Development of Cardiovascular Drugs Based on Isoquinoline Compounds from Chinese Medicinal Materials

By using active principles of Chinese medicinal materials as lead compounds soquinoline derivatives have been designed and synthesized.Their chemical structures include bisbenzylisoquinoline,benzyl-isoquinoline and protoberberine.Their cardiovascular effects were studied involving α-adrenoceptor,adenosine A_1,A_2 and DPH-calcium channel radioreceptor assays.In addition,calmodulin inhibiting,calcium antagonistic potassium channel blocking and antiplatelet aggre- gation activities were also performed.It was found that compound VI_(19) was a new potassium channe blocker with α-adrenoceptor antagonism,compound V_9,and V_(21) lowered blood pressure on various animal models with negative chronotropic action,compound VI_(13)possessed antiarrhythmic and antifi- brillation action,and it may be a candidate tot clinic evaluation.The structure-activity relationships deduced may provide a theoretical basis for further development of new agents.

Cobalt-catalyzed redox-neutral synthesis of isoquinolines: C–H activation assisted by an oxidizing N–S bond

A redox‐neutral avenue to access isoquinolines has been realized by a Co（III）‐catalyzed C–H activa‐tion process. Starting from readily available N‐sulfinyl imine substrates and alkynes, the reaction occurred via N–S cleavage with broad substrate scope and functional group compatibility in the presence of cost‐effective cobalt catalysts.

Reactivity of 1-methylisoquinoline synthesis of pyrazolyl triazoloisoquinoline and thia-diazolyl isoquinoline derivatives

The reaction of 1-methylisoquinoline 1 with hy-drazonoyl halides 2 in ethanol in the presence of chitosan under microwave irradiation affords triazoloisoquinoline 4. Product 4 reacts with dimethylformamide-dimethylacetal to give ena- minones 7 which react with hydrazonoyl halides to give pyrazolyl triazoloisoquinoline 13. Also, 1-methylisoquinoline 1 reacts with arylisothio-cyanate to give thioanilide 15 which reacts with hydrazonoyl halides to give the corresponding thiadiazolyl isoquinoline derivatives 20, 24.

Pyrolysis Mechanisms of Quinoline and Isoquinoline with Density Functional Theory

The pyrolysis mechanisms of quinoline and isoquinoline were investigated using the density functional theory of quantum chemistry,including eight reaction paths and a common tautomeric intermediate 1-indene imine.It is concluded that the conformational tautomerism of the intermediate decides the pyrolysis products(C6H6,HC≡C—C≡N,C6H5C≡N and HC≡CH)to be the same,and also decides the total disappearance rates of the reactants to be the same,for both original reactants quinoline and isoquinoline during the pyrolysis reaction.The results indicate that the intramolecular hydrogen migration is an important reaction step,which often appears in the paths of the pyrolysis mechanism.The activation energies of the rate determining steps are obtained.The calculated results are in good agreement with the experimental results.

A new isoquinoline derivative from the leaves of Magnolia sieboldii K.Koch

Magnoline（1）,a new isoquinoline derivative,was isolated from the leaves of Magnolia sieboldii K.Koch（Magnoliaceae）.Its structure was elucidated on the basis of spectral analysis including 1D,2D NMR and HR-TOF-MS.

Analysis of isoquinoline alkaloids from Mahonia leschenaultia and Mahonia napaulensis roots using UHPLC-Orbitrap-MSn and UHPLC-QqQ LIT-MS/MS

Mahonia leschenaultia（ML） and Mahonia napaulensis（MN） are less known and unexplored medicinal plants of the family Berberidaceae. They are used by the Todas of Nilgiris in their religious and medical practices but chemically less identified. Hence, we decided to do extensive phytochemical analysis to explore the potential of these plant extracts. An ultrahigh performance electrospray tandem mass spectrometry（UHPLC-ESI-MS/MS）method was successfully developed for qualitative analysis of the bioactive components in Mahonia species using Orbitrap Velos Pro mass spectrometer. Sixteen compounds were identified by comparison of their retention times and mass spectra（MS） with authentic standards and reported literature. Multi-stage mass spectra（MS（2-8）） for the identification of protoberberine and aporphine alkaloids showed the sequential expulsion of all the substituents attached with their basic skeleton followed by CO loss. Eight of the identified compounds（berberine, jatrorrhizine, palmatine, magnoflorine, isocorydine, glaucine, tetrahydropalmatine and tetrahydroberberine） were simultaneously determined by another UHPLC-ESI-MS/MS method under the multiple reactions monitoring（MRM） mode quantitatively using triple quadrupole linear ion trap mass spectrometer. The analytical method was validated for 8 bioactive compounds with overall recovery in the range98.5%-103.6%（RSD≤2.2%）, precise（RSD≤2.07%） and linear（r≥0.9995） over the concentration range of 0.5-1000 ng/mL and successfully applied in ML and MN roots, which suggests the suitability of the proposed approach for the routine analysis of Mahonia species and their quality control.

