Synthesis of new thiazolylthiazolidinylbenzothiazoles and thiazolylazetidinylbenzothiazoles as potential insecticidal, antifungal, and antibacterial agents

A series of 2-{[2'-(3'-chloro-2'-oxo-4'-substitutedaryl-1'-azetidinyl)-1',3'-thiazol-4'-yl] thio}benzothiazoles (4a-4e) and 2-{[(2'-(2'-substitutedaryl-4'-thiazolidinon-3'-yl)-1',3'-thiazol-4'-yl]thio}benzothiazoles (5a-5e) have been synthesized from 2-[(2'-substitutedarylidenylimino-1',3'-thiazol-4'-yl)thio]benzothiazoles (3a-3e). The structure of these compounds has been elucidated by elemental (C, H, N) and spectral (IR, (1)H-NMR, Mass) analysis. Furthermore, compounds 3a-3e, 4a-4e, and 5a-5e were screened for insecticidal activity against Periplaneta americana and antifungal, antibacterial activities in vitro against different strains of fungi and bacteria. Out of the fifteen compounds tested, compound 5b, 2-{[2'-(2'-p-hydroxy-m-methoxyphenyl)-4'-thiazolidinon-3'-yl)-1',3'-thiazol-4'-yl]thio}benzothiazole, was found to possess most prominent insecticidal activity.     

Synthesis of newer indolyl/phenothiazinyl substituted 2-oxo/thiobarbituric acid derivatives as potent anticonvulsant agents

2-Amino-5-(heteroarylmethylene)-1,3,4-oxadiazoles/thiadiazoles 7-10 were synthesized by cyclisation of 1-(heteroarylacetyl)semicarbazides/thiosemicarbazides 3-6. 5-(2'-Heteroarylmethylene-5'-aminomethylene-1',3,'4'- oxadiazol-2'-yl/thiadiazol-2'-yl)-2-oxo/thiobarbituric acids 11-18 were synthesized by condensation of compounds 7-10 at the 5th position of 2-oxo/thiobarbituric acids. The newly synthesized compounds showed anticonvulsant activity ranging from 50-90% (seizures protection). Compound 18 (5-(2'-phenothiazinylmethylene-5'-aminomethylene-1',3',4'-thiadiazol-2'- yl)-2-thiobarbituric acid) showed maximum activity being more potent than the reference drug phenytoin sodium (CAS 630-93-3).     

Synthesis, antibacterial, antifungal and anti-HIV evaluation of Schiff and Mannich bases of isatin and its derivatives with triazole

Isatin (indole 2,3-dione) and its 5-chloro and 5-bromo derivatives have been reacted with 3-(4'-pyridyl)-4-amino-5-mercapto-4-(H)-1,2,4-triazole to form Schiff bases and the N-Mannich bases of these compounds were synthesised by reacting them with formaldehyde and several secondary amines. Their chemical structures have been confirmed by means of their IR, 1H-NMR data and by elemental analysis. Investigation of antimicrobial activity of compounds was done by agar dilution method against 27 pathogenic bacteria, 8 pathogenic fungi and anti-HIV activity against replication of HIV-1 (III B) in MT-4 cells. Among the compounds tested 1-(piperidinomethyl) 5-bromo 3-[3'-(4"-pyridyl)-5'-mercapto-4'-(H)-1',2',4'-triazol 4'-yl]imino isatin showed the most favourable antimicrobial activity.     

Simple indole alkaloids from the neotropical rutaceous tree Raputia simulans

The genus Raputia Aubl. comprises 10 neotropical species of the family Rutaceae belonging to the subtribe Cuspariinae. We report herein the investigation of the dichloromethane extract of the stem bark of R. simulans, which has led to the isolation of indole type alkaloids. The isolation procedure was performed by fast centrifugal partition chromatography (FCPC) and adsorption chromatography and afforded 11 isolates: indole-5-carbaldehyde (1), 7-prenylindole (2), 5-prenylindole (3), verticillatine B (4), 5-(but-3'-en-2'-one)indole (5), 5-(2'-methylbut-3'-en-1'-ol)indole (6), 5-[methyl-4'-(2'-methyl-4-oxobutanoate)]indole (7), 5-[4-(methyl)furan-2-yl]indole ( 8), 5-[4-(methoxymethyl)furan-2-yl]indole (9), 5-[5'-(3-methylfuran-2'(5' H)-one)]indole (10), and 5-(4'-methyl-2',5'-dihydrofuran-2'-yl)indole (11). Metabolites 5- 11 were isolated for the first time and bear uncommon substituents on position 5 of the indole moiety.     

