Design, synthesis, and cytotoxic activity of Michael acceptors and enol esters in the benzo[b]acronycine series

A series of 2-acyl-6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7-ones (4-6) was prepared by treatment of 6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one (3) with an excess of an appropriate acyl chloride in the presence of aluminum chloride. Treatment of (+/-)-cis-1-hydroxy-2-acyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-ones (9, 10) or (+/-)-cis-1,2-diacyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-ones (2, 11) with hydrochloric acid gave the corresponding 2-acyloxy-6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7-ones, exemplified by acetate 7 and butyrate 8. None of the Michael acceptors 4-6 showed significant antiproliferative activity. Enol esters 7 and 8 were markedly cytotoxic toward L1210 leukemia cells, with IC50 values within the same range of magnitude as (+/-)-cis-1,2-diacetoxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one (S23906-1), currently under phase I clinical trials. In contrast with S23906-1, enol esters 7 and 8 were not reactive toward purified DNA.     

Synthesis and cytotoxic activity of benzo[a]pyrano[3,2-h] and [2,3-i]xanthone analogues of psorospermine, acronycine, and benzo[a]acronycine

Condensation of 2-hydroxy-1-naphthalenecarboxylic acid with phloroglucinol afforded 9,11-dihydroxy-12H-benzo[a]xanthen-12-one (6). Construction of an additional dimethylpyran ring onto this skeleton, by alkylation with 3-chloro-3-methyl-1-butyne followed by Claisen rearrangement, gave access to 6-hydroxy-3,3-dimethyl-3H,7H-benzo[a]pyrano[3,2-h]xanthen-7-one (12) and 5-hydroxy-2,2-dimethyl-2H,6H-benzo[a]pyrano[2,3-i]xanthen-6-one (13), which were methylated into 6-methoxy-3,3-dimethyl-3H,7H-benzo[a]pyrano[3,2-h]xanthen-7-one (14) and 5-methoxy-2,2-dimethyl-2H,6H-benzo[a]pyrano[2,3-i]xanthen-6-one (15), respectively. Osmium tetroxide oxidation of 14 and 15 gave the corresponding (+/-)-cis-diols 16 and 17, which afforded the corresponding esters 18-21 upon acylation. Similarly, condensation of 2-hydroxy-1-naphthalenecarboxylic acid with 3,5-dimethoxyaniline gave 11-amino-9-methoxy-12H-benzo[a]xanthen-12-one (23) which was converted into 11-amino-9-hydroxy-12H-benzo[a]xanthen-12-one (24) upon treatment with hydrogen bromide in acetic acid. Alkylation with 3-chloro-3-methyl-1-butyne followed by Claisen rearrangement afforded 6-amino-3,3-dimethyl-3H,7H-benzo[a]pyrano[3,2-h]xanthen-7-one (25) and 5-amino-2,2-dimethyl-2H,6H-benzo[a]pyrano[2,3-i]xanthen-6-one (26). The new benzopyranoxanthone derivatives only displayed marginal antiproliferative activity when tested against L1210 and KB-3-1 cell lines. The only compounds found significantly active against L1210 cell line, 16 and 20, belong to the benzo[a]pyrano[3,2-h]xanthen-7-one series, which possess a pyran ring fused angularly onto the xanthone basic core.     

Synthesis and cytotoxic activity of dimeric analogs of acronycine in the benzo[b]pyrano[3,2-h]acridin-7-one series

Coupling of 6-hydroxy-3,3-14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one (6) with alpha,omega-diiodoalkanes of varying length under alkaline conditions gave dimers 7-10. Halogenated ethers 11-14, cyclization products 15-17, and compounds 18-22 were also isolated in small yield from the reaction mixtures. Compounds 7-10 were more potent than acronycine and benzo[b]acronycine in inhibiting L1210 cell proliferation. The length of the alkyl ether linkage between the two benzopyranoacridone units had a dramatic influence on the cytotoxic activity. Compound 9 (n=5) was the most active, with an IC(50) value against L1210 cells within the same range of magnitude as diacetate 5, currently under clinical development.     

Synthesis and cytotoxic and antitumor activity of 1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine diacid hemiesters and carbamates

A series of cis-1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine diacid hemiesters and dicarbamates were prepared by acylation of cis-1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one. The cytotoxicity of the dicarbamates depended on the steric hindrance of the esterifying groups at positions 1 and 2. Diacid hemiesters displayed significant in vitro cytotoxic activities and induced cell cycle perturbations similar to those obtained with cis-1,2-diacetoxy-1,2-dihydrobenzo[b]acronycine (S23906-1) currently under preclinical development. cis-1-Acetoxy-2-hemiglutaryloxy-1,2-dihydrobenzo[b]acronycine was the most promizing compound of the series, inducing complete inhibition of tumor growth when tested against C38 colon adenocarcinoma implanted in mice.     

