SummaryLysR-type transcriptional regulators (LTTRs) constitute the largest family of regulators in prokaryotes. The full-length structures of the LTTR TsaR from Comamonas testosteroni T-2 and its complex with the natural inducer para-toluensulfonate have been characterized by X-ray diffraction. Both ligand-free and complexed forms reveal a dramatically different quaternary structure from that of CbnR from Ralstonia eutropha, or a putative LysR-type regulator from Pseudomonas aeruginosa, the only other determined full-length structures of tetrameric LTTRs. Although all three show a head-to-head tetrameric ring, TsaR displays an open conformation, whereas CbnR and PA01-PR present additional contacts in opposing C-terminal domains that close the ring. Such large differences may be due to a broader structural versatility than previously assumed or either, reflect the intrinsic flexibility of tetrameric LTTRs. On the grounds of the sliding dimer hypothesis of LTTR activation, we propose a structural model in which the closed structures could reflect the conformation of a ligand-free LTTR, whereas inducer binding would bring about local changes to disrupt the interface linking the two compact C-terminal domains. This could lead to a TsaR-like, open structure, where the pairs of recognition helices are closer to each other by more than 10 Å.
Permeability and oral bioavailability of macrocyclic peptides still represent difficult challenges in drug discovery. Despite the recognized potential of macrocyclic peptides as therapeutics, their use is still restricted to extracellular targets and intravenous administration. Indeed, macrocyclic peptides generally suffer from limited proteolytic stability, high clearance, and poor membrane permeability, and this leads to the absence of systemic exposure after oral administration. To overcome these limitations, we started to investigate the development of a general cyclic decapeptide scaffold that possesses ideal features for cell permeability and oral exposure. On the basis of a rigid hairpin structure, the scaffold design aimed to decrease the overall polarity of the compound, thereby limiting the energetic cost of NH desolvation and the entropy penalty during cell penetration. The results of this study also demonstrate the importance of rigidity for the β-turn design regarding clearance. To stabilize the scaffold in the desired β-hairpin conformation, the introduction of d-proline at the i+1 turn position proved to be beneficial for both permeability and clearance. As a result, cyclopeptide decamers with unprecedented high values for oral bioavailability and exposure are reported herein. NMR spectroscopy conformation and dynamic analysis confirmed, for selected examples, the rigidity of the scaffold and the presence of transannular hydrogen bonds in polar and apolar environments. Furthermore, we showed, for one compound, that its transition from a polar environment to an apolar one was accompanied by an increased molecular motion, revealing an entropy contribution to membrane permeation.
An efficient synthesis of [2.2]paracyclophane-4,15-dicarboxylic acid (11) from [2.2]paracyclophane (8) has been developed. The diacid was converted via the diazide 14 into the 4,15-diisocyanato[2.2]paracyclophane (15), a versatile intermediate that could be transformed into many new pseudogeminally substituted derivatives of 8. For example, treatment of 15 with alcohols provided the carbamates 16 and 17. On treatment of 15 with diisopropylamine, the urea 18 was obtained, whereas reduction with lithium aluminium hydride afforded the cyclic urea 20. Hydrolysis of 15 furnished the
MP2 and DFT calculations have been carried out for [n]circulenes for n=3 to 20 in order to predict the strain energy and topology of these cyclically condensed aromatic systems. To synthesise [4]circulene (2), 1,5,7,8-tetrakis(bromomethyl)biphenylene (14) was prepared from the corresponding tetramethyl derivative (8) and subjected to various dehalogenation reactions; all attempts to obtain [2.2]biphenylenophane (7) as a precursor for 2 by this route failed. Treatment of 14 with sodium sulfide furnished the thiaphanes 16 and 17, thermal and photochemical desulfurization of which also failed to provide 7. In a second approach [2.2]paracyclophane was converted to the pseudo-geminal dithiol 23, which was subsequently bridged to the thiaphanes 22 and 24. On flash vacuum pyrolysis at 800 degrees C these were converted exclusively into phenanthrene (30). An approach to dehydrochlorinate the commercial product PARYLENE C to the tetrahydro[4]circulene 7 led only to polymerisation. The X-ray structures of the intermediates 8, 14, 17, 23, 24, 26, and 35 are reported.
We report the synthesis and single crystal X-ray analysis of C 84 ( 14)ÁAgTPP (Ag tetraphenylporphyrin) cocrystal-the first ordered crystal structure containing a pristine higher fullerene.
