Biaryl Moiety Research Articles

Perfect Partners: Biocatalytic Halogenation and Metal Catalysis for Protein Bioconjugation.

Flavin-dependent halogenases (FDHs) are the most extensively researched halogenases and show great potential for biotransformation applications. These enzymes use chloride, bromide, or iodide ions as halogen donors to catalyze the oxygen-dependent halogenation of electron-rich aryl moieties, requiring stochiometric amounts of FADH2 in the process. This makes FDH-catalyzed aryl halogenation a highly selective and environmentally friendly tool for the synthesis of aryl halides. The latter in turn serve as valuable intermediates for transition metal catalyzed cross coupling reactions for C-C bond formation. Previous research made extensive use of this approach to halogenate small molecules as building blocks for late-stage functionalization by transition-metal catalyzed cross-coupling reactions. Based on these results, several groups have managed to expand this research to protein targets over the past two years. Their work indicates an emerging methodology for bioconjugation using late-stage biocatalytic halogenation in conjunction with biorthogonal Suzuki-Miyaura cross-coupling. This strategy could present an attractive alternative to existing approaches due to the stability of the C-C bond bridging the generated biaryl moiety and the ease of late-stage enzymatic modification while maintaining excellent selectivity under mild conditions.

Dynamic Kinetic Resolution of 2‐Hydroxybiaryl Atropisomers via Lipase‐Catalyzed Enantioselective O‐Acylation

AbstractThe increasing interest in axially chiral biaryl moieties, which are prevalent in chiral ligands, organocatalysts, and bioactive molecules, has raised the need for developing novel efficient synthetic methods for these types of molecules. In addition to the currently available methods, such as kinetic resolution, desymmetrization and enantio‐ and diastereo‐selective biaryl coupling, we herein report a lipase‐catalyzed dynamic kinetic resolution (DKR) of racemic 2‐hydroxybiaryls through enantioselective O‐acylation. This method features the production of enantiomerically enriched atropisomers (89 %–98 % ee) in 91 %–99 % yields from eleven racemates. Notably, the DKR proceeds without any racemization catalyst since in situ‐racemization was achieved by easy rotation about the biaryl axis of the substrates. The enzymatic O‐acylation then furnished conformationally stable biaryl‐containing esters, in which the increased steric bulkiness of the O‐acyl moiety suppresses the rotation, i. e., racemization, under the reaction conditions of 35–50 °C. This experimental study was accompanied by a computational determination of the rotational barrier of substrates and products. The choice of suitable substrates with a significant difference in their rotational barrier compared to that of their products turned out to be the key to an efficient implementation of this method.

Insights into the Multisymmetric Tailoring of Julichrome Compounds by the Oxygenases JuiN and JuiO: Enzymatic Processing around the Biaryl C–C Axis

Biaryl moieties, especially in the context of natural products (NPs), constitute a privileged scaffold for drug design. However, compound modifications that follow the installation of the defining C–C biaryl axis have not been well documented. Here, we report two iterative monooxygenases, JuiN and JuiO, that catalyze tandem and symmetric hydroxylation and epoxidation chemistries following C–C axis formation en route to the NP julichrome Q6-6. The crystal structure of JuiN-FAD-Q6-6 and mutagenesis experiments revealed the substrate recognition mechanisms driving iterative hydroxylations along the C–C axis. The key to these studies was that the unstable intermediate julichrome Q8-8 was successfully captured using an adsorptive resin in fermentations of a ΔjuiO mutant, thus invoking JuiO in the overall sequence of transformations. A Streptomyces griseorubiginosus-derived enzyme, SgJuiO, was investigated in vitro as a substitute for insoluble JuiO. The biochemical reactions unambiguously demonstrated that SgJuiO iteratively catalyzes the complex sequence of epoxidations on both sides of the C–C biaryl linkage. These findings showcase a tailoring paradigm for biaryl NP biosynthesis and engineering.

