Ruthenium complexes of analogues of the antitumor antibiotic streptonigrin

The complexes Ru(L1-CH3)(CO)3Cl, RuL2(CO)2Cl2, and RuL3(CO)2Cl2 (L1= 6-methoxy-5,8-quinolinedione, L2 = 7-amino-6-methoxy-5,8-quinolinedione, L3 = 6,6'-dimethoxycarbonyl-2,2'-bipyridine) were prepared by reaction of L1-L3 with the tricarbonyldichlororuthenium(II) dimer. L1-L3 act as bidentates through the ortho oxygen atoms, the pyridyl nitrogen and the adjacent quinone oxygen, and the bipyridyl nitrogens, respectively. RuL3(CO)2Cl2 is characterized by X-ray crystallography. 15N NMR correlation spectra give upfield shifts of around 60 ppm for the pyridyl nitrogens that are coordinated to the metal, while 13C NMR correlation spectra give a downfield shift of 10 ppm for the quinone carbonyl group that is coordinated to the metal. The electrochemistry of RuL2(CO)2Cl2 is examined, and the implications for the formation of metal complexes of the antitumor antibiotic streptonigrin, which cleaves DNA in the presence of metal ions, are discussed.     

Aza-polycyclic aromatic hydrocarbons: 1—Elucidation of the regiochemistry of 1,2,3,4-tetrahydroazabenz-[a]anthracene-7,12-diones by long-range carbon–proton coupling constants

The ¹³C NMR spectra of 5,8-quinolinedione, 6-chloro-5,8-quinolinedione and 7-chloro-5,8-quinolinedione have been examined in detail. Utilization of long-range proton-carbon coupling constants have allowed the unambiguous identification of the regioisomeric 8-aza-1,2,3,4-tetrahydrobenz[a]anthracene-7,12-dione and 11-aza-1,2,3,4-tetrahydrobenz[a]anthracene-7,12-dione.     

Streptonigrin and related compounds. I. Some 2-phenyl- and 2,2-pyridylquinoline-5,8-diones

Methods for the synthesis of 6-amino-7-methoxy- and 7-amino-6-methoxy-2,2-pyridylquinoline- 5,8-diones and the corresponding 2-phenylquinoline-5,8-diones are described. The 6-aminoquinone system was generated by direct amination with sodium azide and the 7-aminoquinone system via the novel 6-hydroxy-7-nitroquinone intermediates. The basic skeleton was derived by the application of the Friedlander quinoline synthesis.     

New 2-methyl-6-alkylamino-5,8-quinolinequinones and 1,2,3,4-tetrahydro derivatives

The syntheses of six new 2-methyl-6-alkylamino-5,8-quinolinequinones, three 1,2,3,4-tetrahydro-5,8-quinolinequinones, and 7-(2′,6′,10′-trimethylundecyl)-6-hydroxy-5,8-quinolinequinone are described as potential antimetabolites of coenzyme Q and as potential antimalarial agents. The six 2-methyl-6-alkylamino-5,8-quinolinequinones were prepared by a six-step synthesis. 2-Methyl-6-methoxy-8-nitroquinoline was prepared from 2-nitro-4-methoxyaniline and crotonaldehyde by a Skraup reaction. Raney nickel reduction gave 2-methyl-6-metboxy-8-aminoquinoline, which upon diazotization followed by dithionite reduction yielded 2-methyl-6-methoxy-5,8-diaminoquinoline. Subsequent dichromate oxidation gave 2-methyl-6-methoxy-5,8-quinolinequinone, which yielded the corresponding 2-methyl-6-alkylamino-5,8-quinolinequinone in good yield when treated with the appropriate alkylamine. The telrahydro-5,8-quinolinequinones were prepared by catalytic hydrogenation of the appropriate 5,8-quinolinequinones at elevated H₂ pressure followed by air oxidation of the reduction product. 7-(2′,6′,10′-Trimethylundecyl)-6-hydroxy-5,8-quinolinequinone was synthesized by radical alkylation of 6-hydroxy-5,8-quinolinequinone by thermal decomposition of di-3,7,11-trimethyldodecanoyl peroxide, which was prepared by a multistep procedure from farnesol. Of the five new 2-methyl-6-alkylamino-5,8-quinoline-quinones tested against P. berghei in mice (blood schizonticidal test), only 2-methyl-6-cycloheptylamino-5,8-quinolinequinone was active (T-C = 6.1 at 320 mg./kg.). Both 7-(2′,6′,10′-trimelhytundecyl)-6-hydroxy-5,8-quinolinequinone and the tetrahydro derivatives were inactive in this same test system.     

