Suberitamides A–C, Marine Sponge Alkaloids

Suberitamides A–C, Aryl Alkaloids from a Pseudosuberites sp. Marine Sponge that Inhibit Cbl-b Ubiquitin Ligase Activity, by Chang-Kwon Kim, Dongdong Wang, Brice A. P. Wilson Josep Saurí, Donna Voeller, Stanley Lipkowitz, Barry R. O’Keefe and Kirk R. Gustafson. Mar. Drugs 202018(11), 536; https://doi.org/10.3390/md18110536

Three new aryl alkaloids named suberitamides A–C (13), were isolated from an extract of the marine sponge Pseudosuberites sp. collected along the coast of North Carolina. Their planar structures were established by extensive nuclear magnetic resonance (NMR) and mass spectrometry (MS) analysis. To assign the challenging relative configuration of the saturated five-membered ring in suberitamide A (1), a simple and efficient NMR protocol was applied that is based on the analysis of 2- and 3-bond 1H-13C spin-spin coupling constants using a PIP (pure in-phase) HSQMBC (heteronuclear single quantum multiple bond correlation) IPAP (in-phase and anti-phase) experiment. Suberitamides A (1) and B (2) inhibited Cbl-b, an E3 ubiquitin ligase that is an important modulator of immune cell function, with IC50 values of approximately 11 μM.

Discovery of Bicyclic Inhibitors of Human Arginase

amclct.2020.11.issue-4.largecoverDiscovery and Optimization of Rationally Designed Bicyclic Inhibitors of Human Arginase to Enhance Cancer Immunotherapy, by Matthew J. Mitcheltree, Derun Li, Abdelghani Achab, Adam Beard, Kalyan Chakravarthy, Mangeng Cheng, Hyelim Cho, Padmanabhan Eangoor, Peter Fan, Symon Gathiaka, Hai-Young Kim, Charles A. Lesburg, Thomas W. Lyons, Theodore A. Martinot, J. Richard Miller, Spencer McMinn, Jennifer O’Neil, Anand Palani, Rachel L. Palte, Josep Saurí, David L. Sloman, Hongjun Zhang, Jared N. Cumming, and Christian Fischer. ACS Med. Chem. Lett. 2020, 11, 4, 582-588. DOI: https://doi.org/10.1021

The action of arginase, a metalloenzyme responsible for the hydrolysis of arginine to urea and ornithine, is hypothesized to suppress immune-cell activity within the tumor microenvironment, and thus its inhibition may constitute a means by which to potentiate the efficacy of immunotherapeutics such as anti-PD-1 checkpoint inhibitors. Taking inspiration from reported enzyme–inhibitor cocrystal structures, we designed and synthesized novel inhibitors of human arginase possessing a fused 5,5-bicyclic ring system. The prototypical member of this class, 3, when dosed orally, successfully demonstrated serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model, despite modest oral bioavailability. Structure-based design strategies to improve the bioavailability of this class, including scaffold modification, fluorination, and installation of active-transport recognition motifs were explored.

ml0c00058_0013

LR-HSQMBC versus LR-selHSQMBC

largecoverLR-HSQMBC versus LR-selHSQMBC: Enhancing the Observation of Tiny Long-Range Heteronuclear NMR Correlations, by Kumar Motiram-Corral, Pau Nolis, Josep Saurí and Teodor Parella. J. Nat. Prod. March 10, 2020. DOI: https://doi.org/10.1021

The detection of ultra-long-range (4JCH and higher) heteronuclear connectivities can complement the conventional use of HMBC/HSQMBC data in structure elucidation NMR studies of proton-deficient natural products, where two-bond and three-bond correlations are usually observed. The performance of the selHSQMBC experiment with respect to its broadband HSQMBC counterpart is evaluated. Despite its frequency-selectivity nature, selHSQMBC efficiently prevents any unwanted signal phase and intensity modulations due to passive proton–proton coupling constants typically involved in HSQMBC. As a result, selHSQMBC offers a significant sensitivity enhancement and provides pure in-phase multiplets, improving the detection levels for short- and long-range cross-peaks corresponding to small heteronuclear coupling values. This is particularly relevant for experiments optimized to small nJCH values (2–3 Hz), referred to as LR-selHSQMBC, where key cross-peaks that are not visible in the equivalent broadband LR-HSQMBC spectrum can become observable in optimum conditions.