Synthesis and cytotoxic activity of benzopyranoxanthone analogues of benz.

Condensation of 3-hydroxy-2-naphthalenecarboxylic acid with phloroglucinol afforded 1,3-dihydroxy-12H-benzo[b]xanthen-12-one. Construction of an additional dimethylpyran ring onto this skeleton, by alkylation with 3-chloro-3-methyl-1-butyne followed by Claisen rearrangement, gave access to a series of benzo[b]pyrano[2,3-i]xanthen-6-ones and benzo[b]pyrano[3,2-h]xanthen-7-ones related to psorospermine and benzo[b]acronycine. In contrast with what is observed in the pyridoacridone and benzopyridoacridone series, the linear benzo[b]-pyrano[2,3-i]xanthen-6-one derivatives were more potent than their angular benzo[b]pyrano[3,2-h]xanthen-7-one isomers. cis-3,4-Diacetoxy-5-methoxy-2,2-dimethyl-3,4-dihydro-2H,6H-benzo[b]pyrano[2,3-i]xanthen-6-one, the most active among the new compounds, was more potent than acronycine in inhibiting the proliferation of L1210 murine leukemia cells.     

Synthesis and cytotoxic activity of benzophenanthrolinone analogues of acronycine

Condensation of either 2-bromobenzoic acid (4) or 2-chloro-3-nitrobenzoic acid (5) with suitable aminoquinolines 6-8 afforded phenylquinolylamines 9-13. Acid mediated cyclization gave the corresponding 12H-benzo[b][1,7]phenanthrolin-7-ones 14 and 15, and 12H-benzo[b][1,10]phenanthrolin-7-ones 16-18. Compounds 14, 16, and 17 were subsequently N-methylated to 6-demethoxyacronycine and acronycine analogues 19-21, whereas reduction of the aromatic nitro group of 18 gave the amino derivative 22. Unsubstituted 12H-benzo[b][1,10]phenanthrolin-7-ones 16, 17, 20, and 21 were devoid of significant cytotoxic activity, whereas 18 and 22, bearing a nitrogen substituent at position 11, were significantly active. Unsubstituted 12H-benzo[b][1,7]phenanthrolin-7-ones 14 and 19, which include a pyridine nitrogen in the same 4-position as the pyran oxygen of acronycine exhibited cytotoxic activities within the same range of magnitude as acronycine itself.     

Ionic Liquid-Mediated Facile Synthesis and Antimicrobial Study of Thiazolo [2,3-b]Benzo[h]Quinazolines and Thiazino[2,3-b] Benzo-[h]Quinazolines

Abstract

8-Methoxy-4-phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thione, obtained by the condensation of 2-benzylidene-6-methoxy-3,4-dihydronapthalene-1(2H)-one with thiourea, on reaction with chloroacetic acid and 3-chloropropanoic acid in the presence of the ionic liquid N-methylpyridinium tosylate furnishes 3-methoxy-7-phenyl-7,10-dihydro-5H- benzo[h]thiazolo[2,3-b]quinazoline-9(6H)-one and 3-methoxy-7-phenyl-5,6,10,11-tetrahydro- benzo[h][1,3]thiazino[2,3-b]quinazoline-9(7H)-one. Further, condensation of the thione with 1,2-dibromoethane and 1,3-dibromopropane yields 3-methoxy-7-phenyl-6,7,9,10-tetrahydro-5 H-benzo[h]thiazolo[2,3-b]quinazoline and 3-methoxy-7-phenyl-5,6,7,9,10,11-hexahydrobenzo [h][1,3]thiazino[2,3-b]quinazoline respectively. Arylidene derivatives have been obtained by two routes. The structures of the cyclized compounds have been established on the basis of elemental analysis and spectroscopic data. The synthesized compounds were screened for antimicrobial activity. Some of the compounds showed promising antimicrobial activities.     

