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PubMed2005

Synthesis and structure-activity relationships of soluble 7-substituted 3-(3,5-dimethoxyphenyl)-1,6-naphthyridin-2-amines and related ureas as dual inhibitors of the fibroblast growth factor receptor-1 and vascular endothelial growth factor receptor-2 tyrosine kinases.

7-Substituted 3-aryl-1,6-naphthyridine-2,7-diamines and related 2-ureas are inhibitors of fibroblast growth factor receptor-1 (FGFR-1) and vascular endothelial growth factor receptor-2 (VEGFR-2). 3-(3,5-Dimethoxyphenyl) and 3-phenyl analogues were prepared from 7-acetamido-2-tert-butylureas by alkylation with benzyl omega-iodoalkyl ethers, debenzylation, and amination, followed by selective cleavage of the 7-N-acetamide. 3-(2,6-Dichlorophenyl) analogues were prepared from the 7-fluoro-2-amine by displacement with substituted alkylamines, followed by selective acylation of the resulting substituted naphthyridine-2,7-diamines with alkyl isocyanates. The 3-(3,5-dimethoxyphenyl) derivatives were low nanomolar inhibitors of both FGFR and VEGFR and were highly selective (>100-fold) over PDGFR and c-Src. Variations in the base strength or spatial position of the 7-side chain base had only small effects on the potency (<5-fold) or selectivity (<20-fold). The 3-(2,6-dichlorophenyl)-2-urea derivatives were slightly less active against VEGFR and less selective, being more effective against PDGFR (ca. 10-fold) and c-Src (ca. 500-fold). The 3-(3,5-dimethoxyphenyl)-1,6-naphthyridines were generally more potent than the corresponding pyrido[2,3-d]pyrimidines against both VEGFR and FGFR (2- to 20-fold), with only slightly increased PDGFR and c-Src activity. The 3-(3,5-dimethoxyphenyl)-1,6-naphthyridine 2-ureas were also low nanomolar inhibitors of the growth of human umbilical vein endothelial cells (HUVECs) stimulated by serum, FGF, or VEGF, at concentrations that did not affect the growth of representative tumor cell lines, and were more (3- to 65-fold) potent than the corresponding pyrido[2,3-d]pyrimidines.

Angiogenesis Inhibitors↗

PubMed1997

Antitumor agents. 174. 2',3',4',5,6,7-Substituted 2-phenyl-1,8-naphthyridin-4-ones: their synthesis, cytotoxicity, and inhibition of tubulin polymerization.

Two series of 2',3',4',5,6,7-substituted 2-phenyl-1,8-naphthyridin-4-ones and 2-phenylpyrido[1,2-alpha]pyrimidin-4-ones have been synthesized and evaluated as cytotoxic compounds and as inhibitors of tubulin polymerization. Most 2-phenyl-1,8-naphthyridin-4-ones showed potent cytotoxic and antitubulin activities, whereas 2-phenylpyrido[1,2-alpha]pyrimidin-4-ones showed no activity in either assay. In general, a good correlation was found between cytotoxicity and inhibition of tubulin polymerization in the 2-phenyl-1,8-naphthyridin-4-one series. The 2-phenyl-1,8-naphthyridin-4-ones (44-49) with a methoxy group at the 3'-position showed potent cytotoxicity against most tumor cell lines with GI50 values in the low micromolar to nanomolar concentration range in the National Cancer Institute's 60 human tumor cell line in vitro screen. Introduction of substituents (e.g. F, Cl, CH3, and OCH3) at the 4'-position led to compounds with reduced or little activity and substitution at the 2'-position resulted in inactive compounds. The effects of various A-ring substitutions on activity depend on the substitution in ring C. Compounds 44-50 were potent inhibitors of tubulin polymerization, with activity nearly comparable to that of the potent antimitotic natural products colchicine, podophyllotoxin, and combretastatin A-4. Compounds 44-49 also inhibited the binding of radiolabeled colchicine to tubulin, but the inhibition was less potent than that obtained with the natural products. Further investigation is underway to determine if substitution at the 3'-position and multisubstitutions in ring C will result in compounds with increased activity.

