Guanidines. Organic Synth 92:91-102
Kwon, Ki-Hyeok; Serrano, Catherine M; Koch, Michael et al. (2014) Synthesis of bicyclic guanidines via cascade hydroamination/Michael additions of mono-N-acryloylpropargylguanidines. Org Lett 16:6048-51
Basham, Kaitlin J; Bhonde, Vasudev R; Kieffer, Collin et al. (2014) Bis-aryloxadiazoles as effective activators of the aryl hydrocarbon receptor. Bioorg Med Chem Lett 24:2473-6
Yang, Miao; Odelberg, Shannon J; Tong, Zongzhong et al. (2013) Cationic dirhodium carboxylate-catalyzed synthesis of dihydropyrimidones from propargyl ureas. Tetrahedron 69:5744-5750
Gligorich, Keith M; Vaden, Rachel M; Shelton, Dawne N et al. (2013) Development of a screen to identify selective small molecules active against patient-derived metastatic and chemoresistant breast cancer cells. Breast Cancer Res 15:R58

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