Lactam Ring Research Articles

Regio‐ and Diastereoselective One‐pot Double Cascade Hybrid Formation/[3+3] Spirocyclization for the Synthesis of 3‐Spiropiperidines Under Phase Transfer Conditions.

Herein, we report an efficient approach to synthesizing hybrid 3‐spiropiperidines heterocycles that incorporate both 3‐isochromanone and 3‐isoindolinone units through a one‐pot, double cascade reaction facilitated by an economical K₂CO₃/TBAB catalytic system. By examining the nucleophilicity of the lactone 3‐isochromanone, we developed a cascade reaction pathway that first generates a bi‐nucleophilic hybrid intermediate, which then undergoes [3+3] spirocyclization with α,β‐unsaturated aldehydes. The regioselectivity of the spirocyclization strongly depends on the substitution pattern of lactam ring. The process exhibits high diastereoselectivity, even with the formation of three or four stereocenters, including two contiguous quaternary carbons. These sequential cascade reactions were successfully scaled up, and the subsequent reactivity was readily analyzed, enabling the transformation of existing functional groups into valuable new functionalities.

Reversible pH-switchable NIR-II nano-photosensitizer for precise imaging and photodynamic therapy of tumors

Photodynamic therapy (PDT) has attracted widespread attention from researchers as an emerging cancer treatment method. There have been many reports on various types of NIR-II photosensitizers for imaging and treatment of tumor sites. However, there are few reports on the development of NIR-II organic small molecule photosensitizers that have intelligent response to the tumor microenvironment, precise imaging, real-time treatment, and high biocompatibility. In this work, we developed a series of NIR-II photosensitizers (RBTs) with near-infrared excitation, good photostability, and large Stokes shift. Among them, RBT-Br exhibited higher reactive oxygen species (ROS) generation efficiency due to the introduction of halogen heavy atoms to enhance intersystem crossing (ISC). It is noteworthy that RBT-Br can generate singlet oxygen (1O2) and superoxide anion radicals (•O2−) simultaneously under 730 nm laser. Subsequently, we used molecular engineering technology to construct three pH-responsive NIR-II photosensitizers (RBT-pHs) by utilizing the closure of the lactam ring, among which RBT-pH-1 (pKa = 6.78) is able to be directionally activated under the stimulation of tumor micro-acid environment, with its fluorescence emission window reaching 933 nm. Subsequently, RBT-pH-1 NPs encapsulated in DSPE-mPEG5k were applied for PDT treatment of mouse tumors. The results showed that RBT-pH-1 NPs were activated by the acidic tumor microenvironment and generated ROS under laser excitation, exhibiting precise tumor imaging and significant tumor growth inhibition. We look forward to these multifunctional NIR-II organic small molecule photosensitizers providing a more efficient approach for clinical treatment of tumors. Statement of significanceA reversible pH-switchable NIR-II nano-photosensitizer RBT-pH-1 NPs (pKa = 6.76) is developed for precise imaging and PDT therapy of mouse tumors, which can be effectively used for targeted enrichment and activation of tumor micro-acid environments. The results show that this NIR-II photosensitizer generates ROS through tumor micro-acid environment stimulation and laser triggering, showing precise tumor imaging guidance and significant tumor growth inhibition.

Reduction of 2-phenyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione with NaBH4: Investigation of exo-selectivity and reaction mechanism via theoretical computations

The reaction of the bicyclic imide with NaBH4 afforded acylaminocarbinol and carboxamide derivatives. The exact configuration of acylaminocarbinol 7 was determined by X-ray crystal analysis. Theoretical studies were carried out to explain the mechanism of the exo-selectivity observed in the first step of the reduction reaction and the formation of the secondary product in the second step. According to the obtained findings, i) in the first step of the reaction, the exo-path is kinetically more favorable, and ii) an alternative mechanism has been proposed instead of the mechanism proposed in the literature. The canonical forms of the amide group in the lactam ring were found to make an important contribution to the mechanism. iii) The amount of products formed in the reduction reaction depends on the reaction conditions.