Integrated molecular and quantum mechanical approach to identify novel potent natural bioactive compound against 2′-O-methyltransferase (nsp16) of SARS-CoV-2

With the advent of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) outbreak, efforts are still in progress to find out a functional cure for the infection. Among the various protein targets, nsp16 capping protein is one of the vital targets for drug development as it protects the virus against the host cell nucleases and evading innate immunity. The nsp16 protein forms a heterodimer with a co-factor nsp10 and triggers 2′-O-methyltransferase activity which catalyzes the conversion of S-adenosyl methionine into S-adenosyl homocysteine. The free methyl group is transferred to the 2′-O position on ribose sugar at the 5′ end of mRNA to form the cap-1 structure which is essential for replication of the virus and evading the innate immunity of the host. In this study, we identify a potential lead natural bioactive compound against nsp16 protein by systematic cheminformatic analysis of more than 144k natural compounds. Virtual screening, molecular docking interactions, ADMET profiling, molecular dynamics (MD) simulations, molecular mechanics-generalized born surface area (MM-GBSA), free energy analysis and density functional theory analysis were used to discover the potential lead compound. Our investigation revealed that ZINC8952607 (methyl-[(6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-yl)aminomethyl]BLAHone) has the greatest binding affinity and best pharmacokinetic parameters due to presence of carbazol and BLAHone (biaryl moiety). Further, time-dependent MD simulation analysis substantiates the stability and rigidness of nsp16 protein even after interaction with the lead compound. We believe that the compound ZINC8952607 might establish as a novel natural drug candidate against CoVID-19 infection. Communicated by Ramaswamy H. Sarma

Double approaches for obtaining an asymmetric one-pot addition/reduction reaction

In the last decades, one of the most important goals in synthetic chemistry consists in having both a low environmentally impact process and a more economic one. Based on this consideration, the one-pot reaction represents a valid alternative to realize this challenge, thanks to its decreasing of energy and time consumption, avoiding a lengthy separation process for purification of the chemical intermediates. The here proposed one-pot reaction consists in a first step involving an asymmetric conjugate addition of aryl boronic acids to 3-azaarylpropenones containing pyridine core followed by an asymmetric transfer hydrogenation of the aryl ketone in the case of biaryl moieties and by an asymmetric biocatalytic reduction in the case of alkyl derivatives. Studying the kinetic of the first reaction, the second catalytic step can be successfully carried out with good results in terms of conversion and stereoselectivity with both the approaches.

Addressing Atropisomerism in the Development of Sotorasib, a Covalent Inhibitor of KRAS G12C: Structural, Analytical, and Synthetic Considerations.

ConspectusNearly a century after its first description, configurationally stable axial chirality remains a rare feature in marketed drugs. In the development of the KRASG12C inhibitor sotorasib (LUMAKRAS/LUMYKRAS), an axially chiral biaryl moiety proved a critical structural element in engaging a “cryptic” protein binding pocket and enhancing inhibitor potency. Restricted rotation about this axis of chirality gave rise to configurationally stable atropisomers that demonstrated a 10-fold difference in potency. The decision to develop sotorasib as a single-atropisomer drug gave rise to a range of analytical and synthetic challenges, whose resolution we review here.Assessing the configurational stability of differentially substituted biaryl units in early inhibitor candidates represented the first challenge to be overcome, as differing atropisomer stability profiles called for differing development strategies (e.g., as rapidly equilibrating rotamers vs as single atropisomers). We relied on a range of NMR, HPLC, and computational methods to assess atropisomer stability. Here, we describe the various variable-temperature NMR, time-course NMR, and chiral HPLC approaches used to assess the configurational stability of axially chiral bonds displaying a range of rotational barriers.As optimal engagement of the “cryptic” pocket of KRASG12C was ultimately achieved with a configurationally stable atropisomeric linkage, the second challenge to be overcome entailed preparing the preferred (M)-atropisomer of sotorasib on industrial scale. This synthetic challenge centered on the large-scale synthesis of an atropisomerically pure building block comprising the central azaquinazolinone and pyridine rings of sotorasib. We examined a range of strategies to prepare this compound as a single atropisomer: asymmetric catalysis, chiral chromatographic purification, and classical resolution. Although chiral liquid and simulated moving bed chromatography provided expedient access to initial multikilo supplies of this key intermediate, a classical resolution process was ultimately developed that proved significantly more efficient on metric-ton scale. To avoid discarding half of the material from this resolution, this process was subsequently refined to enable thermal recycling of the undesired atropisomer, providing an even more efficient commercial process that proved both robust and green.While the preparation of sotorasib as a single atropisomer significantly increased both the analytical and synthetic complexity of its development, the axially chiral biaryl linkage that gave rise to the atropisomerism of sotorasib proved a key design element in optimizing sotorasib’s binding to KRASG12C. It is hoped that this review will help in outlining the range of analytical techniques and synthetic strategies that can be brought to bear in addressing the challenges posed by such axially chiral compounds and that this account may provide helpful guidelines for future efforts aimed at the development of such single atropisomer, axially chiral pharmaceutical agents.

