ABSTRACT
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 (IC50 =0.16â µM, EC50 =0.3â 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.
Subject(s)
Enzyme Inhibitors/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
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. AlCl3 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.
ABSTRACT
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.
Subject(s)
Duocarmycins/pharmacology , Protein Kinase Inhibitors/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Aldehyde Dehydrogenase 1 Family/antagonists & inhibitors , Aldehyde Dehydrogenase 1 Family/chemistry , Humans , Vascular Endothelial Growth Factor Receptor-2/chemistryABSTRACT
The kinetics of (3+2) cycloaddition reactions of 18 different donor-acceptor cyclopropanes with the same aldehyde were studied by inâ 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 1 H and 13 Câ 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.
ABSTRACT
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.
ABSTRACT
A synthetic procedure to access 2-unsubstituted pyrrolidines and piperidines is presented. In the presence of MgI2 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.