Heterocycles containing nitrogen and sulfur. Part 49. Synthesis of derivatives of new heterocyclic systems: 1,2-Dioxocyclopenta(hexa)[g]oxazolidino-[3,2-f] pyrimido[4,5-b][1,4]thiazine, 1,2-dioxocyclopenta(hexa)-[g] imidazolidino[3,2-f]pyrimido[4,5-b][1,4]thiazine, and 1,2-oxazino[5,4-g]pyrimidino[4,5-b][1,4]thiazine

The reaction of 4-methoxy-5-amino-6-mercaptopyrimidine with 2-oxo-1-chlorocyclopentyl(hexyl)glyoxalate esters gave derivatives of the previously unknown tetracyclic systems 1,2-dioxocyclopenta (hexa)[g]oxazolidino[3,2-f]pyrimido[4,5-b][1,4]thiazines, which are transformed by ammonium acetate into derivatives of 1,2-dioxocyclopenta(hexa) [g]imidazolidino[3,2-f]pyrimido[4,5-b]-[1,4] thiazines. Derivatives of the new tricyclic 1-oxazino [5,4-g]pyrimido[4,5-b][1,4]thiazine system were obrtained by reaction of 6-carbethoxy-7-acetylpyrimido [4,5-b] [1,4] thiazines with hydroxylamine.     

In vitro cytotoxicity activity on several cancer cell lines of acridone alkaloids and N-phenylethyl-benzamide derivatives from Swinglea glutinosa (Bl.) Merr

The methanol extract from the stems and fruits of Swinglea glutinosa (Rutaceae) afforded 11 known acridone alkaloids and three N-phenylethyl-benzamide derivatives, glycocitrine-IV, 1,3,5-trihydroxy-4-methoxy-10-methyl-2,8-bis(3-methylbut-2-enyl)acridin-9(10H)-one, 1,3,5- trihydroxy-2,8-bis(3-methylbut-2-enyl)-10-methyl-9-acridone, citbrasine, citrusinine-II, citrusinine-I, 5-dihydroxyacronycine, pyranofoline, 3,4-dihydro-3,5,8-trihydroxy-6-methoxy-2,2,7-trimethyl-2H-pyrano[2,3-a]acridin-12(7H)-one, 2,3-dihydro-4,9-dihydroxy-2-(2-hydroxy-propan-2-yl)-11-methoxy-10-methylfuro[3,2-b]acridin-5(10H)-one, bis-5-hydroxyacronycine, N-(2-{4-[(3,7-dimethylocta-2,6-dien-1-yl)oxy]phenyl}ethyl)benzamide, N-(2-{4-[(3,7-dimethyl-4-acethyl-octa-2,6-dien-1-yl)oxy]phenyl}ethyl)benzamide, and severine acetate. All compounds isolated were examined for their activity against three cancer cell lines: human lung carcinoma (COR-L23), human breast adenocarcinoma (MCF7), human melanoma (C32), and normal human fetal lung cell line, MRC-5. The acridones tested exhibited weak cytotoxicity but the amides showed moderate nonselective cytotoxic activity.     

Condensed isoquinolines 27*. Synthesis and oxidation reactions of 5,13-dihydro-11H-isoquino[3,2-<Emphasis Type="Italic">b</Emphasis>]quinazolin-11-one

Condensation of 2-(cyanomethyl)benzoic acid with 2-aminobenzylamine gave 6,11-dihydro-13H-isoquino[3,2-b]quinazolin-11-one. Its oxidation in nitrobenzene led to the formation of 5,13,5′,13′-hexahydro[6,6′]bi[isoquino[3,2-b]quinazoline]-11,11′-dione, but in dichlorobenzene in the presence of elemental sulfur and iodine it gave the rearrangement product 6H-dibenzo[b,f][1,8]naphthyridin-5-one. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.2, 273–279, February, 2008.     

Vanillin esters of aromatic carboxylic acids in the synthesis of benzo[a]acridine and benzo[b][4,7]phenanthroline derivatives

By condensation of vanillin esters of substituted benzoic acids with 2-naphthylamine and 6-quinolylamines and also with cyclic β-diketones (1,3-cyclohexanedione and dimedone) 2-methoxy-4-(11-oxo-7,8,9,10,11,12-hexahydrobenzo[a]acridin-12-yl)-and 2-methoxy-4-(11-oxo-7,8,9,10,11,12-hexahydrobenzo[b][4,7]-phenanthrolin-12-yl)phenyl benzoates were prepared.     

Condensation of 5-quinolylamine with aromatic aldehydes and dimedone

Condensation of 5-quinolylamine with dimedone and aldehydes of aromatic and heteroaromatic series afforded 10,10-dimethyl-7-aryl(heteryl)-7,10,11,12-tetrahydro-9H-benzo[b]-1,7-phenanthrolin-8-ones.     

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.     

