Publications by authors named "Deborah A Smithen"

12 Publications

  • Page 1 of 1

2-Aminomethylene-5-sulfonylthiazole Inhibitors of Lysyl Oxidase (LOX) and LOXL2 Show Significant Efficacy in Delaying Tumor Growth.

J Med Chem 2020 03 4;63(5):2308-2324. Epub 2019 Sep 4.

Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield SK10 4TG, United Kingdom.

The lysyl oxidase (LOX) family of extracellular proteins plays a vital role in catalyzing the formation of cross-links in fibrillar elastin and collagens leading to extracellular matrix (ECM) stabilization. These enzymes have also been implicated in tumor progression and metastatic disease and have thus become an attractive therapeutic target for many types of invasive cancers. Following our recently published work on the discovery of aminomethylenethiophenes (AMTs) as potent, orally bioavailable LOX/LOXL2 inhibitors, we report herein the discovery of a series of dual LOX/LOXL2 inhibitors, as well as a subseries of LOXL2-selective inhibitors, bearing an aminomethylenethiazole (AMTz) scaffold. Incorporation of a thiazole core leads to improved potency toward LOXL2 inhibition via an irreversible binding mode of inhibition. SAR studies have enabled the discovery of a predictive 3DQSAR model. Lead AMTz inhibitors exhibit improved pharmacokinetic properties and excellent antitumor efficacy, with significantly reduced tumor growth in a spontaneous breast cancer genetically engineered mouse model.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073924PMC
March 2020

Synthesis and Photobiological Activity of Ru(II) Dyads Derived from Pyrrole-2-carboxylate Thionoesters.

Inorg Chem 2017 Apr 16;56(7):4121-4132. Epub 2017 Mar 16.

Department of Chemistry, Dalhousie University , P.O. Box 15000, Halifax, Nova Scotia B3H 4R2, Canada.

The synthesis and characterization of a series of heteroleptic ruthenium(II) dyads derived from pyrrole-2-carboxylate thionoesters are reported. Ligands bearing a conjugated thiocarbonyl group were found to be more reactive toward Ru(II) complexation compared to analogous all-oxygen pyrrole-2-carboxylate esters, and salient features of the resulting complexes were determined using X-ray crystallography, electronic absorption, and NMR spectroscopy. Selected complexes were evaluated for their potential in photobiological applications, whereupon all compounds demonstrated in vitro photodynamic therapy effects in HL-60 and SK-MEL-28 cells, with low nanomolar activities observed, and exhibited some of the largest photocytotoxicity indices to date (>2000). Importantly, the Ru(II) dyads could be activated by relatively soft doses of visible (100 J cm, 29 mW cm) or red light (100 J cm, 34 mW cm), which is compatible with therapeutic applications. Some compounds even demonstrated up to five-fold selectivity for malignant cells over noncancerous cells. These complexes were also shown to photocleave, and in some cases unwind, DNA in cell-free experiments. Thus, this new class of Ru(II) dyads has the capacity to interact with and damage biological macromolecules in the cell, making them attractive agents for photodynamic therapy.
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http://dx.doi.org/10.1021/acs.inorgchem.7b00072DOI Listing
April 2017

Probing the hydrolytic reactivity of 2-difluoromethyl pyrroles.

Org Biomol Chem 2016 Dec;15(1):144-152

Department of Chemistry, Dalhousie University, P.O. Box 15000, Halifax, NS B3H 4R2, Canada.

α-Difluoromethyl pyrroles were found to be stable while N-protected with an electron-withdrawing group. Due to the propensity of pyrroles to access azafulvenium-like intermediates, the C-F bonds of an α-difluoromethyl substituent are labile under hydrolytic conditions. The presence of certain electron-withdrawing substituents about the pyrrolic ring can accelerate this process, as determined through a kinetic comparison of the deprotection and subsequent hydrolysis reactions of N-protected β-aryl α-difluoromethyl pyrroles.
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http://dx.doi.org/10.1039/c6ob01441kDOI Listing
December 2016

Eight-membered ring-containing jadomycins: implications for non-enzymatic natural products biosynthesis.

