Synthesis and cytotoxic activities of a new benzo[c]phenanthridine alkaloid, 7-hydroxynitidine, and some 9-oxygenated benzo[c]phenanthridine derivatives

[formula: see text] A new benzo[c]phenanthridine alkaloid, 7-hydroxynitidine, was synthesized by a novel synthetic procedure. The cytotoxic activity of this compound against HeLa S3 cells was strong, but not greater than those of its mother compounds, nitidine and NK109. We also synthesized other 9-oxygenated benzo[c]phenanthridine alkaloids, 7-methoxynitidine, 9-demethylnitidine, nitidine, and fagaronine, and tested their cytotoxic activities. These results suggest that the 7-hydroxy group enhances antitumor activity and an 8- or 9-hydroxy group weakens this activity.     

Transformation of protoberberines into benzo[C]phenanthridines a novel and efficient synthesis of antitumor benzo[C]phenanthridine alkaloids,fagaronine and nitidine

Antileukemic benzo[C]phenanthridine alkaloids, fagaronine (1a) and nitidine (1c) were synthesized from the corresponding protoberberines through C₆-N bond fission and subsequent cyclization between C₆ and C₁₃ position of the protoberberines.     

Total synthesis of oxyfagaronine, phenolic benzo[c]phenanthridine and general synthetic way of 2,3,7,8- and 2,3,8,9-tetrasubstituted benzo[c]phenanthridine alkaloids

Benzo[c]phenanthridine alkaloids such as oxynitidine, oxysanguinarine, oxyavicine and phenolic oxyfagaronine were synthesized from easily available starting benzonitriles 5 and toluamides 6 using a lithiated toluamide-benzonitrile cycloaddition reaction. The coupling reaction provided 3-arylisoquinolinones that were transformed to the benzo[c]phenanthridones. This method is highly efficient and could be useful for preparing diverse substituted aromatic benzo[c]phenanthridine compounds on a multi gram scale.     

Alkaloids from the stem bark of an Australian population of Zanthoxylum ovalifolium

The aerial parts of Zanthoxylum ovalifolium (Rutaceae) have yielded the two novel benzo[c]phenanthridine alkaloids terihanine (8-demethylnitidine) and isoterihanine (9-demethylnitidine) together with nitidine, the unusual furoquinoline 5-methoxydictamnine, canthin-6-one and several common furocoumarins. The finding of benzo[c]phenanthridine and furoquinoline alkaloids in Australian material of this species confirms its chemical homogeneity throughout its range from India to Australia.     

Palladium-catalyzed tandem reaction to construct benzo[c]phenanthridine: application to the total synthesis of benzo[c]phenanthridine alkaloids

A concise and efficient synthesis of benzo[c]phenanthridines was accomplished by the palladium-catalyzed ring-opening coupling of azabicyclic alkene with o-iodobenzoates, followed by tandem cyclization. The strategy was successfully applied in the total synthesis of benzo[c]phenanthridine alkaloids such as sanguinarine, chelerythrine, nitidine and avicine.     

Investigation of the appropriateness of using ethoxychelerythrine as a representative quality marker of Zanthoxylum nitidum

JPC – Journal of Planar Chromatography – Modern TLC - Quaternary benzo[c]phenanthridine alkaloids (QBAs), such as chelerythrine (CHE) and nitidine (NIT), represent the important...     

Bischler-Napieralski Cyclization-N/C-Alkylation Sequences for the Construction of Isoquinoline Alkaloids. Synthesis of Protoberberines and Benzo[c]phenanthridines via C-2'-Functionalized 3-Arylisoquinolines(1)

Efficient synthetic routes to isoquinoline alkaloids of the protoberberine and benzo[c]phenanthridine classes are reported. The key transformations are derived from the intramolecular cyclization of C-2'-functionalized N-(1,2-diarylethyl)amides or enamides via 3-arylisoquinoline derivatives. Thus, under Bischler-Napieralski reaction conditions (PCl(5), nitrile as solvent, room temperature) N-(1,2-diarylethyl)amides 12 regioselectively yielded 2,3-disubstituted 13,14-dihydroprotoberberinium salts 20, a scarcely studied oxidation state in this class of alkaloids. Subsequent reduction of the iminium bond gave the known coralydine (21a) and O-methylcorytenchirine (21b) and their 8-phenyl analogue 21c. The one-pot preparation of these dihydroprotoberberinium salts 20 is shown to proceed with cleavage of the silyl ether and immediate halogenation of the resulting hydroxyl group, followed by cyclization of the obtained N-(1,2-diarylethyl)amide 18 to a 3,4-dihydroisoquinoline derivative 19 and subsequent intramolecular in situ N-alkylation of the latter imine. Ready access to planar 8,9-dialkoxylated benzo[c]phenanthridinium salts is also described. Condensation of ketoester 23 with benzylamine in the presence of titanium(IV) chloride, followed by acetylation, afforded a mixture of naphthylamide 24 and (E)-enamide 25. Both enamides were efficiently cyclized by POCl(3). While the planar benzo[c]phenanthridinium salt 26 was directly produced from 24, the (E)-enamide 25 gave the 3-arylisoquinolinium salt 27, which was reduced and intramolecularly C-alkylated to yield the tetracyclic nucleus of these alkaloids.     

