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Aristolactams are a small group of aporphinoid alkaloids containing the phenanthrene chromophore that were first isolated from Aristolochia argentina (Aristolochiaceae), which is the richest source of this family of alkaloids. Plants containing aristolactam alkaloids have also been used in traditional medicine to treat various diseases. Thus, in this review, we compile and summarise the recent structures, isolation and biological activities of new and known aristolactam alkaloids from 2014 to 2022, and the total synthetic approaches to the natural products bearing an aristolactam motif from 1978 to 2022. Focus has been given to ingenious strategies to functionalize the aristolactam moiety at multiple positions. In addition, the SAR studies of a potential naturally engineered aristolactam scaffold are discussed. [ABSTRACT FROM AUTHOR]

The ruthenium-catalyzed ortho alkenylation of substituted aromatic and heteroaromatic nitriles with activated alkenes providing ortho alkenylated aromatic and heteroaromatic nitriles in a highly regio- and stereoselective manner is described. [ABSTRACT FROM AUTHOR]

The oxidative coupling of phenyl carbamates and acetates with alkenes in the presence of a catalytic amount of [RuCl2( p-cymene)]2, AgSbF6, and Cu(OAc)2 ·H2O under air provided substituted alkene derivatives in a highly regio- and stereoselective manner. The catalytic reaction was compatible with various alkenes such as acrylates, vinyl sulfones, acrylonitrile, and substituted styrenes. The present catalytic reaction was also compatible with phenyl carbamates and acetates with various electron-rich, electron-deficient, and halogen substituents on the aromatic ring. Further examination of the catalytic reaction was done with the substituted phenyl acetates. By using LiOH ·H2O or K2CO3 as a base, the substituted alkene derivatives were converted into the corresponding phenol derivatives. To account for the catalytic reaction, a possible mechanism is proposed that involves a six-membered ruthenacycle as the key intermediate. [ABSTRACT FROM AUTHOR]

The oxidative cyclization of aromatic and heteroaromatic nitriles with alkynes in the presence of a catalytic amount of [{RuCl2(p-cymene)}2], Cu(OAc)2·H2O and KPF6 in acetic acid under air gave isoquinolones in good to excellent yields. [ABSTRACT FROM AUTHOR]

Chelation-assisted alkenylation of ortho C–H bond of aryl carbamates with alkynes in the presence of a ruthenium catalyst, AgSbF6 and pivalic acid gives highly substituted alkene derivatives in good to excellent yields in a highly regio- and stereoselective manner. [ABSTRACT FROM AUTHOR]

A series of mono-alkenylated arenes is prepared by reaction of aromatic nitriles with acrylate esters. [ABSTRACT FROM AUTHOR]

Aromatic nitriles undergo cyclization with activated alkenes in the presence of a ruthenium catalyst providing substituted 3-methyleneisoindolin-1-ones with high Z-stereoselectivity. [ABSTRACT FROM AUTHOR]

Unsymmetrically substituted alkynes (XIII) are found to regioselectively react in a fashion where the less hindered C-H bond of the aromatic nitrile is preferably attacked by the alkyl substituted site of the alkyne. [ABSTRACT FROM AUTHOR]

The aerobic oxidative coupling of phenyl carbamates and acetates with alkenes proceeds with high regio- and stereoselectivity. [ABSTRACT FROM AUTHOR]

Chelation-assisted alkenylation of the ortho-C-H bond of aryl carbamates with alkynes gives highly substituted alkene derivatives such as (III), (V), and (VIII) in a highly regio- and stereoselective manner. [ABSTRACT FROM AUTHOR]

Several new structurally diverse carbonyl functional group-based iodoantimonate organic–inorganic hybrid crystals are synthesized using an in situ formed oxonium cationic precursor. These crystals exhibit interesting optoelectronic properties consistent with DFT calculations. Charge transfer and photoluminescence quenching between these crystals and Au nanoparticulate films are examined for potential application interest. [ABSTRACT FROM AUTHOR]