Rapid Synthesis of Fused Polycyclic Heteroaromatics through Successive Vinylic/Aromatic C−F Bond Activation

AbstractThe synthesis of fused polycyclic heteroaromatics was achieved via successive vinylic/aromatic carbon−fluorine (C−F) bond activation. The Suzuki‐Miyaura coupling of (1‐bromo‐2,2‐difluorovinyl)biaryls with 2‐hydroxy‐ or 2‐aminophenylboronic acids (esters) followed by defluorinative 5‐endo‐trig cyclization yielded 2‐fluorobenzofurans (indoles) with a biaryl moiety in one‐pot operation. The obtained 2‐fluorobenzoheteroles underwent acid‐mediated intramolecular C−F/C−H coupling to yield tetra‐, penta‐, and hexacyclic heteroaromatics. This protocol allowed the synthesis of various substituted benzo‐fused dibenzofurans and carbazoles.

Abstract 1750: Design and development of a novel highly sequence-selective guanine mono-alkylating DNA-interactive ADC payload suitable for solid tumor treatments

Abstract Antibody-Drug Conjugates (ADCs) are a fast-growing class of targeted cancer therapeutic agents with over ten approved and greater than 100 in various stages of clinical development. The pyridinobenzodiazepines (PDDs) are a new class of DNA-interactive sequence-selective Guanine mono-alkylating ADC payloads which contain a sequence recognition component with sufficient span to guide them to specific DNA sequences (e.g., transcription factor binding sites). A high potency PDD, FGX15-147, has been developed that contains a bi-aryl moiety capable of forming an intramolecular ‘sigma-hole’ interaction with DNA bases, thus providing the molecule with a unique sequence-selectivity profile when compared to other DNA-interactive agents. DNA footprinting data will be presented indicating that the molecule, which spans 8-9 DNA base pairs in the minor groove, has an increased sequence selectivity compared with related analogues, preferring DNA regions containing two guanines 2-4 base pairs apart. FGX15-147 is highly cytotoxic in vitro (e.g., IC50 = 0.30 nM in SW60; 1.6 nM in LIM1215 and 0.142 nM in SW48, after 96 hours incubation), and is thought to exert its activity through a combination of DNA alkylation and inhibiting the binding of important oncogenic transcription factors such as Hypoxia Inducible Factor (HIF) to DNA (demonstrated through an in vitro Transcription Factor Array assay). HIF is known to be involved in the development of a large number of solid malignancies, including pancreatic cancer. To explore the utility of FGX15-147 as an ADC payload, it was conjugated to trastuzumab in a stochastic manner (DAR 1.6) using a Maleimide-Valine-Alanine linker construct. The resulting ADC exhibited significant in vivo efficacy in a low copy number HER2+ pancreatic cancer Human Tumor Xenograft model using BALB-c mice transplanted with the CAPAN-1 cell line. Complete tumor regression was observed out to 60 days after a single dose of 2 mg/kg comparing favorably to a 10 mg/kg dose of trastuzumab deruxtecan (Enhertu®) in the same study in which substantial tumor regrowth had occurred by 57 days. In a standard mouse model, the FGX15-147-based ADC had a good tolerability profile with a Maximum Tolerated Dose (MTD) of at least 16 mg/kg. Overall, the favorable tolerability and efficacy profile of FGX15-147 in an ADC format suggests that it represents a potentially valuable approach for the treatment of solid tumors. Citation Format: Paolo Andriollo, George Procopiou, Daniella M. di Mascio, Paul J. Jackson, Khondaker M. Rahman, Keith R. Fox, David E. Thurston. Design and development of a novel highly sequence-selective guanine mono-alkylating DNA-interactive ADC payload suitable for solid tumor treatments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1750.