Synthesis and benzodiazepine receptor binding activity of 2, 9-disubstituted quinolino[2', 3'-5, 4](3-pyrazolino)[3, 2-b]purin-4-ones

2, 9-Disubstituted quinolino[2', 3'-5, 4](3-pyrazolino)pyrimidin-2-ones and purin-4-ones were synthesized and their benzodiazepine receptor activity was evaluated for their ability to displace [(3)H]R015-1788 from its specific binding in bovine brain membranes. Compound 5c caused 83 +/- 8 %inhibition in [(3)H]R015-1788 specific benzodiazepine receptor binding followed by compounds 5f, 5h, and 5i while other analogs were inactive at 10 microM concentration.     

Synthesis of some novel quinoline-3-carboxylic acids and pyrimidoquinoline derivatives as potential antimicrobial agents

The synthesis and in vitro antimicrobial evaluation of several quinoline and pyrimidoquinoline derivatives are described. Treatment of 7-substituted quinolin-2(1H)-one-3-carboxylic acids 2a-c with phosphoryl chloride or thionyl chloride gave rise to the 7-substituted 2-chloroquinoline-3-carboxylic acids 3a-c and 7-substituted 2-chloro-3-chlorocarbonylquinolines 5a-c respectively. The 2-chloro function in compounds 3a-c was replaced by 2-aminothiazole or 2-aminopyridine to give 2-(thiazol-2-yl)aminoquinoline-3-carboxylic acids 4a-c or 2-(pyrid-2-yl)aminoquinoline-3-carboxylic acids 4d-f. Treatment of 5a-c with the same heterocyclic amines at room temperature furnished the corresponding 7-substituted 2-chloro-3-heteryl-aminocarbonylquinolines 6a-f. The tetracyclic 9-substituted thiazolo[3', 2':1, 2]-pyrimido[4, 5-b]quinolin-5-ones 7a-c and 10-substituted pyrido[1', 2':1, 2]-pyrimido[4, 5-b]quinolin-6-ones 7d-f were synthesized by heating 5a-c with the heterocyclic amines in toluene or by heating 6a-f under reflux in dimethylformamide. The products were evaluated in vitro for potential antimicrobial activity.     

Synthesis and anti-inflammatory activity of some heterocyclic derivatives of phenothiazine

Some new 10-{[5'-amino-(1"-ace tyl-5"-substituted aryl-2"-pyrazolin-3"-yl)-1',3',4'-thiadiazol-2'-yl] methyl}-phenothiazines (11-16) and 10-{[5'-amino-(1"-acetyl-5"-substituted aryl-2"-pyrazolin-3"-yl)-1',3',4'-oxadiazol-2'-yl]methyl}phenothiazines (26-31) have been synthesized from 10-{[5'-substituted benzylideneacetylamino-(1',3',4'-thiadiazol-2'-yl)]methyl}phenothiazines (5-10) and 10-{[5'-substituted benzylideneacetylamino-(1',3',4'-oxadiazol-2'-yl)]methyl}phenothiazines (20-25), respectively. All these compounds of the present series have been screened in vivo for their anti-inflammatory and acute toxicity. Compounds 16 and 31 were found to be potent members of the present series, which showed 46.2% and 48.0% anti-inflammatory activity, respectively, at a dose of 50 mg/kg p.o., while standard drug, phenylbutazone, exhibited 44.52% anti-inflammatory activity at same dose. However, 10-{[5'-amino-(1"-acetyl-5"-(o-methoxyphenyl)-2"-pyrazolin-3"-yl)-1',3',4'-oxadiazol-2'-yl]methyl}phenothiazine (31) was found to be most active and less ulcerogenic compound of this series. The structure of these compounds have been elucidated by IR, 1H NMR, mass spectroscopy and elemental analysis.     