Total synthesis of 12-methoxydihydrochelerythrine and anti-tumour activity of its quaternary base: toward an efficient synthetic route for 12-alkoxybenzo[c]phenanthridine bases via naphthoquinone monooxime from 2-benzofuranyl-1-tetralone derivative

A concise total synthesis of 12-methoxydihydrochelerythrine (6), isolated from Bocconia integrifolia, is described. The synthesis features an efficient route to a 12-alkoxybenzo[c]phenanthridine skeleton via naphthoquinone monooxime 11 as a key compound. Starting from 7-methoxy-2-methylbenzo[b]furan (9), 3-aryl-1-tetralone 10 was synthesised, followed by aromatisation to 3-aryl-1-naphthol 17. After oxidative cleavage of the furan ring, basic nitrosation of naphthol 22 gave the naphthoquinone 11. The benzo[c]phenanthridine skeleton was formed by reductive cyclisation of 11. Deoxygenation of the lactam moiety in 23 afforded nor-base 32 and methylation of 32 under reductive conditions gave the target dihydro base 6 (23 steps from benzofuran 9 in 10% overall yield). The corresponding quaternary base 7 showed moderate anti-tumour activity against cancer cell lines; on NCI-H460: IC50 4.5 microM and on MDA-MB-231: IC50 1.2 microM. Introduction of a methoxy group into the 12-position of the benzo[c]phenanthridine skeleton could cause enhanced activity against MDA-MB-231 by comparison of 7 with chelerythrine (35) (IC50 5.3 microM).     

5-取代氨基-12-取代苯并[c]菲啶衍生物的合成、晶体结构及生物活性

为了寻找新的高活性农药, 利用2-甲基苯甲腈与不同的醛反应, 再通过2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ)脱氢或NaH和CH3I氮甲基化, 合成了3个系列共18个5-取代氨基-12-取代苯并[c]菲啶衍生物, 其中15个是未见文献报道的化合物. 它们的结构均经1H NMR, 13C NMR, IR和高分辨质谱表征; 用X射线衍射测定了化合物5-氨基-12-(4-二乙氨基苯基)-11,12-2H-苯并[c]菲啶盐酸盐(3c)的晶体结构. 初步的生物活性测试结果表明, 部分化合物具有一定的杀菌活性和促进黄瓜子叶生根活性.     

Rapid structural characterization of isomeric benzo[c]phenanthridine alkaloids from the roots of Zanthoxylum nitidium by liquid chromatography combined with electrospray ionization tandem mass spectrometry

The fragmentation mechanism of six alkaloids, namely: dihydronitidine, dihydrochelerythrine, 8-acetonyldihydronitidine, 8-acetonyldrochelerythrine, nitidine and 1,3-bis(8-dihydronitidinyl)acetone, was investigated by electrospray ionization multi-stage tandem mass spectrometry (ESI-MSn). Tandem mass spectrometry experiments indicated that different substitution sites of the methoxyl groups at C-9 and C-10 or at C-10 and C-11 determined the different abundances of the MS2 fragmentation ions using the same collision energy. According to the different abundances of MS2 product ions, positional isomeric benzo[c]phenanthridine alkaloids can be differentiated. Moreover, ten constituents in the crude alkaloidol extract from the roots of Zanthoxylum nitidium were rapidly identified by high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC/MSn), through comparing the retention times and ESI-MSn spectra with the authentic standards. This work demonstrates that not only the characteristic fragments but also the characteristic abundances of the fragment ions can be used for detailed structural characterization.     

Formal synthesis of nitidine and NK109 via palladium-catalyzed domino direct arylation/N-arylation of aryl triflates

The use of aryl triflates as reaction partners in a palladium-catalyzed domino direct arylation/N-arylation provides a great advantage due to the availability of starting materials. Furthermore, it allows expedient access to biologically interesting benzo[c]phenanthridine alkaloids.     