Amides,Isoquinoline Alkaloids and Dipeptides from the Aerial Parts of Piper mullesua

One undescribedamide,pipermullesine A,twoundescribed isoquinoline alkaloids,pipermullesinesBand C,and six undescribed dipeptides,pipermullamides A–F,along with 28 known compounds,were isolated from the aerial parts of Piper mullesua.The structures of the undescribed compounds were elucidated based on the analysis of 1D and 2D NMR and MS data.Furthermore,the structures of pipermullesines A–Cwere confirmed by single crystal X-ray diffraction analysis.All isolates were evaluated for inhibitory activity against platelet aggregation induced by thrombin(IIa)or platelet-activating factor(PAF).(-)-Mangochinine,pellitorine,and(2E,4E)-N-isobutyl-2,4-dodecadienamide showed weak inhibitory activity against rabbit platelet aggregation induced by PAF,with IC_(50)values of 470.3μg/mL,614.9μg/mL,and 579.7μg/mL,respectively.

Two New Isoquinoline Alkaloids from Carduus crispus

Two new isoquinoline alkaloids: carcrisine A and B, have been isolated from the whole plant of Carduus crispus L.. Their structures were elucidated by chemical and spectroscopic methods.

Efficient One-pot Synthesis of Pyrrolo[2,1-a]isoquinoline and Pyrrolo[1,2-a]quinoline Derivatives

A one-pot sequential reaction for efficient synthesis of pyrrolo[2,1-a]isoquinoline and pyrrolo[1,2-a]quinoline derivatives has been developed.The reaction included firstly the Cu-catalyzed three-component reaction of isoquinoline（quinoline）,acetylenedicarboxylate and alkynylbenzene and then Cs 2 CO 3-promoted intramolecular cyclization reaction of initially formed 1-alkenyl-2-alkynyl-1,2-dihydroisoquinoline（1,2-dihydroquinoline）.

Synthesis and Cytotoxicity Evaluation of Some Isoquinoline Derivatives Related to 1-Arylnaphthalene Lignans

Two series of novel compounds designed as hybrids of 1-arylnaphthalene lignans with dihydroisoquinolines or isoquinolines were synthesized and evaluated for their cytotoxicities on human tumor cell lines, such as A549, Hela, PC-3 and KB. Some of the synthetic compounds exhibited their IC50 values on selected cell lines at μmol/L scale.

Synthesis and Pregnancy Terminating Activity of 2-Aryl imidazo [2,1-a] isoquinolines

Two 2-aryl imidazo [2,1-a] isoquinolines were synthesized and tested for pregnancy terminating activities. Both of them are new compounds and their structures were confirmed by IR, (HNMR)-H-1, MS and elemental analysis. They both showed high activities in NIH mice.

Radical cascade cyclization for the green and simple synthesis of silylated indolo[2,1-a]isoquinoline derivatives via visible light-mediated Si–H bonds activation

Photocatalytic and photoinduced silyl radicals cascade cyclization procedures for the green and simple preparation of fused tetracyclic skeleton silylated indolo[2,1-a]isoquinoline-6(5H)-ones from 2-aryl-N-acryloyl indoles with hydrosilanes are developed.The photocatalytic reaction is carried out with 9,10-dicyanoanthracene(DCA)as an organophotocatalyst and 3-acetoxyquinuclidine as hydrogen atom transfer(HAT)catalyst at room temperature under metal-and oxidant-free conditions.The keys to the success of photoredox-catalytic conversion include(1)the reductive quenching of DCA^(*)[E_(1/2)(*P/P^(-))=+1.97 V vs.SCE in MeCN]by 3-acetoxyquinuclidine(E_(p)=+1.22 V vs.SCE in MeCN),and(2)the thermodynamic feasibility of hydrogen atom abstraction from hydridic Si-H bond by electrophilic N^(+·).Particularly,the simple photoinduced cascade cyclization using(TMS)3SiH with 2-aryl-N-acryloyl indoles was exploited via an electron-donor-acceptor(EDA)complex under visible light irradiation.