Synthesis of some triazolophthalazine derivatives for their anti-inflammatory and antimicrobial activities

Several novel series of triazolophthalazine derivatives namely; pyrazolylethenyltriazolophthalazinones (4a-d), styryltriazolophthalazinones (5a,b), aryloxopropenyltriazolophthalazinones (7a,b), pyrazolinyl- (8a,b), (9a,b) and (10a-f), pyrazolyl- (11a-d), (1,2-oxazol-5-yl)-1,2,4-triazolo[3,4-a]phthalazin-6(5H)-ones (14a,b), triazolo[3,4-a]phthalazin-3-yl-pyridine-3-carbonitriles (12a,b), triazolo[3,4-a]phthalazin-3-yl)ethylthioacetic acids (13a,b) and 2-aryl-5-arylamino-1H,5H-pyrazolo[2″,3″-1',5']imidazo[3',4'-1,5]-1,2,4-triazolo[3,4-a]phthalazin-12(13H)-ones (15a-c) have been synthesized. The anti-inflammatory activity of representative compounds has been studied. Compounds 8b, 10c, 10f, 11b, 12a, 13b, and 15a showed anti-inflammatory activities comparable to that of the reference standard, indomethacin. They exhibit also minimal ulcerogenic effect relevant to the reference standard and were found to be non-toxic up to 120 mg/kg orally or up to 75 mg/kg through parenteral route. Concerning the antimicrobial activity; compounds 12b and 13b were found to be equipotent to ampicillin against Staphylococcus aureus, while compounds 10a and 10f were found to be as potent as ampicillin against E. coli, whereas compound 14b exhibited equipotency to clotrimazole against Candida albicans. Compounds 8b, 10f, 11b, 12a, and 13b exhibited, besides their antimicrobial activity, moderate to potent anti-inflammatory profiles. This represents a fruitful matrix for the development of a new class of dual non-acidic anti-inflammatory/antimicrobial agents.     

Studies on the synthesis andin vitro antitumor activity of the isoquinolone derivatives

3-Arylisoquinolin-1(2H)-ones (2) are possible bioisosteres of the 5-[4'-(piperidinomethyl)phenyl]-2,3-dihydroimidazo[2,1-a]iso quinoline (1) which is in clinical evaluation for the treatment of cancer. Structure-activity relationship studies of 3-arylisoquinolin-1(2H)-ones (2) led to the synthesis of 3-arylquinolin-2(1H)-ones (3). A number of 3-phenyl substituted quinolin-2(1H)-ones were synthesized and tested for their in vitro antitumor activity against four different human tumor cell lines and 3-phenyl-N-benzyl-3,4-dihydroquinolin-2(1H)-one (12) showed the most potent activity.     

Synthesis, anti-inflammatory and analgesic activity of some new 4(3H)-quinazolinone derivatives

4(3H)-quinazolinone and pyrazole derivatives have been shown to have analgesic and anti-inflammatory properties. In this study, 14 new 3-methyl-4(3H)quinazolinone derivatives bearing 2-[1'-phenyl-3'-(substituted-phenyl)-2'-propenylidene]hydrazino or 2[5'-(substituted phenyl)-3'-phenyl-2'-pyrazolin-1'-yl] groups have been synthesized with the aim of obtaining new analgesic and anti-inflammatory leads. The structures were elucidated by means of UV, IR, 1H-NMR, 13C-NMR, mass spectroscopy, and elemental analysis data. The anti-inflammatory activities of the synthesized compounds were determined by carrageenan-induced hind paw edema test in mice. All the compounds showed statistically significant effects. For analgesic activity assessment, p-benzoquinone-induced writhing test was applied in mice. The results obtained were in accordance with the anti-inflammatory activity tests.     

Characterization of the reaction products of 2'-deoxyguanosine and 1,2,3,4-diepoxybutane after acid hydrolysis: formation of novel guanine and pyrimidine adducts

