Antineoplastic anthraquinones. II. Design and synthesis of 1,2-Heteroannelated anthraquinones

Based on the “2-phenyinaphthalene-type” structural pattern hypothesis, a number of heterocycle-fused anthraquinones were designed by taking morindaparvin-A ( 2a ) as the lead structure. The compounds we synthesized and tested for antineoplastic activity include 1,2-alkylenedioxyanthraquinone, naphtho [2,3-f]-quinoxaline-7,12-dione, anthra[1,2-d]imidazole-6,11-dione and naphtho[2,3-f]quinoxaline-7,12-dione derivatives. Most of the synthesized anthraquinones possessed various degrees of anticancer activity. One of these compounds, 2-chloromethyl-1H-anthra[1,2-d]imidazole-6,11-dione ( 4b ), exhibited cytotoxic activity against all tested human carcinoma cell lines.     

Heterocyclic Analogs of 5,12-Naphthacenequinone. 1. Synthesis of Heterocyclic Analogs Starting from 2,3-Diaminoquinizarine

The amination of 2-nitroquinizarine using hydroxylamine gives 2-amino-3-nitroquinizarine, which, upon reduction, gives previously unreported 2,3-diaminoquinizarine, a key intermediate in the synthesis of heterocyclic analogs of 5,12-naphthacenequinone, namely, 4,11-dihydroxyanthra[2,3-d]imidazole-5,10-dione (imidazoloquinizarine), 4,11-dihydroxyanthra[2,3-d][1,2,3]triazole-5,10-dione (triazoloquinizarine), and 5,12-dihydroxynaphtho[2,3-g]quinoxaline-6,11-dione (pyrazinoquinizarine). __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1081–1088, July, 2005.     

Synthesis of 2-substituted naphtho[2,3-f]isoquinoline-7, 12-dione N-oxides

1-Acetylenyl-2-formylanthraquinone oximes cyclize upon heating in an ethanol-water solution of K₂CO₃ to give 2-substituted naphtho[2,3-f]isoquinoline-7,12-dione N-oxides.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 6, pp. 1447–1450, June, 1991.     

Heterocyclic analogs of 5,12-naphthacenequinone. 2. Synthesis of 4,11-dihydroxynaphtho[2,3-f]indazole-5,10-dione and its n-methyl derivatives

On methylating 4,11-dimethoxynaphtho[2,3-f]indazole-5,10-dione with methyl iodide in the presence of base a mixture is formed of its 1-and 2-methyl derivatives. Demethylation of the methoxy groups of the starting material and of the products of its alkylation leads to the formation of 4,11-dihydroxynaphtho[2,3-f]indazole-5,10-dione (pyrazoloquinizarine) and its 1-and 2-methyl derivatives. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 691–696, May, 2006.     

Synthesis of 5,8-dihydroxynaphtho[2,3-c][1,2,5]thiadiazole-6,9-dione and 6,9-dihydroxybenzo[g]quinoxaline-5,10-dione

The synthesis of 5,8-dihydroxynaphtho[2,3-c][1,2,5]thiadiazole-4,9-dione 3 , 6,9-dihydroxybenzo[g]quinoxaline-5,10-dione 4 , and their lesser oxygenated analogs via Friedel-Crafts and Diels-Alder synthesis is reported.     

Heterocyclic analogs of 5,12-naphthacenequinone 9*. Study of the synthesis and reactivity of 4,11-dimethoxynaphtho[2,3-<Emphasis Type="Italic">f</Emphasis>]isatin-5,10-diones

A preparative method has been developed for N-alkyl 4,11-dimethoxynaphtho[2,3-f]isatin-5,10-diones. Condensation reactions with several N- and C-nucleophiles have been carried out to give the corresponding derivatives at position 3. An efficient method has been discovered for the demethylation of the N-alkyl-4,11-dimethoxynaphtho[2,3-f]isatin-5,10-diones to give a high yield of N-substituted 4,11-dihydroxynaphtho[2,3-f]isatin-5,10-diones. Successive halogenation using phosphorus penta-chloride and acylation of tert-butylamine by the intermediate 2-chloro derivative converted 4,11-di-methoxynaphtho[2,3-f]isatin-5,10-dione to the 2-amino-3H-naphtho[2,3-f]indole-3,5,10-trione derivative.     

