Diverse Isoquinoline Research Articles

Structurally diverse isoquinoline alkaloids from the barks of Alangium salviifolium (L. f.) Wangerin and their cytotoxicity

Eleven undescribed isoquinoline alkaloids (1−8, 14, 15, and 24), along with 19 analogues (9−13, 16−23, and 25−30) were isolated from the barks of Alangium salviifolium. The structures of the undescribed compounds were elucidated through the analysis of their HR-ESI-MS, 1D and 2D NMR, IR, UV, and X-ray diffraction. The absolute configuration of 8 was established via the ECD calculation. Notably, compounds 1/2 and 3/4 were two pairs of C-14 epimers. The isolated alkaloids were evaluated for their cytotoxicity against various cancer cell lines, including SGC-7901, HeLa, K562, A549, BEL-7402, HepG2, and B16, β-carboline-benzoquinolizidine (14−22) and cepheline-type (24−28) alkaloids exhibited remarkable cytotoxicity, with IC50 values ranging from 0.01 to 48.12 μM. Remarkably, compounds 17 and 21 demonstrated greater cytotoxicity than the positive control doxorubicin hydrochloride. Furthermore, a significant proportion of these bioactive alkaloids possess a C-1′ epimer configuration. The exploration of their structure-activity relationship holds promise for directing future investigations into alkaloids derived from Alangium, potentially leading to novel insights and therapeutic advancements.

Menisperdaurines A-W, structurally diverse isoquinoline alkaloids from Menispermum dauricum and their dopamine D1 receptor activities

A total of 33 structurally diverse isoquinoline alkaloids were isolated from the rhizomes of Menispermum dauricum, including seventeen benzylisoquinoline analogues (menisperdaurines A-Q, 1–17), five protoberberine analogues (menisperdaurines R-V, 18–22), a quaternary phenanthrene alkaloid (menisperdaurine W, 23) and ten known compounds (24–33). Compound structures, including absolute configurations, were determined by extensive spectroscopic methods, quantum chemical calculations of chemical shifts, and calculated and experimental electronic circular dichroism (ECD) data. Compounds 1–5 were glycosidic benzylisoquinolines with glucose moieties attached at the C-12 position. Compound 8 was the first example that was isolated from the rhizomes of Menispermum dauricum, benzylisoquinoline and an aromatic unit connected by a sugar bridge. Compounds were evaluated for their inhibitory effects on the dopamine D1 receptor. Compounds 1, 8, 21, 24 and 29 showed potent D1 antagonistic activities, with IC50 values ranging from 1.0 to 4.5 μM. Compound 1 exhibited the highest antagonistic activity with an IC50 value of 1.0 ± 0.2 μM.

Structurally diverse isoquinoline and amide alkaloids with dopamine D2 receptor antagonism from Corydalis bungeana

Four new isoquinoline alkaloids including a benzophenanthridine alkaloid (1), a morphine derivative (2), a narceine-type alkaloid (3) and a simple isoquinoline alkaloid (4), a new amide alkaloid (5) and a new phthalic acid derivative (6), together with eleven known alkaloids (7–17) were obtained from the whole herbs extract of Corydalis bungeana Turcz. Their structures and absolute configurations were elucidated by extensive spectroscopic data analysis including HRESIMS, NMR and electronic circular dichroism (ECD) and ECD calculation. Compounds 1–17 were evaluated for dopamine D2 receptor activity in CHO-D2 cells. Among them, 16 showed the highest antagonistic activity on the D2 receptor with an IC50 value of 2.04 ± 0.01 μM. Compounds 14 and 15 exhibited moderate antagonism with IC50 values of 13.66 ± 2.28 and 31.72 ± 2.52 μM, respectively.

Synthesis of Isoquinolines via Rh(III)‐Catalyzed C−H Annulation of Primary Benzylamines with α‐Cl Ketones

AbstractAn efficient Rh(III)‐catalyzed C−H activation and annulation cascade of primary benzylamines with readily accessible α‐Cl ketones was developed. This transformation provides an easy and robust approach to diverse isoquinolines under air with broad functional group tolerance.

Diverse isoquinolines with anti-inflammatory and analgesic bioactivities from Hypecoum erectum