Oxetane Promise Delivered: Discovery of Long-Acting IDO1 Inhibitors Suitable for Q3W Oral or Parenteral Dosing.

3,3-Disubstituted oxetanes have been utilized as bioisosteres for gem-dimethyl and cyclobutane functionalities. We report the discovery of a novel class of oxetane indole-amine 2,3-dioxygenase (IDO1) inhibitors suitable for Q3W (once every 3 weeks) oral and parenteral dosing. A diamide class of IDO inhibitors was discovered through an automated ligand identification system (ALIS). Installation of an oxetane and fluorophenyl dramatically improved the potency. Identification of a biaryl moiety as an unconventional amide isostere addressed the metabolic liability of amide hydrolysis. Metabolism identification (Met-ID)-guided target design and the introduction of polarity resulted in the discovery of potent IDO inhibitors with excellent pharmacokinetic (PK) profiles in multiple species. To enable rapid synthesis of the key oxetane intermediate, a novel oxetane ring cyclization was also developed, as well as optimization of a literature route on kg scale. These IDO inhibitors may enable unambiguous proof-of-concept testing for the IDO1 inhibition mechanism for oncology.

Transition metal-free domino aryl-aryl coupling/phospha-Michael addition of diarylphosphinite to α,β-unsaturated ketones triggered by alkaline hydrolysis of (4-(2-alkenoyl)phenyl)triarylphosphonium salts

Alkaline hydrolysis of a variety of (4-(2-alkenoyl)phenyl)triarylphosphonium bromides is reported. This hydrolysis triggers coupling of 4-(2-alkenoyl)phenyl with one aryl via phosphorus(V). Both diarylphosphinite and an α,β-unsaturated ketone are in situ generated and then undergo phospha-Michael addition to provide β-diarylphosphoryl ketones bearing a biaryl moiety in 27–70% yields in the absence of a transition metal.

Atroposelective Synthesis of Isoriccardin C through a C−H Activated Heck Type Macrocyclization

AbstractMacrocyclization is typically the key step in syntheses of cyclophane‐type natural products. Considering compounds with axially chiral biaryl moieties, the control of atroposelectivity is essential for biological activity and is synthetically challenging. Herein we report on atroposelective macrocyclization involving an oxidative Heck type process and enabling the first atropo‐enantiopure synthesis of isoriccardin C. A chiral sulfinyl auxiliary in the ortho‐position of a biaryl axis (still flexible) was used to induce a C−H activated atropodiastereoselective oxidative Heck coupling (>98 % de). The traceless character of the sulfinyl auxiliary enables the introduction of a hydroxy group to give the target molecule with >98 % ee as well.