1,2,3,4-diepoxybutane (DEB), an important in vivo metabolite of 1,3-butadiene (BD), is a potent mutagen and a known carcinogen. Recently, DEB has been shown to react with 2'-deoxyguanosine (dG) at 37 degrees C and pH 7.4 to yield a series of nucleoside adducts, resulting from alkylation at the 7-, 1-, and N(2)-positions of dG. In addition, adducts with fused ring systems are formed. In the present study, new adducts are characterized after DEB was allowed to react with dG at pH 7.4 and the reaction mixture was then subjected to acid hydrolysis. These adducts are 7-hydroxy-6-hydroxymethyl-5,6,7,8-tetrahydropyrimido[1,2-a]purin-10(1H)one (H2), 2-amino-1-(4-chloro-2,3-dihydroxybutyl)-1,7-dihydro-6H-purin-6-one (H4), 2-amino-1-(2,3,4-trihydroxybutyl)-1,7-dihydro-6H-purin-6-one (H1'/H5'), 7,8-dihydroxy-1,5,6,7,8,9-hexahydro-1,3-diazepino[1,2-a]purin-11(11H)one (H2'), and 5-(3,4-dihydroxy-1-pyrrolidinyl)-2,6-diamino-4(3H)pyrimidinone (H3'). The previously characterized guanine adducts, 2-amino-7-(3-chloro-2,4-dihydroxybutyl)-1,7-dihydro-6H-purin-6-one (H3) and 2-amino-7-(2,3,4-trihydroxybutyl)-1,7-dihydro-6H-purin-6-one (H4'), were also detected. Acid hydrolysis of purified dG-DEB adducts confirmed that H2, H3/H4', H2', and H4/H1'/H5' are the hydrolysis products of N-(2-hydroxy-1-oxiranylethyl)-2'-deoxyguanosine (P4-1 and P4-2), 6-oxo-2-amino-9-(2-deoxy-beta-d-erythro-pentofuranosyl)-7-(2-hydroxy-2-oxiranylethyl)-6,9-dihydro-1H-purinium ion (P5 and P5'), 7,8-dihydroxy-3-(2-deoxy-beta-d-erythro-pentofuranosyl)-3,5,6,7,8,9-hexahydro-1,3-diazepino[1,2-a]purin-11(11H)one (P6), and 1-(2-hydroxy-2-oxiranylethyl)-2'-deoxyguanosine (P8 and P9), respectively. On the other hand, the novel pyrimidine adduct H3' is formed by the decomposition of P5 and P5' during the incubation and hydrolysis. These results may facilitate the development of useful biomarkers of exposure to DEB and its precursor BD.     

Design and synthesis of poly ADP-ribose polymerase-1 inhibitors. 2. Biological evaluation of aza-5[H]-phenanthridin-6-ones as potent,aqueous-soluble compounds for the treatment of ischemic injuries

A series of aza-5[H]-phenanthridin-6-ones were synthesized and evaluated as inhibitors of poly ADP-ribose polymerase-1 (PARP-1). Inhibitory potency of the unsubstituted aza-5[H]-phenanthridin-6-ones (i.e., benzonaphthyridones) was dependent on the position of the nitrogen atom within the core structure. The A ring nitrogen analogues (7-, 8-, and 10-aza-5[H]-phenanthridin-6-ones) were an order of magnitude less potent than C ring nitrogen analogues (1-, 2-, 3-, and 4-aza-5[H]-phenanthridin-6-ones). Preliminary stroke results from 1- and 2-aza-5[H]-phenanthridin-6-one prompted structure-activity relationships to be established for several 2- and 3-substituted 1-aza-5[H]-phenanthridin-6-ones. The 2-substituted 1-aza-5[H]-phenanthridin-6-ones were designed to improve the solubility and pharmacokinetic profiles for this series of PARP-1 inhibitors. Most importantly, three compounds from this series demonstrated statistically significant protective effects in rat models of stroke and heart ischemia.     

Anticonvulsant and neurotoxicity evaluation of 5-(un)-substituted isatinimino derivatives

Various Schiff bases were prepared by reacting 5-(un)-substituted isatin with some heterocyclic compounds, viz., N-[4-(4'-chlorophenyl-thiazol-2-yl] semicarbazide, 3-amino-2-methylmercaptoquinazolin-4-one, 3-(4'-pyridyl)-4-amino-5-mercapto-4(H)-1,2,4-triazole and 4-(4'-chlorophenyl)-6-(4"-methylphenyl)-2-aminopyrimidine. The compounds were evaluated for anticonvulsant and neurotoxic properties. The compound 3-(3',4'-dihydro-2'-methylmercapto-4'-oxoquinazolin-3'-yl) iminoisatin (3) emerged as the most active analogue showing anti-MES and anti-PTZ activities better than valproic acid. All the compounds showed lower neurotoxicity than phenytoin and carbamazepine.     

A facile synthesis and anticancer activity evaluation of spiro[thiazolidinone-isatin] conjugates

The synthesis and evaluation of the anticancer activity of 3'-aryl-5'-arylidene-spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)-diones and spiro[3H-indole-3,2'-thi-azolidine]-2,4'(1H)-dione-3'-alkanoic acid esters were described. The structure of the compounds was determined by (1)H and (13)C NMR and their in vitro anticancer activity was tested in the National Cancer Institute. Among the tested compounds, (5'Z)-5'-(benzylidene)-3'-(4-chlorophenyl)spiro[3H-indole-3,2'-thia-zolidine]-2,4'(1H)-dione (IIa) and (5'Z)-3'-(4-chlorophenyl)-5'-[4-(1-methylethyl)-benzylidene]spiro[3H-indole-3,2'-thiazolidine]-2,4'(1H)-dione (IIb) were superior to other related compounds.     

