The kinetics of 18 different donor-acceptor cyclopropanes in the (3+2)-cycloaddition reaction with aldehyde were studied by insitu NMR spectroscopy. Increasing the electron density of the donor residue accelerates the reaction to a factor up to 50 compared to the unsubstituted one whereas electron withdrawing substituents slow down the reaction 660 times. This behavior is in agreement with the Hammett substituent parameter σ. The obtained rate constants form the (3+2)-cycloaddition correlated well with respective data from additionally studied (3+n)-cycloadditions with nitrone (n = 3) and isobenzofurane (n = 4). A comparison of the kinetic data with bond lengths in the cyclopropane (obtained by X-ray and computations), and 1 H and 13 C NMR shifts revealed no correlation. However, computed relaxed force constants of D-A cyclopropanes proved to be a good indicator for the reactivity of the three-membered-ring.
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.
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.
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 3 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.
Dedicated to the memory of Prof. Walter A. SzarekIndoleamine 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 50 = 0.16 μM, EC 50 = 0.3 μM). Structuralactivity 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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