np0c00058_0009

 

Detection and Quantification of Very Weak Long‐Range Heteronuclear NMR Correlations

cphc.v21.3.cover_LR‐selHSQMBC: Simultaneous Detection and Quantification of Very Weak Long‐Range Heteronuclear NMR Correlations, by Kumar Motiram‐Corral, Alexandre A. Souza, Josep Saurí, Pau Nolis and Teodor Parella. ChemPhysChem, 17 January 2020. DOI: 10.1002/cphc.201901142

The optimum detection and accurate measurement of longer‐range (4J and higher) heteronuclear NMR correlations is described. The magnitude and/or the sign of a wide range of large and small long‐range couplings can be simultaneously determined for protonated and non‐protonated 13C and 15N nuclei using the LR‐selHSQMBC experiment.

 

LRSEL

C–H Functionalization of Saturated Aza-Cycles

largecoverC–C Cleavage Approach to C–H Functionalization of Saturated Aza-Cycles, by Jose B. Roque, Yusuke Kuroda, Justin Jurczyk, Li-Ping Xu, Jin Su Ham, Lucas T. Göttemann, Charis A. Roberts, Donovon Adpressa, Josep Saurí, Leo A Joyce, Djamaladdin G Musaev, Charles S. Yeung and Richmond Sarpong. ACS Catalysis, 2020. Just Accepted. DOI: 10.1021/acscatal.9b04551

Saturated cyclic amines (aza-cycles) are ubiquitous structural motifs found in pharmaceuticals, agrochemicals, and bioactive natural products. Given their importance, methods that directly functionalize aza-cycles are in high de-mand. Herein, we disclose a fundamentally different approach to functionalizing cyclic amines that relies on C–C cleavage and attendant cross-coupling. The initial functionalization step is the generation of underexplored N-fused bicyclo α-hydroxy-β-lactams under mild, visible light conditions using a Norrish-Yang process to effect α-functionalization of saturated cyclic amines. This approach is complementary to previous methods for the C–H functionalization of aza-cycles and provides unique access to various cross-coupling adducts. In the course of these studies, we have also uncovered an orthogonal, base-promoted, opening of the N-fused bicyclo α-hydroxy-β-lactams. Computational studies have provided insight into the origin of the complementary C–C cleavage processes.

2020-01-31 13_55_07-ACS_Catal_TOC.pdf - Google Drive

Diastereoselective Cyclization to N-(Hetero)Aryl Piperidines

largecoverA Modular and Diastereoselective 5 + 1 Cyclization Approach to N-(Hetero)Aryl Piperidines, by Matthew A. Larsen, Elisabeth T. Hennessy, Madeleine C. Deem, Yu-hong Lam, Josep Saurí and Aaron C. Sather. J. Am. Chem. Soc. 2020, 142, 2, 726-732. DOI: 10.1021/jacs.9b13114

A new general de novo synthesis of pharmaceutically important N-(hetero)aryl piperidines is reported. This protocol uses a robustly diastereoselective reductive amination/aza-Michael reaction sequence to achieve rapid construction of complex polysubstituted ring systems starting from widely available heterocyclic amine nucleophiles and carbonyl electrophiles. Notably, the diastereoselectivity of this process is enhanced by the presence of water, and DFT calculations support a stereochemical model involving a facially selective protonation of a water-coordinated enol intermediate.

ja9b13114_0008

Pyonitrins A–D: Chimeric Natural Products

largecover

Pyonitrins A–D: Chimeric Natural Products Produced by Pseudomonas protegens, by Emily Mevers, Josep Saurí, Eric J. N. Helfrich, Matthew Henke, Kenneth J. Barns, Tim S. Bugni, David Andes, Cameron R. Currie and Jon Clardy. J. Am. Chem. Soc. 2019, 141, 43, 17098-17101. DOI: https://pubs.acs.org/doi/10.1021/jacs.9b09739