Synthesis of new functionalized triarylmethanes via Suzuki cross-coupling and Heck-type vinylation reactions

A novel class of triarylmethanes (TRAMs) containing one or two biaryl moieties was synthesized efficiently through the Pd(PPh 3 ) 4 -catalyzed Suzuki–Miyaura cross-coupling reaction of brominated TRAMs with arylboronic acid derivatives. We also demonstrate that brominated TRAMs can be efficiently functionalized via a one-pot, two-step Pd-catalyzed Heck-type process. This protocol provides convenient access to diverse vinylated TRAMs that are generally not obtained by using the common synthetic methods for TRAMs.

Biaryl Sulfonamides Based on the 2-Azabicycloalkane Skeleton-Synthesis and Antiproliferative Activity.

In a search for new, selective antitumor agents, we prepared a series of sulfonamides built on bicyclic scaffolds of 2-azabicyclo(2.2.1)heptane and 2-azabicyclo(3.2.1)octane. To this end, aza-Diels–Alder cycloadducts were converted into amines bearing 2-azanorbornane or a bridged azepane skeleton; their treatment with sulfonyl chlorides containing biaryl moieties led to the title compounds. The study of antiproliferative activity of the new agents showed that some of them inhibited the growth of chosen cell lines with the IC50 values comparable with cisplatin, and some derivatives were found considerably less toxic for nonmalignant cells.

Exploring the physicochemical and antiproliferative properties of biaryl-linked [13]-macrodilactones

A macrocyclic motif fosters productive protein-small molecule interactions. There are numerous examples of both natural product and designed, synthetic macrocycles that modulate the immune system, slow microbial infection, or kill eukaryotic cells. Reported here are the synthesis, physicochemical characterization, and antiproliferative activity of a group of [13]-macrodilactones decorated with a pendant biaryl moiety. Biaryl analogs were prepared by Suzuki reactions conducted on a common intermediate that contained a bromophenyl unit alpha to one of the carbonyls of the [13]-macrodilactone. Principal component analysis placed the new compounds in physicochemical context relative to a variety of pharmaceuticals and natural products. Modest inhibition of proliferation was observed in ASZ cells, a murine basal cell carcinoma line. This work underscores the value of an approach toward the identification of bioactive compounds that places the evaluation of physicochemical parameters early in the search process.

Palladium‐Catalzyed Atroposelective 16‐Membered Macrocyclization: Total Synthesis of Isoplagiochin D†

Summary of main observation and conclusionIsoplagiochin D is a ring‐strained macrocyclic bisbibenzylis, which showed stable axial chirality in one biaryl structure, and semistable axial chirality in the other biaryl moiety. We reported here an unprecedented example for the catalytically asymmetric synthesis of ring‐strained atropisomers via Pd‐catalyzed macrocyclization between benzyl halides and carbenes. This newly developed Pd‐catalyzed asymmetric macrocyclization protocol enabled us a quick synthesis of isoplagiochin D in a highly enantioselective manner.

Pharmacophore modeling of pretomanid (PA-824) derivatives for antitubercular potency against replicating and non-replicating Mycobacterium tuberculosis

Pretomanid (PA-824) is the recently (2019) approved drug for the treatment of extensively drug-resistant (XDR) TB and the multidrug-resistant (MDR) TB by US FDA. The experimental data of antitubercular activity of 543 pretomanid derivatives (total 6 datasets) against replicating (active) and non-replicating (dormant) forms of Mycobacterium tuberculosis (strain H37Rv) are available in the literature. Such vast experimental data of pretomanid derivatives against both of these endpoints, and recent approval of pretomanid molecule as a drug encouraged us to utilize this existing experimental information for the development of the 3D-pharmacophore models. The developed model (Hypo-1, MABA) showed the three physicochemical features namely, the oxygen atom of nitro group (HBA_1), fused pyran ring of imidazopyran heterocycle (HYAl_2) and the 4-fluorophenyl moiety (HYAr_3) are crucial for the antitubercular activity against replicating M. tb. Subsequently, the pharmacophore model (Hypo-1, LORA) developed against the non-replicating form of M. tb also showed the contribution of three physicochemical features namely, the 4-tri-fluoromethyl group (HYAl_2) and both the phenyl groups (HYAr_3, HYAr_4) of biaryl moiety in increasing the antitubercular activity. Both the pharmacophoric classifier models showed the classification accuracies of 82.98 and 74.42% for the training set compounds, and 63.91 and 61.60% for the test set compounds respectively, for labelling the compounds into higher and lower active classes. Both the models were also found to be retaining the higher active compounds in top 1.00% of the total number of compounds (decoys and actives), after performing the decoy set screening. Communicated by Ramaswamy H. Sarma