Arylthio analogs of 5,8-quinolinedione: Synthesis,characterization, antibacterial,and antifungal evaluations

Abstract

A set of bis(arylthio) substituted 5,8-quinolinedione derivatives were synthesized and investigated for their in vitro antimicrobial effect. The antibacterial and antifungal activities of 6,7-bis(arylthio)-5,8-quinolinedione (4a–f) and 6,7-bis(arylthio)-2-methyl-5,8-quinolinedione (5a–f) were evaluated against four gram-negative bacteria, three gram-positive bacteria, and three fungi strains. The bis(methoxyarylthio) 5,8-quinolinedione analogs presented better activity against especially gram-positive bacteria compared to bis(halogenarylthio) 5,8-quinolinedione analogs. Bis(3-methoxyarylthio) 5,8-quinolinedione (4e) had the same activity of the reference drug against Staphylococcus aureus. Bis(2-methoxyarylthio) 5,8-quinolinedione (4f) showed two-and-a half-fold better activity with 89.69?μM against Enterococcus faecalis, and two-fold better activity with 11.20?μM against Staphylococcus epidermidis. Bis(2-methoxyarylthio)-2-methyl-5,8-quinolinedione 5f exhibited five-fold higher antibacterial activity with 43.44?μM against E. faecalis and also eight-fold activity of the reference drug with 2.71?μM against S. epidermidis.     

7-Amino-5-imino-8(5H)-quinolones, 6-Amino-8-imino-5(8H)-quinolones and 7-Alkyl-4,6-dihydroxy-5,8-quinolinediones as potential antiprotozoal agents

Oxidation of 7-amino-8-hydroxyquinoline-5-sulfonic acid with silver oxide in dimethylformamide and in the presence of arylamines provided a series of 7-amino-5-arylimino-8(5H)-quinolones (VIIIb). Reaction of 8-dialkylamino-5,6-quinolinediones with triethyloxonium tetrafluoborate gave a series of unstable but synthetically useful enol ethers. These reacted with amines to give 6-amino-8-imino-5(8H)-quinolones, isolated and characterized as tetrafluoborate salts (XIa). Proton magnetic resonance studies showed these to be vinylogous amidinium salts, analogous to those previously obtained with 2-amino-1,4-naphthoquinone imines. 4,6-Dihydroxy-5,8-quinolinedione underwent free radical alkylation to give a 7-alkyl-4,6-dihydroxy-5,8-quinolinedione. Evaluation of the new compounds against various Plasmodium species in rodents, birds and mosquitoes revealed no significant antimalarial activity.     

5,8-isoquinolinediones. II. Chemical and electrochemical behavior of the 5,8-isoquinolinedione system

We have devised two general synthetic schemes to 5,8-isoquinolinediones and have investigated the chemical and electrochemical behavior of these compounds. The 1,4-addition reactions of these quinones with amines was shown to occur at the 7-position and a number of 7-amino-5,8-isoquinolinediones. were synthesized. The 1,4-addition of hydrogen bromide was also studied. The ethylenic double bond of the 5,8-quinone system underwent Diels-Alder additions to yield the oxidized forms of the adducts. The nucleophilic displacement of the methoxy group in 7-methoxy-5,8-isoquinoline was accomplished with both potassium hydroxide and morpholine. A Polarographic study of the half-wave potentials of substituted 5,8-isoquinolinediones showed a linear correlation between the change in the half-wave potential of the quinone system (ΔE° 1/2) resulting from the introduction of different substituents, and the substituent constants (σ_p-x).     

Chemistry of naphthazarin derivatives: XV. Bromination of naphthazarin and its derivatives

Bromination of a number of naphthazarin (5,8-dihydroxy-1,4-naphthoquinone) derivatives having different substituents in the aromatic ring with molecular bromine in carbon tetrachloride was studied. Preparative procedures for the synthesis of 2-bromo-5,8-dihydroxy-7-methoxy-1,4-naphthoquinone, 2-bromo-6,7-dichloro-5,8-dihydroxy-1,4-naphthoquinone, 2-bromo-3,5,8-trihydroxy-1,4-naphthoquinone, and 2-bromo-6,7-dichloro-3,5,8-trihydroxy-1,4-naphthoquinone were developed.     

