Publications by authors named "Alexander Kreft"

6 Publications

  • Page 1 of 1

A Series of 2-((1-Phenyl-1H-imidazol-5-yl)methyl)-1H-indoles as Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors.

ChemMedChem 2021 Jul 26;16(14):2195-2205. Epub 2021 May 26.

Krembil Research Institute, University Health Network, 60 Leonard Avenue, Toronto, ON M5T 2S8, Canada.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a promising therapeutic target in cancer immunotherapy and neurological disease. Thus, searching for highly active inhibitors for use in human cancers is now a focus of widespread research and development efforts. In this study, we report the structure-based design of 2-(5-imidazolyl)indole derivatives, a series of novel IDO1 inhibitors which have been designed and synthesized based on our previous study using N1-substituted 5-indoleimidazoles. Among these, we have identified one with a strong IDO1 inhibitory activity (IC =0.16 μM, EC =0.3 μM). Structural-activity relationship (SAR) and computational docking simulations suggest that a hydroxyl group favorably interacts with a proximal Ser167 residue in Pocket A, improving IDO1 inhibitory potency. The brain penetrance of potent compounds was estimated by calculation of the Blood Brain Barrier (BBB) Score and Brain Exposure Efficiency (BEE) Score. Many compounds had favorable scores and the two most promising compounds were advanced to a pharmacokinetic study which demonstrated that both compounds were brain penetrant. We have thus discovered a flexible scaffold for brain penetrant IDO1 inhibitors, exemplified by several potent, brain penetrant, agents. With this promising scaffold, we provide herein a basis for further development of brain penetrant IDO1 inhibitors.
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http://dx.doi.org/10.1002/cmdc.202100107DOI Listing
July 2021

Ring-Opening Reactions of Donor-Acceptor Cyclobutanes with Electron-Rich Arenes, Thiols, and Selenols.

Org Lett 2019 Aug 5;21(16):6315-6319. Epub 2019 Aug 5.

Donor-acceptor (D-A) cyclobutanes with two geminal ester groups as acceptors are reacted with electron-rich arenes as nucleophiles to afford ring-opened products. AlCl mediates this Friedel-Crafts-type reaction. A variety of donors and electron-rich arenes are used. Nucleophilic thiols and selenols also trigger this ring-opening reaction. Furthermore, a comparison of various physical parameters has been carried out for several D-A cyclobutanes.
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http://dx.doi.org/10.1021/acs.orglett.9b02197DOI Listing
August 2019

Bifunctional Duocarmycin Analogues as Inhibitors of Protein Tyrosine Kinases.

J Nat Prod 2019 01 8;82(1):16-26. Epub 2019 Jan 8.

Department of Pharmaceutical Biology and Biotechnology , Albert Ludwigs University Freiburg , Stefan-Meier-Strasse 19 , D-79104 Freiburg , Germany.

Bifunctional duocarmycin analogues are highly cytotoxic compounds that have been shown to be irreversible aldehyde dehydrogenase 1 inhibitors. Interestingly, cells with low aldehyde dehydrogenase 1 expression are also sensitive to bifunctional duocarmycin analogues, suggesting the existence of another target. Through in silico approaches, including principal component analysis, structure-similarity search, and docking calculations, protein tyrosine kinases, and especially the vascular endothelial growth factor receptor 2 (VEGFR-2), were predicted as targets of bifunctional duocarmycin analogues. Biochemical validation was performed in vitro, confirming the in silico results. Structural optimization was performed to mainly target VEGFR-2, but not aldehyde dehydrogenase 1. The optimized bifunctional duocarmycin analogue was synthesized. In vitro assays revealed this bifunctional duocarmycin analogue as a strong inhibitor of VEGFR-2, with low residual aldehyde dehydrogenase 1 activity. Altogether, studies revealed bifunctional duocarmycin analogues as a new class of naturally derived compounds that express a very high cytotoxicity to cancer cells overexpressing aldehyde dehydrogenase 1 as well as VEGFR-2.
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http://dx.doi.org/10.1021/acs.jnatprod.8b00233DOI Listing
January 2019

Kinetic Studies of Donor-Acceptor Cyclopropanes: The Influence of Structural and Electronic Properties on the Reactivity.

Angew Chem Int Ed Engl 2019 Feb 24;58(7):1955-1959. Epub 2019 Jan 24.

Technische Universität Braunschweig, Institut für Organische Chemie, Hagenring 30, 38106, Braunschweig, Germany.

The kinetics of (3+2) cycloaddition reactions of 18 different donor-acceptor cyclopropanes with the same aldehyde were studied by in situ NMR spectroscopy. Increasing the electron density of the donor residue accelerates the reaction by a factor of up to 50 compared to the standard system (donor group=phenyl), whereas electron-withdrawing substituents slow down the reaction by a factor up to 660. This behavior is in agreement with the Hammett substituent parameter σ. The obtained rate constants from the (3+2) cycloadditions correlate well with data from additionally studied (3+n) cycloadditions with a nitrone (n=3) and an isobenzofuran (n=4). A comparison of the kinetic data with the bond lengths in the cyclopropane (obtained by X-ray diffraction and computation), or the H and C NMR shifts, revealed no correlation. However, the computed relaxed force constants of donor-acceptor cyclopropanes proved to be a good indicator for the reactivity of the three-membered ring.
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http://dx.doi.org/10.1002/anie.201812880DOI Listing
February 2019

The Cyclopropyl Group as a Neglected Donor in Donor-Acceptor Cyclopropane Chemistry.

Org Lett 2018 04 20;20(7):2059-2062. Epub 2018 Mar 20.

D-A cyclopropanes bearing a simple cyclopropyl group as donor are shown to undergo a variety of [3+ n]-cycloaddition reactions ( n = 2-4). This behavior contrasts sharply with that of common D-A cyclopropanes with aliphatic donors. Kinetic experiments demonstrate that, in terms of donor ability, the cyclopropyl substituent lies between electron-rich and electron-neutral aryl donors.
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http://dx.doi.org/10.1021/acs.orglett.8b00603DOI Listing
April 2018

Synthesis of 2-Unsubstituted Pyrrolidines and Piperidines from Donor-Acceptor Cyclopropanes and Cyclobutanes: 1,3,5-Triazinanes as Surrogates for Formylimines.

J Org Chem 2017 09 15;82(17):9235-9242. Epub 2017 Aug 15.

Institute for Organic Chemistry, TU Braunschweig , Hagenring 30, 38106 Braunschweig, Germany.

A synthetic procedure to access 2-unsubstituted pyrrolidines and piperidines is presented. In the presence of MgI as Lewis acid, donor-acceptor cyclopropanes or corresponding cyclobutanes were treated with 1,3,5-triazinanes, leading to the five- or six-membered ring systems under mild conditions in yields up to 93%. This protocol tolerates a great variety of functional groups and thus provides an efficient entry to this class of pyrrolidines and piperidines.
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http://dx.doi.org/10.1021/acs.joc.7b01631DOI Listing
September 2017
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