Naphthindoles. 2. Naphtho[2,3-e]indole-4,9-diones and naphtho[2,3-f]indole-5,10-diones

The reactivity of naphtho[2,3-e]indole-4,9-dione and naphtho[2,3-f]indole-5,10-dione towards electrophiles (acylation, azocoupling, and the Mannich and Vilsmeier reactions) has been examined.For communication 1, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 783–786, June, 1989.     

Synthesis of naphtho[2',3':4,5]imidazo[2,1-<Emphasis Type="Italic">b</Emphasis>][1,3]-thiazole-5,10-dione and naphtho[2',3':4,5]imidazo-[2,1-<Emphasis Type="Italic">b</Emphasis>][1,3]benzothiazole-7,12-dione

The reaction of 2,3-dibromo-1,4-naphthoquinone with 2-aminothiazole in MeONa/MeOH at 60oC for 3 h gave naphtho[2',3':4,5]imidazo[2,1-b][1,3]thiazole-5,10-dione in 64% yield. The reaction of 2,3-dibromo-1,4-naphthoquinone with 2-aminobenzothiazole under the above-mentioned conditions gave 2-(benzo[d]thiazol-2-ylamino)-3-bromonaphthalene-1,4-dione in 64% yield, which on treatment with Na/THF or NaN₃/acetone under reflux conditions gave naphtho[2',3':4,5]imidazo[2,1-b][1,3]- benzothiazole-7,12-dione in 69 and 56% yields, respectively.     

Naphthoindoles

Naphtho[2,3-e]indole-4,9-dione and naphtho[2,3-f]indole-5,10-dione were synthesized by the Friedel-Crafts reaction from phthalic anhydride and N-acetylindoline and by the Fischer reaction by cyclization of 2-anthraquinonyl hydrazone of ethyl pyruvate.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 69–73, January, 1989.     

First synthesis of nitro-substituted bicyclo[1.1.0]butane derivatives and new method for generation of tricyclo[4.1.0.0<Superscript>2,7</Superscript>]hept-1(7)-ene

Successive treatment of 1-phenylsulfonyltricyclo[4.1.0.0^2,7]heptane with butyllithium and ethyl nitrate leads to the formation of 7-nitro-7′-phenylsulfonyl-1,1′-bi(tricyclo[4.1.0.0^2,7]heptane) through intermediate tricyclo[4.1.0.0^2,7]hept-1(7)-ene which is generated by 1,2-elimination of benzenesulfinic acid from the initial compound. Analogous treatment of 1-phenyltricyclo[4.1.0.0^2,7]heptane gives 1-nitro-7-phenyltricyclo[4.1.0.0^2,7]heptane.     

Synthesis of 4-Amino-substituted-6-hydroxy and 11-hydroxynaphtho[2,3-g]quinoline-5,12-diones,and the unexpected formation of disubstituted imidazo[4,5,l-i,j]naphtho[2,3-g]quinolin-7-ones

4-Chloroquinoline-5,8-dione ( 8a ) and 6-bromo-4-chloroquinoline-5,8-dione ( 8b ) were reacted with homophthalic anhydride to give tetracyclic compounds 10 and 11 respectively. The 6,11-dihydroxy derivative 12 was prepared in low yield by photochemical addition of benzocyclobutenedione to 4-chloroquinoline-5,8-dione ( 8a ) and in better yield through a Friedel-Crafts reaction of phthalic anhydride with 4-chloro-5,8-dimethoxyquinoline ( 7a ). Whereas 4-chloro-6-hydroxynaphtho[2,3-g]quinoline-5,12-dione ( 11 ) was substituted by amines in the usual way to the corresponding 4-amino-substituted derivatives, 4-chloro-11-hydroxynaph-tho[2,3-g]quinoline-5,12-dione ( 10 ) led to a mixture of 4-amino derivatives and the unexpected 2,6-disubstituted-imidazo[4,5,l-I-j]naphtho[2,3-g]quinolin-7-ones, 13a-b .     