Effects of Metal Cations and Counter Anions on the Structural Stability of Isoquinoline-Based Metallo-Supramolecular Cages

Metallo-supramolecular architectures that are constructed by coordination-driven self-assembly have received tremendous attention on account of their diverse yet molecular-level precise structures and broad applications.Of particular,metal cations and counter anions are fundamentally important in terms of self-assembly,characterization and property;however,their effects on the structural stabilities of metallo-supramolecular architectures have seldom been investigated.To address this issue,herein,a series of octahedral metallo-cages that are capable of tolerating with five metal cations(Pd^(2+),Cu^(2+),Ni^(2+),Co^(2+)and Zn^(2+)),and five counter anions(ClO_(4)^(–),OTf^(–),BF_(4)^(–),NTf_(2)^(–)and NO_(3)^(–))are constructed by the coordination-driven self-assembly of a well-designed tritopic isoquinoline-based ligand with corresponding metal salts.Structural stability studies show that metal cations and counter anions play a critical role in the stability of the resulting cages depending on their coordination abilities and stacking manners.This work provides deep insights in the ever-diversifying field of metallo-supramolecular chemistry,and will enable us to design more sophisticated assembled structure with desired function.

Palladium-catalyzed carbonylative cyclization of alkene-tethered indoles with phenols or arylboronic acids:Construction of carbonyl-containing indolo[2,1-a]isoquinoline derivatives

A novel palladium-catalyzed carbonylative cyclization of alkene-tethered indoles with phenols or arylboronic acids is described,which provides a facile approach to access indolo[2,1-a]isoquinoline scaffolds.This method employs benzene-1,3,5-triyl triformate(TFBen)as the CO surrogate for the incorporation of a carbonyl group into indolo[2,1-a]isoquinoline scaffolds,and a variety of carbonyl-containing indolo[2,1-a]isoquinoline derivatives are prepared in good yields.

Efficient Synthesis of Pyrrolo[2,1-a]isoquinoline and Pyrrolo[1,2-a]quinoline Derivatives via One-pot Two- step Metal-catalyzed Three-component Reactions

A sequential one-pot two-step reaction for efficient synthesis of pyrrolo[2,1-a]isoquinoline and pyrrolo[1,2-a]- quinoline derivatives in good yields has been successfully developed. The reaction included firstly Cu-catalyzed three-component reaction of isoquinoline （quinoline）, acetylenedicarboxylate and alkynylbenzene and then Pd-catalyzed intramolecular C（sp）-C（sp^2） coupling reaction of initially formed 1-alkenyl-2-alkynyl- 1,2-dihydroiso- quinoline （1,2-dihydroquinoline）.

Tandem synthesis of functionalized hexaalkyl benzoisoquinolinopyrrolonaphthyridine-hexacarboxylate, via isoquinoline based multi-component reaction

An expedient,synthetic method to fused polycyclic derivatives of isoquinoline is described via tandem reaction of isoquinoline,dialkyl acetylenedicarboxylates and dialkyl chloromalonate.

Efficient Synthesis of Isoquinolines by AgNO3-Catalyzed Sequential Imination-Annulation of 2-Alkynyl Aldehydes with Ammonium Bicarbonate

An operationally simple approach for the tandem synthesis of isoquinolines by the reaction of o-alkynylalde- hydes with ammonium bicarbonate via Ag-catalyzed 6-endo-dig ring closure is described. The reaction conditions and the scope of the reaction are examined, and a variety of substituted isoquinolines are prepared in moderate to excellent yields.

Three-component synthesis and antibacterial evaluation of some novel 1,2-dihydroisoquinoline derivatives

Isoquinoline reacts with dialkyl acetylenedicarboxylates in the presence of kojic acid or8-hydroxyquinoline to generate 1,2-dihydroisoquinoline derivatives. The simplicity, mild reaction conditions and high yields of products make it an interesting process compared to other approaches. The compounds have been analyzed for antibacterial activity against Gram negative and Gram positive bacteria. The results indicated that 1,2-dihydroisoquinolines derived from kojic acid are effective against all of the studied bacteria especially against Bacillus subtilis, while the products obtained from8-hydroxyquinoline are active only against Gram positive bacteria.

Tungstophosphoric acid catalyzed synthesis of N-sulfonyl-1,2,3,4-tetrahydroisoquinoline analogs

An operationally simple and eco-friendly protocol has been developed for the synthesis of N-sulfonyl- 1,2,3,4-tetrahydroisoquinolines 3 using the modified Pictet-Spengler reaction of N-sulfonylphenylethy- lamines 1 and various aldehydes 2 in the presence of tungstophosphoric acid hydrate.

Isoquinoline-mediated 5-vinylation and N-vinylation of benzo[d]oxazole-2-thiol and benzo[d]thiazole-2-thiol

An effective route to 5-vinylated and N-vinylated benzo[d]oxazole-2（3H）-thiones and benzo[d]thiazole-2（3H）-thiones is described via reaction of acetylenic esters and benzo[d]oxazole-2-thiol and benzo[d]thiazole-2-thiol in the presence of 15 mol%of isoquinoline.