Streptonigrin and related compounds III. Synthesis and microbiological activity of destrioxyphenylstreptonigrin and analogues

Synthesis of three tricyclic analogues of streptonigrin, based on the 2-(2′-pyridyl)quinoline-5,8-dione system and with the characteristic substitution pattern of rings A and C of streptonigrin is described. The C-ring precursor, in the form of a substituted 2-acetylpyridine was condensed with either 3-hydroxy-5-methoxy-2-nitrobenzaldehyde or 3-hydroxy-4-methoxy-2-nitrobenzaldehyde, followed by reductive cyclization and oxidation to the corresponding quinones 12 and 29 . The 7-amino substitution was introduced in 12 via bromination and azidation. The 6-amino substitution was introduced through direct reaction of 29 with sodium azide. Destrioxyphenylstreptonigrin 2 was twice as active and the 6-amino-7-inethoxy analogue 4 was as active as streptonigrin in a microbiological assay. A 4′-bromo analogue of 2 was 60% as active as streptonigrin.     

Synthesis of 1-functionalized-6-hydroxy-4-methyl and 6,11-dihydroxy-4-methylnaphtho[2,3-g]isoquinoline-5,12-quinones

Using 2-methoxy- and 2,5-dimethoxyacetophenones 8a and 8b as starting materials, 1-chloro-4-methylisoquinoline-5,8-quinone ( 6 ) and its 6-bromo derivative 7 were obtained via multistep sequences. Whereas Diels-Alder condensation of the former compound with homophthalic anhydride ( 22 ) led to a mixture of the two possible isomers: 1-chloro-11-hydroxy-4-methylnaphtho[2,3-g]isoquinoline-5,12-quinone ( 23 ) and 1-chloro-6-hydroxy-4-methylnaphtho[2,3-g]isoquinoline-5,12-quinone ( 24 ), this last tetracyclic chloroquinone was specifically obtained from 6-bromo-1-chloro-4-methylisoquinoline-5,8-quinone ( 7 ) and homophthalic anhydride. The 6,11-dihydroxy derivative was then prepared by ammonium nitrate oxidation or photochemically by cycloaddition of benzocyclobutenedione ( 28 ) and 1-chloro-4-methylisoquinoline-5,8-quinone ( 6 ). Chloro compounds were easily substituted by diamines to provide corresponding 1-amino substituted hydroxy tetracyclic quinones.     

Triterpene and coumarins from Skimmia laureola

In the course of our studies on the chemical constituents of the leaves of Skimmia laureola, a new triterpene O-methyl cyclolaudenol (1) and a new coumarin, (+)-7-methoxy-6-(2'R-methoxy-3'-hydroxy-3'-methyl butyl) coumarin (2) were isolated. In addition five known coumarins, isogospherol (3), heraclenol (4), 5,8-dimethoxy coumarin-2H-1-benzopyran-2-one (5), 7-methoxy-6[2'-oxo-3'-methyl butyl] coumarin (6), and (+)-ulopterol (7) were also isolated for the first time from this plant. The structures were identified by spectroscopic studies and the stereochemistry at C-2' in compounds 3 and 4 were established by Horeau's procedure.     

Reactivity of cyclic sulfides in reactions with quinones

Sulfonium salts are obtained by the reaction of cyclic sulfides with 1,4-benzoquinone and 5,8-quinolinedione in an acidic medium. It is shown by the method of concurrent reactions that the introduction of alkyl substituents into molecules of thiacyclopentane and thiacyclohexane decreases the reactivity of the sulfides. Quinolinedione is less reactive towards sulfides than is benzoquinone.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 891–894, July, 1986.     

Streptonigrin and related compounds IV. Precursors for the a-ring

The synthesis of streptonigrin or its tricyclic (ABC) analogues by the Friedlander condensation requires a 2-nitrobenzaldehyde with all the necessary functionalities. A number of alternative syntheses are examined. It is shown that oxidation of 8-amino-5,6-dimethoxy-2,2-pyridylquinoline leads to 8-amino-2,2-pyridylqunoline-5,6-dione instead of 6-methoxy-2,2-pyridylquinoline-5,8-dione. The synthesis of two useful precursors: 4-bromo-3-hydroxy-5,6-dimethoxy-2-nitrobenzaldehyde and 4-bromo-3-hydroxy-5-methoxy-2-nitrobenzaldehyde is described.     

Cesium Carbonate-Mediated Reaction of Dichloronaphthoquinone Derivatives with O-Nucleophiles

Summary. A cesium carbonate-mediated reaction of 2,3-dichloronaphthoquinone, 6,7-dichloro-5,8-quinolinedione, and -isoquinolinedione with oxygen nucleophiles has been described.     