Bacterial symbionts frequently provide chemical defenses for their hosts, and such systems can provide discovery pathways to new antifungals and structurally intriguing metabolites. This report describes a small family of naturally occurring small molecules with chimeric structures and a mixed biosynthesis that features an unexpected but key nonenzymatic step. An insect-associated Pseudomonas protegens strain’s activity in an in vivo murine candidiasis assay led to the discovery of a family of highly hydrogen-deficient metabolites. Bioactivity- and mass-guided fractionation led to the pyonitrins, highly complex aromatic metabolites in which 10 of the 20 carbons are quaternary, and 7 of them are contiguous. The P. protegens genome revealed that the production of the pyonitrins is the result of a spontaneous reaction between biosynthetic intermediates of two well-studied Pseudomonas metabolites, pyochelin and pyrrolnitrin. The combined discovery of the pyonitrins and identification of the responsible biosynthetic gene clusters revealed an unexpected biosynthetic route that would have prevented the discovery of these metabolites by bioinformatic analysis alone.

ja9b09739_0004

NMR Characterization of Dictyospiromide

largecoverCharacterization by Empirical and Computational Methods of Dictyospiromide, an Intriguing Antioxidant Alkaloid from the Marine Alga Dictyota coriacea, by Pengcheng Yan, Ge Li, Chaojie Wang, Jianzhang Wu, Zhongmin Sun, Gary E. Martin, Xiao Wang, Mikhail Reibarkh, Josep Saurí and Kirk R. Gustafson. Org. Lett. 2019. Article ASAP, DOI: https://pubs.acs.org/doi/10.1021/acs.orglett.9b02856

The challenging structural motif of dictyospiromide (1), a spirosuccinimide alkaloid with antioxidant properties that are associated with activation of the Nrf2/ARE signaling pathway, was assigned using contemporary NMR experiments complemented with anisotropic NMR, chiroptical, and computational methodologies. Anisotropic NMR parameters provided critical orthogonal verification of the configuration of the difficult to assign spiro carbon and the other stereogenic centers in 1.

ol9b02856_0005

MEASURING LONG-RANGE HETERONUCLEAR COUPLING CONSTANTS WITH SEL-HSQMBC EXPERIMENTS: A TUTORIAL

MRC coverHow to measure long‐range proton‐carbon coupling constants from 1H‐selective HSQMBC experiments, by Josep Saurí, Pau Nolis and Teodor Parella. Magn. Reson. Chem. 2019. Early View, DOI: https://onlinelibrary.wiley.com/doi/10.1002/mrc.4928

Heteronuclear long‐range scalar coupling constants (nJCH) are a valuable tool for solving problems in organic chemistry and are especially suited for stereochemical and configurational analyses of small molecules and natural products. This tutorial will focus on the step‐by‐step implementation of several 2D 1H frequency selective HSQMBC experiments for the easy and accurate measurement of either the magnitude or both the magnitude and the sign of long‐range nJCH couplings. The performance of these experiments will be showcased with several scenarios in a range of different experimental conditions.

mrc4928_GraphicalAbstract_Tutorial_selHSQMBC

Bruker pulse program code for selHSQMBC experiments available here.

Bruker pulse program code for selHSQMBC-TOCSY experiment available here.

Strychnine dataset examples available here.

New variants of the ADEQUATE experiments

AR_NMRNew variants of the ADEQUATE experiments, by Josep Saurí, Ikenna E. Ndukwe, Mikhail Reibarkh, Yizhou Liu, R. Thomas Williamson and Gary E. Martin. Annual Reports on NMR Spectroscopy, 2019. In Press. DOI: https://doi.org/10.1016/bs.arnmr.2019.04.001

ADEQUATE experiments were first described in the mid-1990s and are a family of proton-detected NMR experiments used to establish carbon–carbon correlations at natural abundance. Applications of these experiments were initially limited by the statistical probability of two 13C nuclides in the same molecule (~ 1:10,000) and the low intrinsic sensitivity of the NMR probe technology of the day. In the intervening two decades, there have been significant advances in NMR probe technology and it is now possible, for example, to perform multiplicity-edited pure shift HSQC NMR experiments on a microgram of material or less. The enhanced NMR sensitivity offered by cryogenic NMR probes has dropped sample requirements for ADEQUATE experiments from the ~ 10 mg range to less than a milligram when working with a 1.7 mm Micro Cryoprobe™ at 600 MHz on a modern spectrometer. In parallel with advances in NMR probe technology, this chapter will detail a number of modifications of the ADEQUATE experiment that have been reported to enhance both the utility and sensitivity of these experiments. Combining newly reported variants of the ADEQUATE experiments with anisotropic NMR and Computer-Assisted Structure Elucidation methods affords an orthogonal means of verifying both the constitution and configuration of complex molecular structures that can stem the flow of incorrectly reported structures into the chemical literature.