Some cyclization reactions of 1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one: preparation and computational analysis of non symmetrical zwitterionic biscyanines

Regioselective nucleophilic addition of bisnucleophiles 1,2-benzenediamine, 2-amino-benzenethiol, and N-phenyl-1,2-benzenediamine to 1,3-diphenylbenzo[e][1,2,4]triazin-7(1H)-one (1) at C6 followed by intramolecular cyclocondensation at the C7 carbonyl afforded highly coloured tetracenes 1,3-diphenyl-1,6-dihydro-[1,2,4]triazino[5,6-b]phenazin-4-ium 4-methylbenzenesulfonate (12), 1,3-diphenyl-1H-[1,2,4]triazino[6,5-b]phenothiazine (14) and 1,3,11-triphenyl-1,6-dihydro-[1,2,4]triazino[5,6-b]phenazin-11-ium 4-methylbenzenesulfonate (15), respectively. Neutralization of the latter with alkali gave the free base 1,3,11-triphenyl-1H-[1,2,4]triazino[5,6-b]phenazin-11-ium-6-ide (16). Furthermore, the benzotriazinone 1 reacts with dimethyl malonate to give 6-(methoxycarbonyl)-7-oxo-1,3-diphenyl-7H-benzofuro[5,6-e][1,2,4]triazin-1-ium-4-ide (17) in 74% yield, while with S(4)N(4) [5,6-c]-thiadiazolo-7-oxo-1,3-diphenyl-1,2,4-benzotriazine (22) was formed in 15% yield. The free bases 16 and 17 display negative solvatochromism, which supports charge separated ground states similar to those of zwitterionic biscyanines, and DFT calculations at the UB3LYP/6-31G(d) level afford ΔE(ST) values of -13.6 and -18.7 kcal mol(-1), respectively that strongly favour the singlet ground state. All ring systems described are new and fully characterized.     

Naturstoffchemie, 174. Mitt. [1]: Oxidation von Acronycin mit Kaliumpermanganat

Zusammenfassung Die Oxidation des Acridonalkaloids Acronycin (1) mit Kaliumpermanganat führt zu (1S-cis)-1,2,3,12-Tetrahydro-1,2-dihydroxy-6-methoxy-3,3,12-trimethyl-7-H-pyrano[2,3-c]acridin-7-on (2), 1-Hydroxy-6-methoxy-3,3,12-trimethyl-1H-pyrano[2,3-c]acridin-2,7(3H,12H)-dion (3) und 1-Hydroxy-6-methoxy-3,3,12-trimethyl-1-(2-oxopropyl)-1H-pyrano[2,3-c]acridin-2,7(3H,12H)-dion (4).

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Natural product chemistry, part. 174 [1]: Oxidation of acronycine by potassium permanganate

Summary Oxidation of the acridone alkaloid acronycine (1) by potassium permanganate results in oxidation of the cromenering to give (1S-cis)-1,2,3,12-tetrahydro-1,2-dihydroxy-6-methoxy-3,3,12-trimethyl-7H-pyrano[2,3-c]acridine-7-one (2), 1-hydroxy-6-methoxy-3,3,12-trimethyl-1H-pyrano-[2,3-c]acridine-2,7(3H,12H)-dione (3) and 1-hydroxy-6-methoxy-3,3,12-trimethyl-1-(2-oxopropyl)-1H-pyrano[2,3-c]acridine-2,7(3H,12H)-dione (4).

     

The synthesis of 5,10-dihydro- and 2,3,5,10-tetrahydrothiazolo-[3,2-b] [2,4]benzodiazepines, 1,2,3,4,7,12-hexahydrobenzothiazolo-[3,2-b] [2,4] benzodiazepine,and 9,14-dihydro-6H-[1]benzothiopyrano-[4′,3′:4,5]thiazolo[3,2-b] [2,4] benzodiazepine via 1,2,4,5-Tetrahydro-3H-2,4-benzodiazepine-3-thione

Catalytic reductive scission of phthalazine (II) utilizing a two-stage palladium-Raney nickel procedure afforded o-xylene-α,α′-diamine (III) in 97% yield. Treatment of III with carbon disulfide gave [o-(aminomethyl)benzyl]dithiocarbamic acid (IV), which upon thermal cyclization furnished 1,2,4,5-tetrahydro-3H-2,4-benzodiazepine-3-thione (V). Reaction of V with 1,2-dibromoethane, chloro-2-propanone, ethyl 2-chloroacetoacetate, ethyl chloroacetate, and ethyl 2-bromohexanoate gave 2,3,5,10-tetrahydrothiazolo[3,2-b][2,4]benzodiazepine (VII) and substituted 5,10-dihydrothiazolo[3,2-b][2,4]benzodiazepines (Villa and b, IX, and X), respectively. Condensation of V with 2-chlorocyclohexanone and 3-bromothiochroman-4-one afforded 1,2,3,4,7,12-hexahydrobenzothiazolo[3,2-b][2,4]benzodiazepine (XII) and 9,14-dihydro-6H-[1]benzothiopyrano[4′,3′:4,5]thiazolo[3,2-b][2,4]benzodiazepine(XIll). None of the compounds possessed appreciable biological activity.     