Cesium Carbonate-Mediated Reaction of Dichloronaphthoquinone Derivatives with O-Nucleophiles

A cesium carbonate-mediated reaction of 2,3-dichloronaphthoquinone, 6,7-dichloro-5,8-quinolinedione, and -isoquinolinedione with oxygen nucleophiles has been described.     

Ring closure of diethyl 2-methoxy-2-[N-(5-amino-1-benzylimidazolyl-4-carbonyl)amino]malonate: Product structures and pathways of product formation

Ring closure of the title compound (1) with sodium methoxide in methanol yielded three products, one 56-fused and two 57-fused heterocyclic systems: 9-benzyl-2-methoxycarbonylhypoxanthine (2), 3-benzyl-4,5,7,8-tetrahydro-6-methoxy-6-methoxycarbonyl-6H-imidazo[4,5-e][1,4]-diazepine-5,8-dione (3), and 3-benzyl-4,5,7,8-tetrahydro-6-methoxy-6H-imidazo[4,5-e][1,4]-diazepine-5,8-dione (4). Structures and pathways of formation of all three products have been described. Structures of2 and3 were confirmed by single-crystal X-ray diffraction analyses.     

Additional evidence for the cyclic GMP signaling pathway resulting in the photophobic behavior of Stentor coeruleus.

We report that exo- and endogenous guanosine 3',5'-cyclic monophosphate (cGMP) specifically influenced the photophobic response. In behavioral experiments the slowly hydrolyzable and membrane-permeable analogs of cGMP (8-bromo-cGMP [Br-cGMP] and N6,2'-o-dibutyryl-cGMP) dramatically prolonged the time for ciliary stop response and decreased the duration of ciliary reversal in a dose-dependent manner. When analogs of adenosine 3',5'-cyclic monophosphate (cAMP) (8-bromo-cAMP or N6,2'-o-dibutyryl-cAMP) were used, no essential effects were detected on the kinetics of the photophobic response. Both nonspecific cyclic nucleotide phosphodiesterase (PDE) activity inhibitors (3-isobutyl-1-methylxanthine [IBMX] and 1,3-dimethylxanthine [theophylline]) and the highly specific cGMP-PDE activity inhibitor 1,4-dihydro-5-[2-propoxyphenyl]-7H-1,2,3-triazolo[4,5-d]pyrimidine-7-one (zaprinast) mimicked the effects of cGMP analogs. Treatment of cells with an inhibitor of guanylate cyclase activity (6-anilino-5,8-quinolinedione [LY 83583]) exerted an effect opposite to that of cGMP analogs and PDE activity inhibitors. The positive physiological effect of LY 83583 was significantly diminished in ciliates that were treated simultaneously with Br-cGMP. In an assay of cell cyclic nucleotide content, the exposure of dark-adapted Stentor to light evoked a transient decrease in the basal level of intracellular cGMP. Alterations in internal cGMP levels were more distinct when the intensity of applied illumination was increased. In the presence of IBMX or theophylline the basal content of cGMP was markedly enhanced, and the photoinduced changes in cGMP level were less pronounced. In this paper the possible whole molecular mechanism by which the ciliary orientation in Stentor is controlled by light is presented.     

Structure and products of oxidative amination of 6-hydroxyquinoxaline

3-Morpholino-6-methoxy-5,8-quinoxalinequinone was synthesized by a method which excludes the formation of isomers, and was used for proving the structure of products of the oxidative amination of 6-hydroxyquinoxaline as 2,8-bis(dialkylamino)-5,6-quinoxalinequinones.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, 1671–1672, December, 1985.     

Isofuranonaphthoquinones from ventilago maderaspatana: Crystal structure of ventilone-C

From the root bark of Ventilago maderaspatana (Rhamnaceae) five isofuranonaphthoquinones have been isolated. Ventilone-A is 4,9-dihydro-5,8-dihydroxy-6,7-methylenedioxy-1-methylnaphtho[2,3-c] furan-4,9-dione and B is the 5-methyl ether. Ventilone-C has the structure 1,3,4,9-tetrahydro-8-hydroxy-5-methoxy-6, 7-methylenedioxy-1-methylnaphtho[2,3-c]furan-4,9-dione, D is the isomeric 8-methyl ether, and E is the 5,8-dimethyl ether. Structures were determined by spectroscopic methods, and X-ray crystallographic analysis of ventilone-C.