Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Investigation of a Bicyclo[1.1.1]pentane as a Phenyl Replacement within an LpPLA₂ Inhibitor.

ABSTRACT: We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA₂ inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis to the target compounds was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane system being the key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained to compare the known inhibitors to their bioisosteric counterparts, which showed the isostere was well tolerated and positively impacted on the physicochemical profile.

SUBMITTER: Measom ND

PROVIDER: S-EPMC5238484 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Investigation of a Bicyclo[1.1.1]pentane as a Phenyl Replacement within an LpPLA2 Inhibitor.

Measom Nicholas D ND Down Kenneth D KD Hirst David J DJ Jamieson Craig C Manas Eric S ES Patel Vipulkumar K VK Somers Don O DO

ACS medicinal chemistry letters 20161115 1

We describe the incorporation of a bicyclo[1.1.1]pentane moiety within two known LpPLA2 inhibitors to act as bioisosteric phenyl replacements. An efficient synthesis to the target compounds was enabled with a dichlorocarbene insertion into a bicyclo[1.1.0]butane system being the key transformation. Potency, physicochemical, and X-ray crystallographic data were obtained to compare the known inhibitors to their bioisosteric counterparts, which showed the isostere was well tolerated and ...[more]

PMID: 28105273

Similar Datasets

An Insight into Non-Covalent Interactions on the Bicyclo[1.1.1]pentane Scaffold.

Project description:Bicyclo[1.1.1]pentane (BCP) is studied extensively as a bioisosteric component of drugs. Not found in nature, this molecular unit approximates the distance of a para-disubstituted benzene which is replaced in medicines as a method of improving treatments. Predicting interactions of these drugs with specific active sites requires knowledge of the non-covalent interactions engaged by this subunit. Structure determinations and computational analysis (Hirshfeld analysis, 2D fingerprint plots, DFT) of seven BCP derivatives chosen to probe specific and directional interactions. X-ray analysis revealed the presence of various non-covalent interactions including I ⋅⋅⋅ I, I ⋅⋅⋅ N, N-H ⋅⋅⋅ O, C-H ⋅⋅⋅ O, and H-C ⋅⋅⋅ H-C contacts. The preference of halogen bonding (I ⋅⋅⋅ I or I ⋅⋅⋅ N) in BCP 1-4 strictly depends upon the electronic nature and angle between bridgehead substituents. The transannular distance in co-crystals 2 and 4 was longer as compared to monomers 1 and 3. Stronger N-H ⋅⋅⋅ O and weaker C-H ⋅⋅⋅ O contacts were observed for BCP 5 while the O ⋅⋅⋅ H interaction was a prominent contact for BCP 6. The presence of 3D BCP units prevented the π ⋅⋅⋅ π stacking between phenyl rings in 3, 4, and 7. The BCP skeleton was often rotationally averaged, indicating fewer interactions compared to bridgehead functional groups. Using DFT analysis, geometries were optimized and molecular electrostatic potentials were calculated on the BCP surfaces. These interaction profiles may be useful for designing BCP analogs of drugs.

| S-EPMC7986844 | biostudies-literature

Large-Scale Synthesis and Modifications of Bicyclo[1.1.1]pentane-1,3-dicarboxylic Acid (BCP).

Project description:In flow photochemical addition of propellane to diacetyl allowed construction of the bicyclo[1.1.1]pentane (BCP) core in a 1 kg scale within 1 day. Haloform reaction of the formed diketone in batch afforded bicyclo[1.1.1]pentane-1,3-dicarboxylic acid in a multigram amount. Representative gram scale transformations of the diacid were also performed to obtain various BCP-containing building blocks-alcohols, acids, amines, trifluoroborates, amino acids, etc.-for medicinal chemistry.

| S-EPMC8524415 | biostudies-literature

Sodium Bicyclo[1.1.1]pentanesulfinate: A Bench-Stable Precursor for Bicyclo[1.1.1]pentylsulfones and Bicyclo- [1.1.1]pentanesulfonamides.