This study investigated the metabolism of LXY18, a quinolone-based compound that suppresses tumorigenesis by blocking AURKB localization. Metabolite profiling of LXY18 in liver microsomes from six species and human S9 fractions revealed that LXY18 undergoes various conserved metabolic reactions, such as N-hydroxylation, N-oxygenation, O-dealkylation, and hydrolysis, resulting in ten metabolites. These metabolites were produced through a combination of CYP450 enzymes, and non-CYP450 enzymes including CES1, and AO. Two metabolites, M1 and M2 were authenticated by chemically synthesized standards. M1 was the hydrolyzed product catalyzed by CES1 whereas M2 was a mono-N-oxidative derivative catalyzed by a CYP450 enzyme. AO was identified as the enzyme responsible for the formation of M3 with the help of AO-specific inhibitors and LXY18 analogs, 5b and 5c. M1 was the intermediate of LXY18 to produce M7, M8, M9, and M10. LXY18 potently inhibited 2C19 with an IC 50 of 290 nM but had a negligible impact on the other CYP450s, indicating a low risk of drug-drug interaction. Altogether, the study provides valuable insights into the metabolic process of LXY18 and its suitability as a drug candidate. The data generated serves as a significant reference point for conducting further safety assessments and optimizing drug development. • Interspecies metabolite profiling LXY18 shows conserved metabolic pathways. • Ten metabolites produced through CYP enzymes, CES1, and AO. • CES1 produces the hydrolyzed product, M1. • Mono-oxidative metabolite M3 by using AO-specific inhibitors and LXY18 analogs. • LXY18 potently inhibits 2C19 but has minimal effect on other CYPs. [ABSTRACT FROM AUTHOR]

[Display omitted] • A mechanism-informed phenotypic screening guides lead optimization. • The structural simplification approach identifies a 4-phenoxy-quinoline-based hit. • Lead compound disables AURKB by disrupting its mitotic localization. • Lead compound elicits cytotoxicity in diverse cancer cell lines at low nM concentrations. We combined a mechanism-informed phenotypic screening (MIPS) assay with a structural simplification strategy to guide the discovery of compounds that disrupt the localization of the mitotic regulator, Aurora kinase B (AURKB), rather than inhibiting its catalytic activity. An initial hit 4-(4-methylthiophen-2-yl)-N-(4-(quinolin-4-yloxy)phenyl)phthalazin-1-amine was identified after screening an in-house library of small molecules and phenocopied the loss of function mutations in AURKB without inhibiting its catalytic activity. We isolated this hit compound activity to its 4-phenoxy-quinoline moiety. The fragment was further optimized into a class of new chemical entities that potently disrupt the mitotic localization of AURKB at low nanomolar concentrations and consequently elicit severe growth inhibition in diverse human cancer cell lines. A lead compound, N-(3-methoxy-5-(6-methoxyquinolin-4-yl)oxy)phenyl)acetamide possessed desirable pharmacokinetic properties such as AUC 0-∞ : 227.15 [ng∙h/mL/(mg/kg)]; C max : 3378.52 ng/mL T 1/2 : 3.52 h; and F%: 42 % and produced the AURKB-inhibitory phenotypes in a mouse xenograft model. A lead compound is a powerful tool for interrogating the regulation of AURKB and has the potential to be further developed as a first-in-class oncology therapeutic. [ABSTRACT FROM AUTHOR]

Activity-based drug screens have successfully led to the development of various inhibitors of the catalytic activity of aurora kinases (AURKs), major regulatory kinases of cell division. Disrupting the localization of AURKB, rather than its catalytic activity, represents a largely unexplored alternative approach to disabling AURKB-dependent processes. Localization disruptors could be just as specific as direct inhibitors of AURKB activity, may bypass their off-target and select on-target toxicities, and are likely less susceptible to drug resistance resulting from mutations of the AURKB catalytic site. In this study, we demonstrate that the pan-AURK inhibitor AMG900 works at a low concentration not by inhibiting the phosphorylation of H3 at Ser10, an AURKB substrate, but by disrupting the mitotic localization of AURKB. Structural deletion studies pinpoint this undescribed activity to the 2-phenoxy-3,4′-bipyridine moiety of AMG900. Guided by a mechanism-informed phenotypic screening (MIPS) assay, the drug fragment is optimized into a novel class of inhibitors that, at low nanomolar concentrations, can disable AURKB through disruption of its mitotic localization and have desirable oral PK properties. Hierarchical clustering of cell fitness profiles reveals that these compounds cluster with each other, rather than with known AURK inhibitors such as AMG900 and VX-680. Validation studies in mice demonstrate that compound 15a elicits mitotic arrest and apoptosis in NCI–H23 human lung adenocarcinoma xenografts, resulting in a pronounced suppression of tumor growth. The discovery and optimization of compounds that disrupt AURKB localization are successfully facilitated by MIPS. Our findings suggest that 2-phenoxy-3, 4′-bipyridine derivatives have the potential to be further developed as effective therapeutics for the treatment of malignancy by delocalizing AURKB. [Display omitted] • Mechanism-informed phenotype approach to guide lead optimization. • Structural simplification to identify 2-phenoxy-3,4′-bipyridine moiety of AMG900. • Lead compound 15a disables AURKB by disrupting its mitotic localization. • 15a elicits broad spectrum cytotoxicity at low nM concentrations. [ABSTRACT FROM AUTHOR]