Green synthesis of naphtho[2,3-f]quinolin-13-one and naphtho[2,3-a]acridin-1(2H)-one derivatives catalyzed by heteropoly acid supported montmorillonite K-10 clay

Herein, synthesis of a series of naphtho[2,3-f]quinolin-13-one and naphtho[2,3-a]acridin-1(2H)-one derivatives directly by one-pot multi-component reaction of 1,3-dicarbonyl compounds (1,3-indanedione/1,3-cyclohexanedione), 2-aminoantharacene/2-naphthylamine and various substituted aldehydes under solvent-free conditions using heteropoly-11-molybdo-1-vanadophosphoric acid supported on montmorillonite K-10 clay catalyst (10% PVMoK-10) is reported. The successful formation of naphtho[2,3-f]quinolin-13-one and naphtho[2,3-a]acridin-1(2H)-one derivatives was confirmed by various spectroscopic techniques. This study offers a green approach for the synthesis of novel quinolinone derivatives.     

Heterocyclic analogs of 5,12-naphthacene-quinone. 3. Synthesis of 4,11-diaminonaphtho-[2,3-f]indole-5,10-dione and certain of its derivatives

Nucleophilic substitution of methoxy groups in 4,11-dimethoxynaphtho[2,3-f]indole-5,10-dione by the action of primary and secondary alkylamines, or arylamines leads to the formation of N-alkyl or N-aryl derivatives of 4,11-diaminonaphtho[2,3-f]indole-5,10-dione respectively. 4,11-Diamino-1H-naphtho-[2,3-f]indole-5,10-dione is obtained by the dealkylation of 4,11-bis[(1-phenylethyl)amino]-1Hnaphtho[ 2,3-f]indole-5,10-dione in the presence of a Lewis acid (BBr₃). __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 854–861, June, 2006.     

Condensed Isoquinolines. 10. Borohydride Reduction in the 5H-Isoquino[2,3-a]quinazolin-5-one Series

Borohydride reduction in a series of 7-benzyl- and newly synthesized 7-arylmethylene-7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-ones leads stereoselectively to erythro-7-benzyl-6,6a,7,12-tetrahydro-5H-isoquino[2,3-a]quinazolin-5-ones. 7,7-Disubstituted 7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-ones are inert to the action of sodium borohydride, but spiro[5H-isoquino[2,3-a]quinazolin-7(12H),2'-indane]-5-one is reduced under rigid conditions to 6,6a-dihydrospiro[5H-isoquino[2,3-a]quinazolin-7(12H),2'-indan]-5-one. 7-Acetyl- and 7-benzoyl-6,11-dihydro-5H-isoquino[2,3-a]quinazolin-5-ones are converted in an aqueous alcoholic solution of sodium borohydride to the previously described 6,6a,7,12-tetrahydro-5H-isoquino[2,3-a]quinazolin-5-one. The structure and special features of the conformational behavior of the reduction products obtained were demonstrated by ¹H NMR spectroscopy.!     

Synthesis of a peralkynylated pyrazino[2,3-g]quinoxaline

[structure: see text] The synthesis of a hexaethynyl[2,3-g]pyrazinoquinoxaline and its crystal structure are reported. Starting from tetraaminobenzoquinone, condensation to bis(triisopropylsilyl)hexadiyne-2,3-dione affords 2,3,7,8-tetrakis(triisopropylsilylethynyl)pyrazino[2,3-g]quinoxaline-5,10-dione. Reaction with TIPS-CC-Li followed by reduction with hypophosphite in the presence of KI furnished the title molecule in a yield of 62%. Pd catalysis is not involved in any of these steps.     