Design and synthesis of 7-membered lactam fused hydroxypyridinones as potent metal binding pharmacophores (MBPs) for inhibiting influenza virus PAN endonuclease

Since influenza virus RNA polymerase subunit PAN is a dinuclear Mn2+ dependent endonuclease, metal-binding pharmacophores (MBPs) with Mn2+ coordination has been elucidated as a promising strategy to develop PAN inhibitors for influenza treatment. However, few attentions have been paid to the relationship between the optimal arrangement of the donor atoms in MBPs and anti-influenza A virus (IAV) efficacy. Given that, the privileged hydroxypyridinones fusing a seven-membered lactam ring with diverse side chains, chiral centers or cyclic systems were designed and synthesized. A structure-activity relationship study resulted in a hit compound 16l (IC50 = 2.868 ± 0.063 μM against IAV polymerase), the seven-membered lactam ring of which was fused a pyrrolidine ring. Further optimization of the hydrophobic binding groups on 16l afforded a lead compound (R, S)-16s, which exhibited a 64-fold more potent inhibitory activity (IC50 = 0.045 ± 0.002 μM) toward IAV polymerase. Moreover, (R, S)-16s demonstrated a potent anti-IAV efficacy (EC50 = 0.134 ± 0.093 μM) and weak cytotoxicity (CC50 = 15.35 μM), indicating the high selectivity of (R, S)-16s. Although the lead compound (R, S)-16s exhibited a little weaker activity than baloxavir, these findings illustrated the utility of a metal coordination-based strategy in generating novel MBPs with potent anti-influenza activity.

Ultrasensitive detection of trace Hg(Ⅱ) in acidic conditions using DMABR loaded on sepiolite: Function, application and mechanism studies

Fast and real-time detection of trace Hg(Ⅱ) by fluorescent probes under acidic conditions is urgently required due to the high toxicity and accessibility to creatures and human being. However, fluorescent probes for Hg(Ⅱ) detection in environmental samples are rarely reported due to the protonation potential of acidic mercury sources. In this study, the SD probe was developed by 5-(p-dimethylaminobenzylidene) rhodanine (DMABR) loaded on sepiolite by hydrothermal treatment, and showed excellent Hg(Ⅱ) detection performances for mercury sources at pH 4–10 due to buffering ability of the hyperconjugated lactam rings. Sepiolite functioned as the support skeleton to decrease intermolecular transition, and thus increased the sensitivity. At pH 4, the SD probe showed high selectivity and sensitivity for Hg(Ⅱ) among various species, with low LOD and binding constant of 4.78 × 10−9 M and 1.34 × 106 M−1, respectively. Through DFT calculations, MAS 1H NMR and 2D-COS analysis, the detection mechanism was demonstrated as SN1 substitution of the spontaneous leaving H on amino groups in the transient state during tautomeric equilibrium, rather than the expected high-affinity sulphydryl. Additionally, the SD probe exhibited promising potential in quantifying water-soluble and bioavailable Hg(Ⅱ) in acidic polluted soil and water samples. Moreover, real-time detection was realized by paper-based strips.

Diastereoselective Synthesis of Dihydrobenzofuran Spirooxindoles and Their Transformation into Benzofuroquinolinones by Ring Expansion of Oxindole Core.

A mild and efficient approach for the diastereoselective synthesis of dihydrobenzofuran spirooxindoles using 3-chlorooxindoles and imines is presented. This process involves a formal [4 + 1] annulation, yielding the product with excellent diastereoselectivity. Furthermore, a novel method for constructing benzofuroquinolinone scaffolds through the ring expansion of oxindoles has been established. This method involves a lactam ring expansion to the quinolinone skeleton. Besides, a one-pot procedure for creating benzofuroquinolinone scaffolds from 3-chlorooxindoles and imines is also provided.

Synthesis, kinase inhibition and anti-leukemic activities of diversely substituted indolopyrazolocarbazoles

Pyrazole analogues of the staurosporine aglycone K252c, in which the lactam ring was replaced by a pyrazole moiety, were synthesized. In this series, one or the other nitrogen atoms of the indolocarbazole scaffold was substituted by aminoalkyl chains, aiming at improving protein kinase inhibition as well as cellular potency toward acute myeloid leukemia (AML) cell lines. Compound 19a, substituted at the N12-position by a 3-(methylamino)propyl group, showed high cellular activity in the low micromolar range toward three AML cell lines (MOLM-13, OCI-AML3 and MV4-11) with selectivity over non-cancerous cells (NRK, H9c2). 19a is also a highly potent inhibitor of the three Pim kinase isoforms, Pim-3 being the most inhibited with an IC50 value in the nanomolar range. A selectivity screening toward a panel of 50 protein kinases showed that 19a also potently inhibited PRK2 and to a lower extent AMPK, MARK3, GSK3β and JAK3. Our results enhance the understanding of the structural characteristics of indolopyrazolocarbazoles essential for potent protein kinase inhibition with therapeutic potential against AML.