Animals↗

PubMed2002

Binding analysis between naphthyridine dimers and GG mismatch DNA.

Kinetics and thermodynamics studies of the binding between naphthyridine dimer and DNA duplexes having a G-G mismatch sequence were performed by using Surface Plasmon Resonance (SPR) assay. Naphthyridine dimers possessing a different length of PEG linker were synthesized and immobilized to the dextran surface of the sensor chip to obtain an improved sensitivity of the SPR sensor toward a G-G mismatch. The effect of the directly neighboring base pair to the G-G mismatch was estimated from the thermodynamic parameters of the complex. These results indicate that stacking with adjacent base pair and naphthyridine dimer is the key roll for the formation of the complex between mismatched base pair and naphthyridine dimer.

Base Pair Mismatch↗

PubMed1989

[Study on metabolism of pyridonecarboxylic acid. I. Isolation and identification of metabolites of (+-)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1- (2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid p-toluenesulfonate hydrate (T-3262) in urine].

Metabolism of (+-)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4- dihydro-4- oxo-1,8-naphthyridine-3-carboxylic acid p-toluenesulfonate hydrate (T-3262) was studied. Metabolites were isolated from urine of mouse, rat, rabbit, dog and monkey following oral administration of T-3262, and identified using high performance liquid chromatography and mass spectrometry. Two metabolites, other than unchanged (+-)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4- dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (T-3262 base), in which 3-aminopyrrolidinyl ring of T-3262 was metabolized, were identified as: (+-)-7-(3-acetyl-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro- 1,4- dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid (T-3262A) in all animals: (+-)-1-(2,4-difluorophenyl)-6-fluoro-7-(3-hydroxy-1-pyrrolidinyl)-1,4- dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid (T-3262B) in monkey. The glucuronide of T-3262 was detected in mouse, dog and monkey, the glucuronides of T-3262A and T-3262B were detected in monkey. M-I, unidentified metabolite, was detected only in mouse.

4-Quinolones↗

PubMed2003

Antinociceptive effects of N-acyloctahydropyrido[3,2,1-ij][1,6]naphthyridine in mice: structure-activity relation study of matrine-type alkaloids part II.

N-Acyloctahydropyrido[3,2,1-ij][1,6]naphthyridines were synthesized as derivatives of matrine-type alkaloids, and the structure-activity relations were examined by the acetic acid-induced abdominal contraction test. The antinociceptive potencies of N-acyloctahydropyrido[3,2,1-ij][1,6]naphthyridines were significantly lower than those of (+)-matrine. The antinociceptive effects of N-benzyloctahydropyrido[3,2,1-ij][1,6]naphthyridines are approximately 5.6 to 6.5 times less than those of N-benzoyloctahydropyrido[3,2,1-ij][1,6]naphthyridine. These findings suggest that the amide group of matrine-type alkaloids is an essential functional group that influences antinociceptive potency. The antinociceptive effect of 4c was markedly antagonized by pretreatment with Naloxone, and that of 3c partially so.

Alkaloids↗

PubMed2003

Characterization of the biochemical effects of new 1, 8-naphthyridine derivatives, beta-receptor antagonists, in ventricular myocytes.

Novel derivatives of 1, 8-naphthyridine were synthesized from 7-amino-2-hydroxy-4-morpholinomethyl-1, 8-naphthyridine. The ability of the synthesized compounds to inhibit isoproterenol(ISO)-induced phosphorylation of phospholamban (PLB) was assessed. Their ability to block both beta(1) and beta(2) receptors almost completely abolished all ISO effects on phosphorylation of PLB. Analogues with either a 7-hydroxy-2-N-ethoxycarbonylpiperazine or a 7-hydroxy-2-piperazine substituent, designated as 6 and 9 respectively, showed a higher affinity for beta(1) receptor than that of the methoxy derivatives 12 and 13. However, treatment with 30 microM 9 and 1mM 13 lead to comparable levels of PLB phosphorylation. The reduction to 6-amino derivatives 10 and 17 led to compounds possessing beta(2) receptor blocking properties. The ability of the synthesized compounds to inhibit forskolin-stimulated cAMP production was also studied. Together, these results suggest that the 1, 8-naphthyridine parent structure can be modified, to produce compounds with increased activity whose effect in rat appears to be more clearly related to antagonism of beta(1)-rather than beta(2)-adrenergic receptors.