A facile synthesis of benzo[c]phenanthridine alkaloids: oxynitidine and oxysanguinarine using lithiated toluamide-benzonitrile cycloaddition

Benzo[c]phenanthridine alkaloids oxynitidine and oxysanguinarine were synthesized from easily available starting benzonitrile 5 and toluamide 6 using toluamide-benzonitrile cycloaddition reaction in six steps. This method is so highly efficient that it could be a more useful way for preparing fully aromatized benzo[c]phenanthridine compounds.     

Capillary electrophoretic determination of sanguinarine and chelerythrine in plant extracts and pharmaceutical preparations

Capillary electrophoresis was employed to determine the principal quaternary benzo[c]phenanthridine alkaloids, sanguinarine and chelerythrine, in two plant extracts and one oral hygiene product. Phosphate-Tris buffer of pH 2.5 was used as a background electrolyte, limits of detection were 3 micromol/l(-1) (sanguinarine) and 2.4 micromol,l(-1) (chelerythrine) using UV detection at 270 nm. The method, which correlated well with HPLC, is suitable for serial determination of sanguinarine and chelerythrine in plant products and pharmaceuticals.     

Microwave assisted synthesis and unusual coupling of some novel pyrido[3,2-f][1,4]thiazepines

3-Amino-3-thioxopropanamide (1) reacted with ethyl acetoacetate to form 6-hydroxy-4-methyl-2-thioxo-2,3-dihydropyridine-3-carboxamide (2), which reacted with α-haloketones 3 to produce 2,3-disubstituted-8-hydroxy-6-methyl-2H,5H-pyrido[3,2-f]-[1,4]thiazepin-5-ones 4a-c. Benzoylation of 4c led to the formation of the dibenzoate derivative 9. Compounds 4a-c could be prepared stepwise through the formation of S-alkylated derivatives 10a-c. Compounds 2, 4a-c, 9 and 10a-c were prepared using microwave as a source of heat, and gave better yields in shorter times than those achieved by traditional methods. Coupling of 4a-c with arenediazonium chlorides proceeded unusually to give the 6-hydroxy-4-methyl-2-(arylazo)thieno[2,3-b]pyridin-3(2H)-one ring contraction products 14. Structures of the newly synthesized compounds were proven by spectral and chemical methods.     

Intramolecular Pauson-Khand reactions of methylenecyclopropane and bicyclopropylidene derivatives as an approach to spiro(cyclopropanebicyclo[n.3.0]alkenones)

The trimethylsilyl-protected enynes 9a-c and 14a,b with alkynyl substituents on the three-membered ring or on the double bond of a methylenecyclopropane or a bicyclopropylidene moiety were prepared in two steps from the alcohols 6a-c and 12a,b, respectively, by conversion to the iodides and their coupling with lithium (trimethylsilyl)acetylide (8) in 38-73% overall yields. The bicyclopropylidene derivative 9d was synthesized in 49% yield directly from bicyclopropylidene (3) by lithiation followed by coupling with (5-iodopent-1-ynyl)trimethylsilane (11). Enynes 9b-d were protiodesilylated by treatment with K2CO3 in methanol to give the corresponding unprotected enynes 10b-d in 53, 74 and 94% yield, respectively. Enynes 17a-c with a carbonyl group adjacent to the acetylenic moiety were synthesized from oxo derivatives 15a-c by Wittig olefination followed by coupling with 8 in 47, 18 and 12% overall yield, respectively. Pauson-Khand reactions of the methylenecyclopropane derivatives with a substituent on the ring (9a,b and 10a) as well as on the double bond (14a,b and their in situ prepared protiodesilylated analogues) proceeded smoothly by stirring of the corresponding enyne with [Co2(CO)8] in dichloromethane at ambient temperature followed by treatment of the formed complexes with trimethylamine N-oxide under an oxygen atmosphere at -78 degrees C to give tricyclic or spirocyclopropanated bicyclic enones 18a,b, 19a, 20a,b, 21a,b in good yields. Alkynylbicyclopropylidene derivatives 9c,d and 10c,d formed the corresponding cobalt complexes at -78 to -20 degrees C. Treatment of the latter with N-methylmorpholine N-oxide under an argon atmosphere at -20 degrees C gave the spirocyclopropanated tricyclic enones 18c, 19c and 18d in 31-45% yields. The structure of 19c was proved by X-ray crystal structure analysis. The cyclization of enynones 17a-c in MeCN at 80 degrees C gave the spirocyclopropanated bicyclic diketones 22a-c in 38-65% yields. Intramolecular PKRs of the enynes 25a,d with a chiral auxiliary adjacent to the triple bond gave the corresponding products 26a,d in 70 and 79% yield, respectively, as 5:1 and 8:1 mixtures of diastereomers, respectively. Addition of lithium dimethylcuprate or higher order cuprates to the double bond of the former furnished bridgehead-substituted bicyclo[3.3.0]octanones 27a-c in 57-86% yields. Protiodesilylation of 27a followed by acetal cleavage gave the enantiomerically pure spirocyclopropanated bicyclo[3.3.0]octanedione (1R,5R)- 29a with [alpha]D(20)=-148 (c=1.0 in CHCl3) in 55% overall yield.     