Camphor-based phosphine-carbonyl ligands for Ni catalyzed ethylene oligomerization

Ni and Pd complexes of camphor-based phosphine-carbonyl ligands containing biaryl moiety are designed and synthesized. The Ni complexes can catalyze ethylene oligomerization and generate waxy higher olefins as well as oily lower olefins.

Cyclization of RGD Peptides by Suzuki-Miyaura Cross-Coupling.

Halogenated l- or d-tryptophan obtained by biocatalytic halogenation was incorporated into RGD peptides together with a variety of alkyl or aryl boronic acids. Suzuki-Miyaura cross-coupling either in solution or on-resin results in side chain-to-tail-cyclized RGD peptides, for example, with biaryl moieties, providing a new dimension of structure-activity relationships. An array of RGD peptides differing in macrocycle size, the presence of d-amino acid, N-methylation, or connectivity between the indole moiety and the boronic acid showed that, in particular, connectivity exhibits a major impact on affinities toward integrins, for example, αVβ3. Structure-activity relationship studies yielded peptides with affinities toward αVβ3 in the low nanomolar range, good selectivity, and high plasma stability. Structural characteristics of representative molecules have been investigated by molecular dynamics simulations, which allowed understanding the observed activity differences.

Biaryl synthesis with arenediazonium salts: cross-coupling, CH-arylation and annulation reactions.

The rich legacy of arenediazonium salts in the synthesis of unsymmetrical biaryls, built around the seminal works of Pschorr, Gomberg and Bachmann more than a century ago, continues to make important contributions at various evolutionary stages of modern biaryl synthesis. Based on in-depth mechanistic analysis and design of novel pathways and reaction conditions, the scope of biaryl synthesis with arenediazonium salts has enormously expanded in recent years through applications of transition metal/photoredox-catalysed cross-coupling, thermal/photosensitized radical chain CH-arylation of (hetero)arenes and arylative radical annulation reactions with alkynes. These recent developments have provided facile synthetic access to a wide variety of unsymmetrical biaryls of pharmaceutical, agrochemical and optoelectronic importance with green scale-up options and created opportunities for late-stage modification of peptides, nucleosides, carbon nanotubes and electrodes, the details of which are captured in this review.

Chemoselective methylene oxidation in aromatic molecules.

Despite significant progress in the development of site-selective aliphatic C–H oxidations over the past decade, the ability to oxidize strong methylene C–H bonds in the presence of more oxidatively labile aromatic functionalities remains a major unsolved problem. Such chemoselective reactivity is highly desirable for enabling late stage oxidative derivatizations of pharmaceuticals and medicinally important natural products that often contain such functionality. Herein we report a simple manganese small molecule catalyst Mn(CF3–PDP) system that achieves such chemoselectivity via an unexpected synergy of catalyst design and acid additive. Preparative remote methylene oxidation is obtained in 50 aromatic compounds housing medicinally relevant halogen, oxygen, heterocyclic, and biaryl moieties. Late stage methylene oxidation is demonstrated on four drug scaffolds, including the ethinylestradiol scaffold where other non-directed C–H oxidants that tolerate aromatic groups effect oxidation at only activated tertiary benzylic sites. Rapid generation of a known metabolite (piragliatin) from an advanced intermediate is demonstrated.