Synthesis of novel biologically active heterocyclic compounds from 2-oxo-2H-benzopyran-6-yl-imidazolidine

6-Aminocoumarin on treatment with oxalyl chloride gives coumarinyl-6-isocynate (1a-c) which on treatment with glycine gives 1H-3-[2'-oxo-2'H-benzopyran-6'-yl]-5-imidazolidine-2, 4-dione (2a-c). (2a-c) when refluxed with o-chlorobenzaldehyde, m-hydroxybenzaldehyde, 3,4-dimethoxybenzaldehyde and 3-nitrobenzaldehyde separately gives 1H-5-(2"-chlorobenzylidene)-3-(2'-oxo-2'H-benzopyran-6'-yl) imidazolidine-2,4-dione (3a-c), 1H-5-(3"-hydroxybenzylidene)-3-(2'-oxo-2'H-benzopyran-6'-yl) imidazolidine-2,4-dione (4a-c), 1H-5-(3",4"-dimethoxybenzylidene)-3-(2'-oxo-2'H-benzopyran-6'-yl) imidazolidine-2,4-dione (5a-c) and 1H-5-(3"-nitrobenzylidene)-3-(2'-oxo-2'H-benzopyran-6'-yl) imidazolidine-2,4-dione (6a-c), respectively. 3-(2"-Chlorophenyl)-3a,4-dihydro-6-(2'-oxo-2'H-benzopyran-6'-yl) imidazo[4,5-c]isoxazol-5-one 7a-c is obtained from (3a-c) and hydroxylamine hydrochloride while 2,3a,4-trihydro-3-(3"-hydroxyphenyl)-6-(2'-oxo-2'H-benzopyran-6'-yl) imidazo[4,5-c]pyrazol-5-one (8a-c) obtained by reaction of (4a-c) with hydrazine hydrate. Compound (5a-c) on treatment with urea gives 5,7-dihydro-2-hydroxy-6-(3",4"-dimethoxyphenyl)-9-(2'-oxo-2'H-benzopyran-6'-yl) purin-8-one (9a-c) and compound (6a-c) on treatment with thiourea gives 5,7-dihydro-2-mercapto-6-(3"-nitrophenyl)-9-(2'-oxo-2'H-benzopyran-6'-yl)purin-8-one (10a-c). The structures of the compounds have been established on the basis of spectral analytical data. All the compounds have been screened for their antimicrobial activities against three bacterial strains S. aureus, S. typhi and E. coli. Compounds 2b, 3b, 4b, 5b, 6b, 7b, 8b, 9b and 10b with the presence of methyl groups at C7' and C8' of coumarin moiety were found to be more active than others.     

Newer substituted beta-aminonaphthalenes as potent anti-inflammatory agents

beta-[2-(3'-Chloro-2'-oxo-4'-substituted aryl-1'-azetidinyl)-thiazol-4- yl]aminonaphthalenes 13-17 and beta-[2-(1',3'-disubstitutedphenyl-formazan-4'-yl)-thiazol-4-yl] aminonaphthalenes 8-12 were synthesized from beta-(2-arylideneamino-thiazol-4-yl)aminonaphthalenes 3-7 by diazotisation and by cycloaddition with monochloroacetyl chloride, respectively, on the azomethine group of the compounds 3-7. The newly synthesized compounds showed potent anti-inflammatory and analgesic activities and were less ulcerogenic than phenylbutazone.     

Synthesis and antimicrobial activity of some thiazolinyl tetrahydrobenzo[b]thiophenes and thiazolinyl tetrahydrobenzothieno[2,3-d]pyrimidin-4-ones.

Two series of novel 3-carbethoxy-2-(3',4'-disubstituted-2',3'- dihydrothiazol-2'-ylidenamino)-4,5,6,7-tetrahydrobenzo[b] thiophenes (3a-o) and 2-methyl-3-(3',4'-disubstituted-2',3'-dihydrothiazol-2'-ylidena mino-5,6,7,8- tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H) ones (8a-o) have been synthesized and tested for antimicrobial activity. All members of the series have been found to exhibit in vitro antibacterial and/or antifungal activities. Activity was optimized by cyclization to the thienopyrimidin-4-ones. In particular, compounds 8e and 8fd were the most active against the 3 tested microorganisms. Their antifungal activity was higher than that exhibited by nystatin while their MIC was found to be nearly equal to that of nystatin.     