J Am Chem Soc 2015 Mar 26;137(9):3271-5. Epub 2015 Feb 26.

Department of Chemistry and ⊥College of Pharmacy, Dalhousie University , Halifax, Nova Scotia B3H 4R2, Canada.

Jadomycin Oct (1) was isolated from Streptomyces venezuelae ISP5230 and characterized as a structurally unique eight-membered l-ornithine ring-containing jadomycin. The structure was elucidated through the semisynthetic derivatization of starting material via chemoselective acylation of the l-ornithine α-amino group using activated succinimidyl esters. Incorporation of 5-aminovaleric acid led to jadomycin AVA, a second eight-membered ring-containing jadomycin. These natural products illustrate the structural diversity permissible from a non-enzymatic step within a biosynthetic pathway and exemplifies the potential for discovery of novel scaffolds.
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http://dx.doi.org/10.1021/ja5114672DOI Listing
March 2015

Polyphosphate-containing bisubstrate analogues as inhibitors of a bacterial cell wall thymidylyltransferase.

Org Biomol Chem 2015 Mar;13(11):3347-50

Department of Chemistry, Dalhousie University, 6274 Coburg Rd., PO Box 15, 000, Halifax, Nova Scotia B3H 4R2, Canada.

A series of polyphosphate containing sugar nucleotide analogues were synthesized and evaluated as bisubstrate inhibitors of α-D-glucose 1-phosphate thymidylyltransferase Cps2L, the first enzyme in Streptococcus pneumoniael-rhamnose biosynthesis, and a novel antibacterial target. WaterLOGSY NMR spectroscopy demonstrated binding of bisubstrate analogues to Cps2L and a spectrophotometric coupled assay was used to determine apparent Ki values.
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http://dx.doi.org/10.1039/c4ob02583kDOI Listing
March 2015

Mechanistic evaluation of a nucleoside tetraphosphate with a thymidylyltransferase.

Biochemistry 2015 Mar 16;54(8):1703-7. Epub 2015 Feb 16.

Department of Chemistry, Dalhousie University , P.O. Box 15000, Halifax, Canada B3H 4R2.

Pyrimidine polyphosphates were first detected in cells 5 decades ago; however, their biological significance remains only partially resolved. Such nucleoside polyphosphates are believed to be produced nonspecifically by promiscuous enzymes. Herein, synthetically prepared deoxythymidine 5'-tetraphosphate (p4dT) was evaluated with a thymidylyltransferase, Cps2L. We have identified p4dT as a substrate for Cps2L and evaluated the reaction pathway by analysis of products using high-performance liquid chromatography, liquid chromatography and tandem mass spectrometry, and 31P nuclear magnetic resonance spectroscopy. Product analysis confirmed production of dTDP-Glc and triphosphate (P3) and showed no trace of dTTP-Glc and PPi, which could arise from alternative pathways for the reaction mechanism.
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http://dx.doi.org/10.1021/bi501438pDOI Listing
March 2015

Synthesis and antimalarial activity of prodigiosenes.

Org Biomol Chem 2014 Jun;12(24):4132-42

Department of Chemistry, Dalhousie University, PO BOX 15000, Halifax, NS B3H 4R2, Canada.

Several analogues of the natural compound prodigiosin with modified A- and C-rings were synthesised as were some of their tin, cobalt, boron and zinc complexes. The antimalarial activity of these prodigiosenes was evaluated in vitro using the 3D7 Plasmodium falciparum strain. The presence of a nitrogen atom in the A-ring is needed for antimalarial activity but the presence of an alkyl group at the β'-position of the C-ring seems detrimental. Dibutyl tin complexes exhibit IC50 values mostly in the nanomolar range with equal or improved activity compared to the free-base prodigiosene ligand, despite the fact that the general toxicity of such tin complexes is demonstrably lower than that of the free-bases.
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http://dx.doi.org/10.1039/c3ob42548gDOI Listing
June 2014

Investigations regarding the utility of prodigiosenes to treat leukemia.