5α-androstano [3,2-b]pyridines, 5α-androstano[17,16-b]pyridines and androst-4 and 5-eno[17,16-b]pyridines

A new synthesis of 5α-androstano[3,2-b]pyridin-17β-ol acetate (VIa) and 17-methyl-5α-androstano[3,2-b]pyridin-17β-ol (VIb), first reported by Shimizu, Ohta, Ueno, and Takegoshi, was achieved. The analogous 5α - androstano[17,16-b]pyridin-3β-ol (XII), 5α-androstano[17,16-b]pyridin-3-one (XIVa), and androst-4-eno[17,16-b]pyridin-3-one (XIVb) were also prepared. An illustration of the method follows. Condensation of 3β-hydroxy-5α-androstan-17-one (VIIa) with 3-(2-furyl)acrolein afforded 16-[3-(2-furyl)-2-propenylidene]-3β-hydroxy-5α-androstan-17-one (VIIIa), the oxime (IXa) of which was thermally cyclized to 5α-androstano[17,16-b]-6′-(2-furyl)pyridin-3β-ol (Xa). 3β-Hydroxy-5α-androstano[17,16-b]pyridine-6′-carboxylic acid (XI) was obtained by ozonolysis of Xa. Thermal decarboxylation of XI gave XII. Cinnamaldehyde was used in place of 3-(2-furyl)acrolein to give the corresponding phenylpyridines.     

Condensed isoquinolines 24. Reaction of 6,11-dihydro-13H-isoquino[3,2-<Emphasis Type="Italic">b</Emphasis>]quinazolin-13-one with carbonyl compounds

The reaction of 6,11-dihydro-13H-isoquino[3,2-b]quinazolin-13-one with carbonyl compounds occurs at the C₍₆₎ and/or N₍₅₎ atoms depending on the nature of the reagent and the conditions. Condensation with aldehydes gives 6-arylidene-6,11-dihydro-13H-isoquino[3,2-b]quinazolin-13-ones. Acylation using acid anhydrides or acid chlorides gave 5-acyl-, 6-acyl-, and 5,6-diacyl-5,11-dihydro-13H-isoquino[3,2-b]quinazolin-13-ones depending again on the reaction conditions. Acylation using chloroacetyl chloride is accompanied by an intramolecular alkylation to give 7H,8H-2a, 7a-diaza-cyclopenta[f,g]naphthacene-1,7(2H)-dione. Phenyl isocyanate gave the derivative containing a CONHPh group at position 6. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1509–1520, October, 2007.     

Synthesis of New Thiazolo[3,2-b][1,2,4]triazole Derivatives and Preliminary Evaluation of Their Biological Activity

Russian Journal of General Chemistry - Heterocyclization of 3-[(1H-1,2,4-triazol-3-yl)thio]pentane-2,4-dione afforded 1-(6-methylthiazolo[3,2-b][1,2,4]-triazol-5-yl)ethan-1-one, the reactions of...     

Synthesis of 5H-benzimidazo[1,2-a][1,3,4]thiadiazolo[2,3-d][1,3,5]triazin-5-one and 12H-benzimidazo[1,2-a]pyrimido[6,1-d][1,3,5]triazin-12-one,two new heterocyclic ring systems

2-(2,6-Dimethylpyrimidin-4-ylaminobenzimidazole) (VIIa) and 2-(1,3,4-thiadiazol-2-ylamino)benzimidazole (VIIb) underwent a ring-closure reaction with phosgene giving 1,3-dimethyl-12H-benzirnidazo[1,2-a]pyrirnido[6,1][-d][1,3,5]triazin-12-one (IIa) and 5H-benzimidazo[1,2-a][1,3,4]thiadiazolo[2,3-d][1,3,5]triazin-5-one (IIb) two hitherto unknown heterocyclic systems. A convenient synthesis of 2,6-dimethyl-4-aminopyrimidine is described.