High throughput screening and subsequent hit validation identified 4-isopropyl-3-(2-((1-phenylethyl)amino)-pyrimidin-4-yl)oxazolidin-2-one as a potent inhibitor of IDH1 R132H . Synthesis of the four separate stereoisomers identified the (S,S)-diastereomer (IDH125, 1f) as the most potent isomer. This also showed reasonable cellular activity and excellent selectivity vs IDH1 wt . Initial structure−activity relationship exploration identified the key tolerances and potential for optimization. X-ray crystallography identified a functionally relevant allosteric binding site amenable to inhibitors, which can penetrate the blood−brain barrier, and aided rational optimization. Potency improvement and modulation of the physicochemical properties identified (S,S)-oxazolidinone IDH889 (5x) with good exposure and 2-HG inhibitory activity in a mutant IDH1 xenograft mouse model. KEYWORDS: Mutant IDH1 inhibitor, allosteric inhibition, 2-HG, preclinical in vivo activity, 3-pyrimidin-4-yloxazolidin-2-one, chirality-defined potency H otspot heterozygous mutations in human cytoplasmic isocitrate dehydrogenase 1 (IDH1) at Arg 132 (R132*) have been identified in multiple cancer types, including acute myeloid leukemia (AML), glioma, chondrosarcoma, and cholangiocarcinoma. 1 These mutations have been shown to confer a neomorphic catalytic activity to produce high levels of intracellular R-2-hydroxyglutarate (2-HG) and effect downstream epigenetic markers on DNA and proteins. Recent clinical trials in AML patients with a specific inhibitor of IDH1 has shown clinical benefit, confirming the causal link between this genetic mutation, the production of 2-HG, and cancer.11 Efforts herein focused on the identification of compounds that could potentially target all classes of mutant-IDH1 tumors, including those in the brain.The substrate-binding site of mutant IDH1 is highly polar as defined by the amino acids lining the pocket (Figure 1), in addition to the active-site magnesium ion and NADPH cofactor. This suggests a low probability of being able to optimize a compound for potent binding to this site while also fulfilling the criteria most conducive to crossing the blood− brain barrier (BBB).12 It was decided to explore the identification of catalytic inhibitors with different mechanisms of action, which may bind distal to this polar substrate-binding site.High throughput screening was carried out with a NADPH fluorescence-based biochemical assay using IDH1 R132H homodimer protein, and orthogonal biochemical inhibition confirmation using an LCMS readout of 2-HG levels. Compounds 1a and 1b were identified as selective and functional inhibitors of IDH1R132H from this screen. Both 1a and 1b were screened as diastereomeric mixtures at the amine (Table 1, Am), which necessitated the independent synthesis of the four separate stereoisomers in order to determine the chiral preference for ligand binding. Potency was found to be most strongly dependent upon the chirality at the amine center (Am), . Amino acids lining the pocket are highl...
The syntheses of novel bulky N-substituted 1,3-benzazaphospholes are presented, together with their reactions with tert-butyllithium and coupling with tBu 2PCl to novel P, P'-hybrid ligands that combine the highly basic and bulky di- tert-butylphosphanyl group with pi-acidic low-coordinated phosphorus. The syntheses start with the preparation of new N-secondary 2-bromoanilines 1 by reduction of N-acyl 2-bromoanilides or more generally by Pd-catalyzed selective monoamination of o-dibromobenzene, followed by Pd-catalyzed C-P coupling with P(OEt) 3 to the respective 2-anilino-phosphonates 2. The next steps are reduction to 2-phosphanylanilines 3 and condensation with Me 2NCH(OMe) 2, which leads via phosphaalkenes 4 to the corresponding N-substituted benzazaphospholes 5. The reaction with tBuLi depends on the steric demand of the N substituent. Methyl, neopentyl-, and mesityl-derivatives were converted to P=C Li species 6 and coupled with tBu 2PCl to novel P=C-P tBu 2 ligands 7, whereas N-adamantyl and N-2,6-diisopropylphenyl-derivatives prefer addition of tBuLi at the PC bond to form dihydroderivatives. The chemical shifts of the low-coordinated phosphorus of 5 and 7 were found to reflect electronic and steric effects of the N substituents. The comparison of the crystal structures of N-neopentyl-1,3-benzazaphospholes 5 and 7 gives evidence of steric repulsion between the adjacent di- tert-butyl and neopentyl groups by the preferred anti orientation of the P- tert-butyl groups and moderate deviations of C2 and P3 of 7b from the ring plane.
Lithium malonate enolates 4 or 13 are oxidized to the corresponding radicals by ferrocenium hexafluorophosphate (1) or CuCl2 (2). Trapping by TEMPO (5) to produce 6, dimerization to 7, or radical 5‐exo cyclizations are possible subsequent reaction steps following radical generation. The structure of the radical cyclization acceptor determines the outcome of the overall reaction sequence. Tertiary benzylic, alkyl, and α‐alkoxy radicals are oxidized by 1. The carbenium ions are stabilized by nucleophilic trapping or deprotonation to give compounds 14 and 18. Secondary alkyl and vinyl radicals are not oxidized and, in the absence of trapping reagents, form radical‐derived products. Radical 5‐exo cyclization of 13 induced by CuCl2 (2) was also efficient. At least for alkyl radicals, however, ligand transfer is the exclusive stabilization pathway, giving access to chloroalkylcyclopentane derivatives 21. Radical scavenging studies revealed that malonyl radical trapping is slow, so that 5‐exo cyclizations occurred. The cyclized radicals couple with TEMPO (5) to afford oxygenated cyclopentane derivatives 31, depending on the rate of radical SET oxidation. The reaction behavior of compounds 14, 22, 23, and 31 was investigated. Mechanistic issues are discussed and implications for synthetic planning are given.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.