Org Biomol Chem 2013 Jan;11(1):62-8

Department of Chemistry, Dalhousie University, Halifax, Nova Scotia B4P 2R6, Canada.

Prodigiosenes, possessing a 4-methoxypyrrolyldipyrrin skeleton, are known for their anti-cancer activity. Structural modification of the C-ring resulted in a series of prodigiosenes that displayed promising activity against leukemia cell lines during in vitro analysis against the NCI 60 cancer cell line panel. Further in vivo studies of these compounds using the zebrafish model showed persistence of anti-leukemia properties in human K562 chronic myelogenous leukemia cells.
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http://dx.doi.org/10.1039/c2ob26535dDOI Listing
January 2013

An improved method for the synthesis of F-BODIPYs from dipyrrins and bis(dipyrrin)s.

Org Lett 2012 Apr 4;14(8):2158-61. Epub 2012 Apr 4.

Department of Chemistry, Dalhousie University, P.O. Box 15000, Halifax, NS, B3H 4R2, Canada.

An improved methodology for the synthesis of F-BODIPYs from dipyrrins and bis(dipyrrin)s is reported. This strategy employs lithium salts of dipyrrins as intermediates that are then treated with only 1 equiv of boron trifluoride diethyletherate to obtain the corresponding F-BODIPYs. This scalable route to F-BODIPYs renders high yields with a facile purification process involving merely filtration of the reaction mixture through Celite in many cases.
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http://dx.doi.org/10.1021/ol300681wDOI Listing
April 2012

Asymmetric α-oxyacylation of cyclic ketones.

Org Biomol Chem 2012 May 2;10(18):3756-62. Epub 2012 Apr 2.

School of Chemistry, Cardiff University, Park Place, Cardiff, UK.

Reaction of cyclic ketones with chiral N-alkyl-O-acyl hydroxylamines leads to the corresponding α-oxyacylated carbonyl compound in up to 89% ee. The levels of asymmetric induction were influenced by solvent polarity, acid strength and, to a lesser extent, temperature. Increasing the steric bulk around the nitrogen atom of the hydroxylamine reagent led to increased levels of asymmetric induction, which was also found to be detrimental to the yield observed for the transformation. Examination of N- and O-substituents along with substrates revealed the scope and limitations of the procedure.
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http://dx.doi.org/10.1039/c2ob25293gDOI Listing
May 2012

Use of F-BODIPYs as a protection strategy for dipyrrins: optimization of BF(2) removal.

J Org Chem 2012 Apr 9;77(7):3439-53. Epub 2012 Mar 9.

Department of Chemistry, Dalhousie University, P.O. Box 15000, Halifax, Nova Scotia, Canada.

We recently reported the first general method for the deprotection of 4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes (F-BODIPYs) involving a microwave-assisted procedure for the removal of the BF(2) moiety, and liberation of the corresponding free-base dipyrrin. Further optimization of the reaction has resulted in a more convenient and accessible protocol. The availability of this new methodology enables BF(2)-complexation to be used as a dipyrrin protection strategy. Herein lies a detailed examination of the deprotection reaction, with a view to optimization and gaining mechanistic insight, and its application in facilitating a multistep synthesis of pyrrolyldipyrrins.
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http://dx.doi.org/10.1021/jo3002003DOI Listing
April 2012

One-pot synthesis of asymmetric annulated bis(pyrrole)s.

Org Lett 2011 Nov 12;13(21):5846-9. Epub 2011 Oct 12.

Department of Chemistry, Dalhousie University, 6274 Coburg Road, P.O. Box 15000, Halifax, Nova Scotia, B3H 4R2, Canada.

Condensation of activated functionalized pyrroles with acetone results in asymmetric bis(pyrrole)s, formed via ring annulation. The methodology is somewhat general and can be applied to a variety of ketones, as well as to a range of pyrrolic substrates that do not bear electron-withdrawing groups directly adjacent to the pyrrole ring.
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http://dx.doi.org/10.1021/ol202457nDOI Listing
November 2011