Biomimetic metal-phenolic network with cyclolactam hydrogel coating on PPENK implant facilitate bone repair

Bone defects are often accompanied by infection, which causes great physical pain to patients. Metal-phenolic networks (MPNs) are a newly organic–inorganic hybrid networks system, which has become a multifunctional surface modifier based on the universal adhesion properties of phenolic molecules. Hence, we fabricate a MPN hydrogel coating based on cyclolactam network by spin-coating a mixture of gelatin, iron ions, and polyphenol monomer containing phthalazinone structure (THPZB) on the surface of poly(aryl ether nitrile ketone) (PPENK) (G/THPZB/Fe/PPENK). The method can easily obtain a high strength and versatile surface hydrogel coating based on the combination of the entangled structure on phthalazinone and the characteristic functions of MPNs. The residual polyphenol on the surface not only confer good adhesion ability, but also can cooperate with lactam ring to confer outstanding antibacterial ability to the PPENK implant. Importantly, the antibacterial mechanism of this modified PPENK implant might be consistent with that of penicillin. Besides, it has excellent ability to promote angiogenesis and healing in vitro. Notably, significant effects on biomineralization and osteogenesis in vitro and in vivo are observed. We hypothesis that cyclolactam-based MPN multifunctional hydrogel coating can provide great application prospects for PPENK bone implant materials in the field of bone defect repair.

8-Iodoisoquinolinone, a Conformationally Rigid Highly Reactive 2-Iodobenzamide Catalyst for the Oxidation of Alcohols by Hypervalent Iodine.

The first lactam-type 2-iodobenzamide catalysts, 8-iodoisoquinolinones 8 (IB-lactam) and 9 (MeO-IB-lactam), were developed. These catalysts have a conformationally rigid 6/6 bicyclic lactam structure and are more reactive than the previously reported catalysts 2-iodobenzamides 4 (IBamide) and 5 (MeO-IBamide) for the oxidation of alcohols. The lactam structure could form an efficient intramolecular I---O interaction, depending on the size of the lactam ring.

Total Synthesis of Stachybotrys microspora Triprenol Phenol-7 (SMTP-7).

The first total synthesis of Stachybotrys microspora triprenol phenol (SMTP)-7 is described. Establishment of the two pyran ring stereogenic centers and key reactions featuring a double reductive amination and a double lactam ring formation in flow are described. The (2R,3S)-trans-benzopyran intermediate 7A, isolated by chiral preparative SFC chromatography, was carried forward to afford SMTP-7. Analytical data for synthetic SMTP-7, including 1H and 13C NMR data, HPLC retention time, and UV spectrum, were in excellent agreement with those for natural SMTP-7.

Ring Opening of N-Acyl Lactams Using Nickel-Catalyzed Transamidation.

We successfully developed a nickel-catalyzed transamidation method for the ring opening of N-acyl lactams. The method involves a reaction between N-benzoylpyrrolidin-2-one derivatives and aniline derivatives, with Ni(PPh3)2Cl2 serving as the catalyst, 2,2'-bipyridine as the ligand, and manganese as the reducing agent. This reaction led to the formation of ring-opening-amidated products in good yields. Notably, the method exhibited excellent efficiency for producing the corresponding ring-opening transamidation products for various ring sizes, including four-, five-, six-, seven-, and eight-membered ring lactams.

Identification of Azalamellarin N as a Pyroptosis Inhibitor.

Pyroptosis is a form of regulated cell death that promotes inflammation; it attracts much attention because its dysregulation leads to various inflammatory diseases. To help explore the precise mechanisms by which pyroptosis is regulated, in this study, we searched for chemical compounds that inhibit pyroptosis. From our original compound library, we identified azalamellarin N (AZL-N), a hexacyclic pyrrole alkaloid, as an inhibitor of pyroptosis induced by R837 (also called imiquimod), which is an agonist of the intracellular multiprotein complex nucleotide-binding and oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome. However, whereas the effect of AZL-N on R837-induced pyroptosis was relatively weak, AZL-N strongly inhibited pyroptosis induced by extracellular ATP or nigericin, which are different types of NLRP3 inflammasome agonists. This was in contrast with the results that MCC950, a well-established NLRP3 inhibitor, consistently inhibited pyroptosis irrespective of the type of stimulus. We also found that AZL-N inhibited activation of caspase-1 and apoptosis-associated speck-like proteins containing a caspase activation and recruitment domain (ASC), which are components of the NLRP3 inflammasome. Analysis of the structure-activity relationship revealed that a lactam ring of AZL-N, which has been shown to contribute to the strong binding of AZL-N to its known target protein kinases, is required for its inhibitory effects on pyroptosis. These results suggest that AZL-N inhibits pyroptosis by targeting molecule(s), which may be protein kinase(s), that act upstream of NLRP3 inflammasome activation, rather than by directly targeting the components of the NLRP3 inflammasome. Further identification and analysis of target molecule(s) of AZL-N will shed light on the regulatory mechanisms of pyroptosis, particularly those depending on proinflammatory stimuli.