Ethnopharmacological relevanceHypecoum erectum has been used extensively in folk medicine to treat inflammation, fever, and pain. However, few investigations have been carried out on the biological activities related to its traditional use. The chemical constituents of this plant along with their anti-inflammatory and analgesic effects have yet to be revealed. Aim of the studyThis study aimed to support the traditional use of H. erectum by first assessing its anti-inflammatory and analgesic effects and then investigating its chemical constituents to identify any anti-inflammatory and/or analgesic compounds. Material and methodsThe in vivo anti-inflammatory and analgesic activities of the MeOH extract (ME), total alkaloid (AL), and non-alkaloid (Non-AL) fractions of H. erectum at doses of 200, 100, and 50 mg/kg and four major constituents (20, 21, 22, and 27) at doses of 100 and 50 mg/kg delivered via intragastrical administration were evaluated using carrageenan-induced paw edema and acetic acid-stimulated writhing animal models. A phytochemical study of the bioactive (AL) fraction was conducted using various chromatographic techniques, and the structures of the obtained isoquinolines were identified by multiple spectroscopic analyses and quantum chemical computations. Moreover, the anti-inflammatory activities of all the isolates were assessed in vitro based on the suppression of lipopolysaccharide-activated inflammatory mediators (COX-2, IL-1β, and TNF-α) in RAW 264.7 macrophage cells. ResultsAt the dose of 200 mg/kg, the three fractions (ME, AL, and Non-AL) of H. erectum ameliorated the paw edema by carrageenan-stimulated and reduced the number of writhing by acetic acid-induced in mice compared to the model group, with the AL fraction showing the most potent effects. Subsequent phytochemical investigation of the AL fraction led to the isolation of six new isoquinoline alkaloids (1–6) as well as 23 known analogues (7–29). However, compared to common isoquinolines, compounds 1–4 possess an additional nitrogen atom, while compound 5 has two additional nitrogen atoms. These additional atoms enrich the diversity of natural isoquinoline alkaloids. Further pharmacological evaluation in vivo revealed that the four major constituents (20, 21, 22, and 27) significantly relieved paw edema at 100 mg/kg, while protopine (20) and oxyhydrastinin (27) remarkably decreased the number of writhing at 100 mg/kg. In addition, most of the isolates displayed anti-inflammatory effects, as indicated by the inhibition of inflammatory mediators (COX-2, IL-1β, and/or TNF-α) in vitro at a treatment concentration of 5 μg/mL. trans-benzindenoazepines (13), protopine (20), and 1,3,6,6-tetramethyl-5,6,7,8-tetrahyboisoquiolin-8-one (25) showed comparable anti-inflammatory activity to dexamethasone by inhibiting the secretion of IL-1β. ConclusionsThis investigation validated the traditional use of H. erectum by assessing its anti-inflammatory and analgesic effects. Phytochemical investigation revealed the diversity and novelty of the natural isoquinoline alkaloids in H. erectum. Four major isoquinolines were identified as the bioactive constituents of H. erectum. The findings provide scientific justification to support the traditional application of H. erectum for treating inflammatory and pain disorders.

Palladium(II)-catalyzed asymmetric C-H carbonylation to diverse isoquinoline derivatives bearing all-carbon quaternary stereocenters.

Enantioselective synthesis of tetrahydroisoquinolines bearing an all-carbon quaternary stereogenic center, was achieved via asymmetric C-H activation with high enantioselectivities (up to 93% ee). Fair substrate tolerance was indicated throughout the scope investigation and no evident loss of enantioselectivity was exhibited in late-stage derivatization. This study provides incentives for the construction of diverse chiral isoquinoline derivatives, which are prevalent among pharmaceuticals, natural products, etc.

Diverse Isoquinoline Scaffolds by Ugi/Pomeranz-Fritsch and Ugi/Schlittler-Müller Reactions.

The Pomeranz–Fritsch reaction and its Schlittler–Müller modification were successfully applied in the Ugi postcyclization strategy by using orthogonally protected aminoacetaldehyde diethyl acetal and complementary electron rich building blocks. Several scaffolds, including isoquinolines, carboline, alkaloid-like tetrazole-fused tetracyclic compounds, and benzo[d]azepinone scaffolds, were synthesized in generally moderate to good yield. All our syntheses provide a short MCR-based sequence to novel or otherwise difficult to access scaffolds. Hence, we foresee multiple applications of these synthesis technologies.

Efficient synthesis of isoquinolines in water by a Pd-catalyzed tandem reaction of functionalized alkylnitriles with arylboronic acids

Pd-catalyzed tandem reaction of functionalized alkylnitriles with arylboronic acids for the synthesis of diverse isoquinolines in water.

Tandem Addition/Cyclization for Access to Isoquinolines and Isoquinolones via Catalytic Carbopalladation of Nitriles.

The first example of the palladium-catalyzed sequential nucleophilic addition followed by an intramolecular cyclization of functionalized nitriles with arylboronic acids has been achieved, providing an efficient synthetic pathway to access structurally diverse isoquinolines and isoquinolones. This methodology has also been successfully applied to the total synthesis of the topoisomerase I inhibitor CWJ-a-5 (free base).

ChemInform Abstract: Isoquinoline Skeleton Synthesis via Chelation‐Assisted C—H Activation

AbstractReview: [27 refs.

Total syntheses of menisporphine and daurioxoisoporphine C enabled by photoredox-catalyzed direct C-H arylation of isoquinoline with aryldiazonium salt.

Isoquinoline alkaloids are attractive natural products due to their diverse chemical structures as well as remarkable bioactivities. Herein, we report the concise total syntheses of two isoquinoline alkaloids, menisporphine and daurioxoisoporphine C, through a mild and efficient photoredox-catalyzed direct C-H arylation of isoquinoline core with aryldiazonium salt. This new strategy is complementary to the conventional isoquinoline synthesis and would provide us a useful means to achieve a more convergent and flexible approach to access diverse isoquinoline structures.