Synthesis of oxychelerythrine using lithiated toluamide-benzonitrile cycloaddition

Oxychelerythrine, benzo[c]phenanthridine alkaloid, was synthesized from easily available starting toluamide 5 and benzonitrile 6 using toluamide-benzonitrile cycloaddition reaction in 6 steps.     

Synthesis of some benzo[h]quinoline derivatives

Reaction between 6-methoxy-1-tetralone, methyl propiolate and an ammonia-saturated methanolic solution led to 5,6-dihydro-8-methoxybenzo[h]quinolin-2(1H)-one in good yields. Subsequent aromatization, chlorination, substitution and demethylation enabled us to prepare 2-amino-substituted benzo[h]quinoline derivatives. These compounds, which are structurally related to the antitumor benzo[c]phenanthridine alkaloids by deletion of a ring, were tested on cultured murine lymphoblastic leukaemia cells (L1210). Results showed that they are devoid of cytotoxicity.     

Synthesis, reactions and antimicrobial activities of 8-ethoxycoumarin derivatives

Condensation of 3-acetyl-8-ethoxycoumarin (3) with thiosemicarbazide gave ethylidenehydrazinecarbothioamide 5, which was transformed into the thiazolidin-4-one derivatives 6,7. Interaction of 3 with DMF/POCl(3) gave b-chloroacroline derivative 8. Treatment of 3 with malononitrile gave benzo[c]chromone and 2-aminobenzonitrile derivatives 9 and 10, respectively with respect to the reaction conditions. Condensation of 3-(2-bromoacetyl)-8-ethoxycoumarin (4) with o-phenylenediamine gave 3-(quioxaline-2-yl)-8-ethoxycoumarin hydrobromide (11), while 4 reacted with 2-aminopyridine to give chromenopyridopyrimidine derivative 12. Condensation of 4 with potassium thio-cyanate/methanol gave an unexpected derivative, 2H-chromeno-3-carboxy(methyl-carbonimidic)thioanhydride 16, which upon treatment with (NH(2))(2)·H(2)O gave 3-ethoxy-2-hydroxybenzaldehyde azine 19. Interaction of 4 with thiourea derivatives gave thiazole derivatives 20a-c. The structures of the newly synthesized compounds were confirmed by their spectra data. The newly synthesized compounds were also screened for their antimicrobial activity.     

Facile synthesis of some novel pyrido[3',2':4,5]thieno[2,3-b][1,4]thiazine-8-carboxylic acids

Model tetrahydropyrido[3',2':4,5]thieno[2,3-b][1,4]thiazines 9a-c were synthesized via reductive lactamization, using sodium dithionite, of the respective 2-[(carboxyalkyl)thio]-3-nitro-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acids 7a-c. The latter derivatives were made via interaction of 2-chloro-7-cyclopropyl-3-nitro-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (6) with each of alpha-mercaptoacetic, alpha-mercaptopropionic, and alpha-mercaptosuccinic acids and triethylamine in aqueous acetone at room temperature. The structures of 7a-7c and 9a-9c are supported by microanalytical and spectral (IR, MS, NMR) data. Compounds 9a and 9c showed potent inhibitory activity against the IGROV1 (Ovarian Cancer) cell line.     

Syntheses of phenanthridines and benzophenanthridines by intramolecular ortho-arylation of aryl amide ions with aryl halides via SRN1 reactions

The photostimulated reaction of N-(2-halo-benzyl)aryl amines with t-BuOK in liquid ammonia affords fused azaheterocycles by the S_RN1 mechanism. The starting materials are easily obtained by the reaction of 2-halo-benzyl chloride and aromatic amines to prepare the secondary amines. Through this approach, phenanthridine (90%), 4-phenylphenanthridine (87%), benzo[a]phenanthridine (98%), and benzo[c]phenanthridine (84%) were synthesized.