Mild hydrolysis of chemically stable valerolactams by a biocatalytic ATP-dependent system fueled by metaphosphate.

Medium-sized 5- and 6-membered ring lactams are molecules with remarkable stability, in contrast to smaller β-lactams. As monomers, they grant access to nylon-4 and nylon-5, which are alternative polyamides to widespread caprolactam-based nylon-6. Chemical hydrolysis of monocyclic γ- and δ-lactams to the corresponding amino acids requires harsh reaction conditions and up to now, no mild (enzymatic) protocol has been reported. Herein, the biocatalytic potential of a pair of heterologously expressed bacterial ATP-dependent oxoprolinases - OplA and OplB - was exploited. Strong activity in the presence of excess of ATP was monitored on δ-valerolactam and derivatives thereof, while trace activity was detected on γ-butyrolactam. An ATP recycling system based on cheap Graham's salt (sodium metaphosphate) and a polyphosphate kinase allowed the use of catalytic amounts of ATP, leading to up to full conversion of 10 mM δ-valerolactam at 30 °C in aqueous medium. Further improvements were obtained by co-expressing OplA and OplB using the pETDuet1 vector, a strategy which enhanced the soluble expression yield and the protein stability. Finally, a range of phosphodonors was investigated in place of ATP. With acetyl phosphate and carbamoyl phosphate, turnover numbers up to 176 were reached, providing hints on a possible mechanism, which was studied by 31P-NMR.

Stereoselective Construction of β-, γ-, and δ-Lactam Rings via Enzymatic C-H Amidation.

Lactam rings are found in many biologically active natural products and pharmaceuticals, including important classes of antibiotics. Methods for the asymmetric synthesis of these molecules are therefore highly desirable, particularly through the selective functionalization of unreactive aliphatic C-H bonds. Here we show the development of a strategy for the asymmetric synthesis of β-, γ-, and δ-lactams via hemoprotein-catalysed intramolecular C-H amidation reaction with readily available dioxazolone reagents. Engineered myoglobin variants serve as excellent biocatalysts for this transformation yielding the desired lactam products in high yields, high enantioselectivity, and on preparative scale. Mechanistic and computational studies elucidate the nature of the C-H amination and enantiodetermining steps and provide insights into protein-mediated control of regioselectivity and stereoselectivity. Additionally, an alkaloid natural product and a drug molecule were synthesized chemoenzymatically in much fewer steps (7-8 vs. 11-12) than previously reported, further demonstrating the power of biosynthetic strategy for the preparation of complex bioactive molecules.

The Effect of Deuteration and Homologation of the Lactam Ring of Nirmatrelvir on Its Biochemical Properties and Oxidative Metabolism.

This study explores the relationship between structural alterations of nirmatrelvir, such as homologation and deuteration, and metabolic stability of newly synthesized derivatives. We developed a reliable synthetic protocol toward dideutero-nirmatrelvir and its homologated analogues with high isotopic incorporation. Deuteration of the primary metabolic site of nirmatrelvir provides a 3-fold improvement of its human microsomal stability but is accompanied by an increased metabolism rate at secondary sites. Homologation of the lactam ring allows the capping group modification to decrease and delocalize the molecule's lipophilicity, reducing the metabolic rate at secondary sites. The effect of deuteration was less pronounced for the 6-membered lactam than for its 5-membered analogue in human microsomes, but the trend is reversed in the case of mouse microsomes. X-ray data revealed that the homologation of the lactam ring favors the orientation of the drug's nitrile warhead for interaction with the catalytic sulfur of the SARS-CoV-2 Mpro, improving its binding. Comparable potency against SARS-CoV-2 Mpro from several variants of concern and selectivity over human cysteine proteases cathepsin B, L, and S was observed for the novel deuterated/homologated derivative and nirmatrelvir. Synthesized compounds displayed a large interspecies variability in hamster, rat, and human hepatocyte stability assays. Overall, we aimed to apply a rational approach in changing the physicochemical properties of the drug to refine its biochemical and biological parameters.

New Teixobactin Analogues with a Total Lactam Ring.