ChemInform Abstract: A Silver(I)‐Catalyzed Reaction of 2‐Alkynylbenzaldoxime with Arylsulfonyl Chloride.

Abstract A silver-catalyzed reaction of 2-alkynylbenzaldoxime with arylsulfonyl chloride proceeds smoothly at room temperature to afford 4-tosyloxyisoquinolines in moderate to good yields. Additionally, the resulting 4-tosyloxyisoquinolines could be further elaborated through palladium-catalyzed coupling reactions leading to diverse isoquinolines.

Manganese‐Catalyzed Dehydrogenative [4+2] Annulation of NH Imines and Alkynes by CH/NH Activation

AbstractDescribed herein is a manganese‐catalyzed dehydrogenative [4+2] annulation of NH imines and alkynes, a reaction providing highly atom‐economical access to diverse isoquinolines. This transformation represents the first example of manganese‐catalyzed CH activation of imines; the stoichiometric variant of the cyclomanganation was reported in 1971. The redox neutral reaction produces H2 as the major byproduct and eliminates the need for any oxidants, external ligands, or additives, thus standing out from known isoquinoline synthesis by transition‐metal‐catalyzed CH activation. Mechanistic studies revealed the five‐membered manganacycle and manganese hydride species as key reaction intermediates in the catalytic cycle.

Manganese‐Catalyzed Dehydrogenative [4+2] Annulation of NH Imines and Alkynes by CH/NH Activation

Described herein is a manganese-catalyzed dehydrogenative [4+2] annulation of NH imines and alkynes, a reaction providing highly atom-economical access to diverse isoquinolines. This transformation represents the first example of manganese-catalyzed CH activation of imines; the stoichiometric variant of the cyclomanganation was reported in 1971. The redox neutral reaction produces H2 as the major byproduct and eliminates the need for any oxidants, external ligands, or additives, thus standing out from known isoquinoline synthesis by transition-metal-catalyzed CH activation. Mechanistic studies revealed the five-membered manganacycle and manganese hydride species as key reaction intermediates in the catalytic cycle.

A silver(I)-catalyzed reaction of 2-alkynylbenzaldoxime with arylsulfonyl chloride

A silver-catalyzed reaction of 2-alkynylbenzaldoxime with arylsulfonyl chloride proceeds smoothly at room temperature to afford 4-tosyloxyisoquinolines in moderate to good yields. Additionally, the resulting 4-tosyloxyisoquinolines could be further elaborated through palladium-catalyzed coupling reactions leading to diverse isoquinolines.

Generation of diverse isoquinoline N-oxides in an aqueous system

4-Halo isoquinoline N-oxides could be synthesized efficiently via the electrophilic cyclization of 2-alkynylbenzaldoximes, involving the in situ generation of the halonium ion in water. The one-pot cyclization–Suzuki reaction in an aqueous system afforded the functionalized isoquinoline N-oxides in good yields.

Triterpenoid saponins from a Siberian chemorace of the Thalictrum genus.

Plants of the Thalictrum genus (Ranunculaceae family) grow in the temperate zones of the both hemispheres of the globe. Many of these species are met worldwide. Thalictrum minus, for example, is known in Europe, Asia, and North America. However, secondary metabolism in this species is variable. Thus, in the Bulgarian population of the plant a bisbenzylisoquinoline alkaloid, thalicarpin, has been isolated as a major secondary metabolite [1], whereas the Moldavian chemorace met hereabout produces a secoprotoberberine base, β-allocryptopine [2]. In general, all the Thalictrum species were thought to serve as producers of diverse isoquinoline and, on rare occasions, of diterpene alkaloids. T. minus widely spreads from east to west over the whole territory of Russia and is involved in the Siberian biocenoses. That is why 15 years ago we tried to assess its potential as a producer of alkaloids. However any tertiary bases have not been detected. Instead, we have found a fairly large amount of saponins. This seemed strange, since earlier in the literature there were only scarce and unreliable data on the presence of saponins of unidentified structure in the representatives of this genus. Therefore, we decided to concentrate all research efforts on the elucidation of the chemical nature of the glycosides found.

Isoquinoline alkaloids from cell suspension cultures of Fumaria capreolata

Fumaria capreolata was taken into cell suspension culture. The culture yielded a biomass of about 12 g dry weight per liter of medium; the dried cells contained ca. 0.1% of alkaloids. Besides choline, the following ten known isoquinoline alkaloids were isolated from the cell extract in crystalline form: coptisine, dehydrocheilanthifoline; (+)-isoboldine; magnoflorine; N-methylcoclaurine; (+)-reticuline; (-)-pallidine; protopine; sanguinarine; (-)-scoulerine. This is the most diverse isoquinoline alkaloid spectrum thus far published for a cell suspension culture.