Project description:Herein, we present the synthesis of the bench-stable sodium bicyclo[1.1.1]pentanesulfinate (BCP-SO2 Na) and its application in the synthesis of bicyclo[1.1.1]pentyl (BCP) sulfones and sulfonamides. The salt can be obtained in a four-step procedure from commercially available precursors in multigram scale without the need for column chromatography or crystallization. Sulfinates are known to be useful precursors in radical and nucleophilic reactions and are widely used in medicinal chemistry. This building block enables access to BCP sulfones and sulfonamides avoiding the volatile [1.1.1]propellane which is favorable for the extension of SAR studies. Further, BCP-SO2 Na enables the synthesis of products that were not available with previous methods. A chlorination of BCP-SO2 Na and subsequent reaction with a Grignard reagent provides a new route to BCP sulfoxides. Several products were analyzed by single-crystal X-ray diffraction.

| S-EPMC7187227 | biostudies-literature

Discovery of Potent and Orally Available Bicyclo[1.1.1]pentane-Derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors.

Project description:Indoleamine-2,3-dioxygenase 1 (IDO1) inhibition and its combination with immune checkpoint inhibitors like pembrolizumab have drawn considerable attention from both academia and the pharmaceutical industry. Here, we describe the discovery of a novel class of highly potent IDO1 heme-displacing inhibitors featuring a unique bicyclo[1.1.1]pentane motif. Compound 1, evolving from an ALIS (automated ligand identification system) hit, exhibited excellent potency but lacked the desired pharmacokinetic profile due to extensive amide hydrolysis of the benzamide moiety. Replacing the central phenyl ring in 1 with a bicyclo[1.1.1]pentane bioisostere effectively circumvented the amide hydrolysis issue, resulting in the discovery of compound 2 with a favorable overall profile such as excellent potency, selectivity, pharmacokinetics, and a low predicted human dose.

| S-EPMC7429971 | biostudies-literature

Time-Resolved Fluorescence Anisotropy of Bicyclo[1.1.1]pentane/Tolane-Based Molecular Rods Included in Tris(o-phenylenedioxy)cyclotriphosphazene (TPP).

Project description:We examine the fluorescence anisotropy of rod-shaped guests held inside the channels of tris(o-phenylenedioxy)cyclotriphosphazene (TPP) host nanocrystals, characterized by powder X-ray diffraction and solid state NMR spectroscopy. We address two issues: (i) are light polarization measurements on an aqueous colloidal solution of TPP nanocrystals meaningful, or is depolarization by scattering excessive? (ii) Can measurements of the rotational mobility of the included guests be performed at low enough loading levels to suppress depolarization by intercrystallite energy transfer? We find that meaningful measurements are possible and demonstrate that the long axis of molecular rods included in TPP channels performs negligible vibrational motion.

| S-EPMC4415047 | biostudies-literature

Synthesis of Sulfur-Substituted Bicyclo[1.1.1]pentanes by Iodo-Sulfenylation of [1.1.1]Propellane.

Project description:Thiols easily react with [1.1.1]propellane to give sulfur-substituted bicyclo[1.1.1]pentanes in radical reactions, but this reactivity is not replicated in the case of heterocyclic thiols. Herein, we address this issue by electrophilically activating [1.1.1]propellane to promote its iodo-sulfenylation with 10 classes of heterocyclic thiols in two protocols that can be conducted on a multigram scale without exclusion of air or moisture.

| S-EPMC9531248 | biostudies-literature

Direct catalytic asymmetric synthesis of α-chiral bicyclo[1.1.1]pentanes.