Teixobactin is a new antibiotic peptide with strong efficacy against several Gram-positive resistant bacteria, the structure of which is extremely difficult to obtain in the laboratory via multistep conventional synthesis. To face the increasing antibiotic resistant bacteria, it is fundamental to introduce new types of antibiotics with innovative mechanisms of action without resistance; thus, many scientists are studying and developing new methods to synthesize teixobactin analogues. In this work, seven Arg10-teixobactin analogues with a total lactam ring have been prepared via solid phase peptide synthesis. In order to obtain the total lactam ring, d-Thr8 was replaced by (2R,3S)-diamino-propionic acid. To verify their antimicrobial activity and efficacy, each analogue was tested with MIC against different resistant pathogens, showing an interesting activity for Nle11 containing compounds.

Organocatalysts for the Asymmetric Neber reaction: Synthesis of Chiral 2‐(Tetrazol‐5‐yl)‐2H‐Azirines

Abstract‐ Several novel organocatalysts derived from β‐ and γ‐lactam‐fused thiazolidines and L‐phenylalanine‐based thiazolidines were efficiently synthetized. These organocatalysts, as well as other previously developed thiazolidine‐derived thioureas, were tested in the asymmetric one‐pot Neber reaction of β‐ketoxime‐1H‐tetrazoles towards chiral 2‐(tetrazol‐5‐yl)‐2H‐azirines. The results obtained when using thioureas only differing in the lactam ring size demonstrate that the presence of the 6β‐lactam ring in the catalysts is a requirement to achieve high enantioselectivity in the studied transformation. The new 6β‐aminopenicillanic acid‐derived thiourea afforded the R enantiomer of 3‐phenyl‐2‐(tetrazol‐5‐yl)‐2H‐azirine with >99 % ee.

Enantioselective 1,3-Dipolar Cycloadditions of α-Methylene Lactams to Construct Spirocycles.

Spirocyclic scaffolds are important motifs due to their potential to bestow favorable effects on pharmaceutical compounds. However, there is a need for efficient methods for their enantioselective construction. We report a method for the asymmetric 1,3-dipolar cycloaddition of diazoacetates or nitrile oxides with α-methylene lactams to prepare chiral spirocyclic heterocycles. The methodology is high yielding (up to 91% yield) and enantioselective (up to 89% ee) for a wide range of N-substituents and 6- and 7-membered ring lactam substrates.

Diclofenac-Impregnated Mesoporous Carbon-Based Electrode Material for the Analysis of the Arsenic Drug Roxarsone.

This paper describes a novel electrode material, diclofenac-impregnated mesoporous carbon modified with a cationic surfactant, cetyltrimethylammonium bromide (DF-CMK-3/CTAB), for ultratrace analysis of the arsenic drug roxarsone (ROX). DF-CMK-3 amorphous carbon is a material with a high specific surface area and well-defined, hexagonally ordered, thin mesopores. The functional groups attached to the carbonaceous surface, such as chromene and pyron-like oxygen groups, lactam, and aromatic carbon rings, have the basic character and they can donate electrons. Modification of DF-CMK-3 with a CTAB layer significantly increases the analytical signal due to electrostatic interactions between the cationic surfactant and the anion form of ROX in the acidic medium. The voltammetric procedure at the glassy carbon sensor modified with DF-CMK-3/CTAB exhibited excellent sensitivity (limit of detection of 9.6 × 10-11 M) with a wide range of linearity from 5.0 × 10-10 to 1.0 × 10-4 M. Analysis of real samples (treated municipal wastewater and river water) showed recoveries from 96 to 102% without applying the complicated sample pretreatment step. The sensor demonstrated excellent sensitivity in the analysis of the arsenic drug ROX in the presence of interferences in environmental water samples.

A Piperazine Linked Rhodamine-BODIPY FRET-based Fluorescent Sensor for Highly Selective Pd2+ and Biothiol Detection.

A class of rhodamine-based fluorescent sensors for the selective and sensitive detection of Pd2+ metal ions in aqueous media has been developed. A rhodamine-based sensor PMS and a rhodamine-BODIPY Förster resonance energy transfer (FRET)-pair sensor PRS have been incorporated with a piperazine linker and an O-N-S-N podand ligand for specific recognition of Pd2+ ion. Both probes displayed colorimetric and fluorescent ratiometric changes when exposed to Pd2+, due to their spirolactam rings opening and restoring rhodamine conjugation. PRS is highly selective to Pd2+ over 22 other metal ions, showing a 0.6-fold ratiometric difference at I600nm/I515nm. Additionally, the lactam ring in Pd2+ coordinated PRS-Pd could be switched back to the closed form in the presence of various thiols, providing a "red-green traffic light" detection mechanism between red and green emission. Furthermore, PRS showed excellent cell viability and was successfully employed to image Pd2+ and the PRS-Pd complex ensemble could interchangeably detect biothiols including glutathione (GSH) in A549 human lung cancer cells.