Synthesis and reactivity of debenzorutaecarpine derivatives]

A series of 7,12-dihydropyrimido[1',2';1,2]pyrido[3,4-b]indol-4(6H)-ones was prepared by Fischer indolization of 9-arylhydrazono-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one s. Quantumchemical calculations (ab initio and AM1) indicate that position 3 of 7,12-dihydro-pyrimido[1',2';1,2]pyrido[3,4-b]indol-4(6H)-one can be involved in electrophilic substitutions, while position 2 is sensitive towards nucleophilic attack. Bromination of 6-methyl-7,12-dihydropyrimido[1',2';1,2]pyrido[3,4-b]indol-4(6H)-o ne (16) with bromine afforded 3-bromo derivative (25), which was reacted with cyclic amines to give 2-amino-7,12-dihydro-pyrimido[1',2';1,2]pyrido[3,4-b]indol-4(6H)-ones (26-30) in an addition-elimination reaction. Vielsmeier-Haack formylation of compound (16) give 12-formyl (31) and 3,12-diformyl (32) derivatives (an N-formyl-1-aza derivative of nauclefidine alkaloid (34) at 60 degrees C and 100 degrees C, respectively. 3,12-dformyl compound (32) was oxidized to 3-carboxyl derivative (33). The quaternary salt (35), obtained from compound (16) with dimethyl sulphate, suffered a ring opening on the action of aqueous sodium hydroxide. The new compounds have been characterized by elemental analyses uv, 1H nmr and in some cases by 13C ruler, CD spectra and X-ray investigations.     

Antitumor agents. 194. Synthesis and biological evaluations of 4-beta-mono-, -di-, and -trisubstituted aniline-4'-O-demethyl-podophyllotoxin and related compounds with improved pharmacological profiles.

As a continuation of our structure-activity relationship studies, several new 4-beta-substituted 4'-O-demethyl-4-desoxypodophyllotoxins bearing mono-, di-, or trisubstituted anilines have been synthesized and evaluated as inhibitors of DNA topoisomerase II and tumor cell growth in tissue culture. Selected compounds were further evaluated as cytotoxic agents using a clonogenic survival assay. The target compounds include 4'-O-demethyl-4beta-[(4' '-(benzimidazol-2' '-yl)anilino]-4-desoxypodophyllotoxin (21), 4'-O-demethyl-4beta-(-)-(4' '-camphanamido-anilino)-4-desoxypodophyllotoxin (25), 4-beta-disubstituted-anilino-4'-demethyl-4-desoxypodophyllotoxins (18-20, 26), 4-alpha-disubstituted-anilino-4'-demethyl-4-desoxypodophyllotoxin (27), 4-beta-trisubstituted-anilino-4'-demethyl-desoxypodophyllotoxin (22, 23), and 4'-O-demethyl-4beta-[4' '-(benzimidazol-2' '-yl)amino]-4-desoxypodophyllotoxin (24). Among the target series, 19, 21, and 24 displayed significant growth inhibitory action against a panel of tumor cell lines including human epidermoid carcinoma of the nasopharynx (KB) and its etoposide-resistant (KB7B) and vincristine-resistant (vin20c KB) subclones, lung carcinoma (A549), human ileocecal carcinoma (HCT-8), human kidney carcinoma (CAKI-1), breast adenocarcinoma (MCF-7), and human malignant melanoma (SK-MEL-2) cells. Compounds 19, 21, 24, and 25 were "cleavable-complex"-forming DNA topoisomerase II inhibitors with either improved or similar activity compared with the prototype drug etoposide (VP-16). Compound 21 was the most active analogue, being 10-fold more potent than etoposide in both cell killing and topoisomerase II inhibition in vitro assays. Using mouse models of antitumor activity, 21 was effective against (P388/0) leukemia but not against the growth of a (MCF7) mammary tumor.     

Acutudaurin from cultured roots of Menispermum dauricum

A new alkaloid, acutudaurin, was isolated from cultured roots of Menispermum dauricum, a rich source of the chlorine-containing alkaloid acutumine and its dechlorinated analogue dechloroacutumine. The structure of acutudaurin was determined to be 2',3'-dihydro-5-hydroxy-4,6',7'-trimethoxy- 1'-methylspiro[3-cyclohexene-1,10'-[3a,7a]propano[1H]indole]-2,5'(4'H)-dione by spectroscopic methods.