Project description:Bicyclo[1.1.1]pentanes (BCPs) are important motifs in contemporary drug design as linear spacer units that improve pharmacokinetic profiles. The synthesis of BCPs featuring adjacent stereocenters is highly challenging, but desirable due to the fundamental importance of 3D chemical space in medicinal chemistry. Current methods to access these high-value chiral molecules typically involve transformations of pre-formed BCPs, and can display limitations in substrate scope. Here we describe an approach to synthesize α-chiral BCPs involving the direct, asymmetric addition of simple aldehydes to [1.1.1]propellane, the predominant BCP precursor. This is achieved by combining a photocatalyst and an organocatalyst to generate a chiral α-iminyl radical cation intermediate, which installs a stereocenter simultaneously with ring-opening of [1.1.1]propellane. The reaction proceeds under mild conditions, displays broad scope, and provides an array of α-chiral BCPs in high yield and enantioselectivity. We also present a theoretical model for stereoinduction in this mode of photoredox organocatalysis.

| S-EPMC7955048 | biostudies-literature

Strain-release 2-azaallyl anion addition/borylation of [1.1.1]propellane: synthesis and functionalization of benzylamine bicyclo[1.1.1]pentyl boronates.

Project description:We report a 3-component reaction between N-benzyl ketimines, [1.1.1]propellane, and pinacol boronates to generate benzylamine bicyclo[1.1.1]pentane (BCP) pinacol boronates. These structures are analogous to highly sought diarylmethanamine cores, which are common motifs in bioactive molecules. We demonstrate the versatility of the boronate ester handle via downstream functionalization through a variety of reactions, including a challenging Pd-catalyzed (hetero)arylation that exhibits a broad substrate scope. Together, these methods enable the synthesis of high-value BCP benzylamines which are inaccessible by existing methods. Furthermore, we demonstrate the successful application of these newly developed (hetero)arylation conditions to a variety of challenging tertiary pinacol boronates, including nitrogen-containing heterocycles, 1,1-disubstituted cyclopropanes, and other BCP cores.

| S-EPMC8153217 | biostudies-literature

Skeletal Editing Approach to Bridge-Functionalized Bicyclo[1.1.1]pentanes from Azabicyclo[2.1.1]hexanes.

Project description:Azabicyclo[2.1.1]hexanes (aza-BCHs) and bicyclo[1.1.1]pentanes (BCPs) have emerged as attractive classes of sp3-rich cores for replacing flat, aromatic groups with metabolically resistant, three-dimensional frameworks in drug scaffolds. Strategies to directly convert, or "scaffold hop", between these bioisosteric subclasses through single-atom skeletal editing would enable efficient interpolation within this valuable chemical space. Herein, we describe a strategy to "scaffold hop" between aza-BCH and BCP cores through a nitrogen-deleting skeletal edit. Photochemical [2+2] cycloadditions, used to prepare multifunctionalized aza-BCH frameworks, are coupled with a subsequent deamination step to afford bridge-functionalized BCPs, for which few synthetic solutions currently exist. The modular sequence provides access to various privileged bridged bicycles of pharmaceutical relevance.

| S-EPMC10281541 | biostudies-literature

Synthesis and applications of highly functionalized 1-halo-3-substituted bicyclo[1.1.1]pentanes.

Project description:Bicyclo[1.1.1]pentanes (BCPs) are important bioisosteres of 1,4-disubstituted arenes, tert-butyl and acetylenic groups that can impart physicochemical benefits on drug candidates. Here we describe the synthesis of BCPs bearing carbon and halogen substituents under exceptionally mild reaction conditions, via triethylborane-initiated atom-transfer radical addition ring-opening of tricyclo[1.1.1.01,3]pentane (TCP) with alkyl halides. This chemistry displays broad substrate scope and functional group tolerance, enabling application to BCP analogues of biologically-relevant targets such as peptides, nucleosides, and pharmaceuticals. The BCP halide products can be converted to the parent phenyl/tert-butyl surrogates through triethylborane-promoted dehalogenation, or to other derivatives including carbonyls, alcohols, and heterocycles.

| S-EPMC6001403 | biostudies-literature