Studies on quinones

Anthra[1,2-c][1,2,5]oxadiazole-6,11-dione (I) was added to benzenesulfinic acid and thiophenol with the formation of 4-phenyl-sulfonyl- and 4-phenylmercapto-substituted hydroquinones, which on oxidation were converted into the corresponding quinones III and VII. 4-Phenylsulfonylanthra[1,2-c][1,2,5]oxadiazole-6,11-dione (III), in turn, reacted readily with benzenesulfinic acid, adding a molecule of the latter to the carbonyl oxygen atom and was converted into the O-benzenesulfonic monoester [6] (IV). Using compounds IV and hydroxynaphtho[1,2-c][1,2,5]oxadiazole (XId) the capability of the nitrogen atom of the furazan ring of participating in the formation of intramolecular hydrogen bonds was shown.     

Benzofused tricycles based on 2-quinoxalinol

This paper describes our recent efforts to synthesize novel compound scaffolds integrating 2-quinoxalinol with privileged structures of 1,3-dihydro-benzoimidazol-2-one, 1,3-dihydro-benzoimidazole-2-thione, 3-hydroxy-1H-quinoxalin-2-one, 2H-benzo[1,4]oxazin-3-ol, 2H-benzo[1,4]thiazin-3-ol, and 1,3,4,5-tetrahydro-benzo[1,4]diazepin-2-one, respectively. Eight novel benzofused tricycles and their substituent diversity points were developed. These include pyrazino[2,3-g]quinoxaline-2,8-diol (I), 3-hydroxy-6,8,9,10-tetrahydro-1,4,6,10-tetraaza-cyclohepta[b]naphthalen-7-one (II), 6-hydroxy-4H-1-oxa-4,5,8-triaza-anthracen-3-one (III), 6-hydroxy-4H-1-thia-4,5,8-triaza-anthracen-3-one (IV), 6-hydroxy-1,1-dioxo-1,4-dihydro-2H-1lambda(6)-thia-4,5,8-triaza-anthracen-3-one (V), 6-hydroxy-1,3-dihydro-imidazo[4,5-g]quinoxalin-2-one (VI), 6-hydroxy-1,3-dihydro-imidazo[4,5-g]quinoxaline-2-thione (VII), and 7-hydroxy-1,4-dihydro-pyrazino[2,3-g]quinoxaline-2,3-dione (VIII). This strategy of integrating two benzofused privileged structures into one molecule may provide a greater chance for the discovery of novel lead compounds.     

Arylation of [6,6]-spiroacetal enol ethers: reactivity and rearrangement

Attempts to selectively arylate [6,6]-spiroacetal enol ethers at the 2-position delivered unexpected results. Palladium-mediated arylation conditions afforded the double-Heck product, whereas reaction with benzenesulfinic acid resulted in a facile rearrangement into the corresponding 5-phenylsulfonyl-3,4,5,6-tetrahydrochromans, providing access to 5-aryl-3,4,5,6-tetrahydrochroman and hexahydrochroman derivatives.     

Micellar electrokinetic chromatography (MEKC) separation of furanonaphthoquinones from Tabebuia impetiginosa

The separation of nine furanonaphthoquinones by micellar electrokinetic chromatography (MEKC) is described. The running electrolytes used in this method were 0.03 M sodium dodecyl sulphate (SDS) in 0.09 M borate buffer (pH 9) containing 10% methanol, with an applied voltage of 20 kV. Application of this technique in the determination of the main furanonaphthoquinones, 5-hydroxy-2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-dione, 8-hydroxy-2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-dione, and 2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-dione, of Tabebuia impetiginosa is demonstrated in this paper.     

Condensed isoquinolines. 21. Condensation of <Emphasis Type="Italic">o</Emphasis>-bromomethylphenylacetonitrile with substituted anthranilic acids

The reaction of substituted anthranilic acids and esters with o-bromomethylphenylacetonitrile give 2,3-R,R¹-7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-one hydrobromides. It was found that 7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-ones can exist in the two tautomeric imine and enamine forms. The tautomeric equilibrium position depends on the nature and position of the substituent in the quinazoline fragment. The borohydride reduction, oxidation, and reaction of 2,3-R,R¹-7,12-dihydro-5H-isoquino[2,3-a]quinazolin-5-ones with electrophilic reagents has been studied. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 562–573, April, 2007.