Adrenergic beta-Antagonists↗

PubMed2003

Synthesis and beta-blocking activity of (R,S)-(E)-oximeethers of 2,3-dihydro-1,8-naphthyridine and 2,3-dihydrothiopyrano[2,3-b]pyridine: identification of beta 3-antagonists.

Drugs acting on beta(1)- and beta(2)-adrenergic receptors are widely used for the clinical management of a large number of cardiovascular and respiratory pathologies. In the last decade, the discovery of the third subtype of beta receptors, the beta(3)-adrenoceptor, gave a further pharmacological target for the development of new selective drugs. Initially, a potential therapeutic use of beta(3)-selective agents seemed to be restricted to agonists, for the treatment of metabolic diseases, such as obesity, non-insulin-dependent diabetes, urinary frequency and incontinence. More recently, some interesting theories about a negative role played by the cardio-depressant activity of myocardial beta(3)-adrenoceptors in heart failure, seemed to justify a clinical use of beta(3)-antagonists in the last phases of this cardiac disease. Following the indications deriving from previous experimental work, the beta-antagonist properties of newly-synthesised (R,S)-(E)-oximeethers of 2,3-dihydro-1,8-naphthyridine and of 2,3-dihydrothiopyrano[2,3-b]pyridine were evaluated, in order to identify some useful structure-activity relationships, which might account for selectivity towards the three beta-subtypes and, in particular, the beta(3)-adrenoceptor. Among the various observations regarding possible structure-activity relationships, able to explain the pharmacodynamic patterns of the synthesised compounds on the three subtypes of beta-adrenoceptors, the most significant data derived from the evaluation of the beta(3)-blocking properties of some oximeethers of 1,8-naphthyridine derivatives. In these molecules, although the presence of the large substituents in position 7, such as 4-chloro-phenoxy- or 4-t-butyl-phenoxy groups determined a dramatic decline in both the beta(1)- and beta(2)-activities, this structural characteristic had a modest influence on the beta(3)-affinity, which was only slightly lower. Hence, this last structural requirement of oximeethers of 1,8-naphthyridine derivatives seems to represent a useful expedient to induce an appreciable selectivity towards the beta(3)-receptor, through a markedly negative effect on the beta(1)- and beta(2)-activities rather than an increase in the beta(3)-affinity.

Adrenergic beta-Antagonists↗

PubMed2004

Highly sensitive detection of GG mismatched DNA by surfaces immobilized naphthyridine dimer through poly(ethylene oxide) linkers.

Naphthyridine dimer is a unique molecule that strongly, and selectively, binds to the guanine-guanine mismatch in duplex DNA. We have synthesized naphthyridine dimers possessing a different length of poly(ethylene oxide) (PEO) linker, and immobilized them to CM5 sensor chip to carry out a surface plasmon resonance (SPR) assay of DNA duplexes containing a single base mismatch. The sensitivity of the sensor remarkably increased with increasing numbers of PEO units incorporated into the linker. With the sensor surface immobilized naphthyridine dimer for 1.5 x 10(3) response unit (RU) through three PEO units, the distinct SPR signal was observed at a concentration of 1 nM of the 27-mer G-G mismatch.

Base Pair Mismatch↗

PubMed2004

Syntheses and EGFR kinase inhibitory activity of 6-substituted-4-anilino [1,7] and [1,8] naphthyridine-3-carbonitriles.

The syntheses and EGFR kinase inhibitory activity of a series of 6-substituted-4-anilino [1,7] and [1,8] naphthyridine-3-carbonitriles are described. Both reversible and irreversible binding inhibitors were prepared. These series were compared with each other and with the corresponding 4-anilinoquinoline-3-carbonitriles. Compounds having a 1,7-naphthyridine core structure can retain high potency while those with a 1,8-naphthyridine core are significantly less active. These results are consistent with molecular modeling observations.

Cell Line, Tumor↗

PubMed2004

Microwave assisted synthesis of 2-(4-substituted piperazin-1-yl)-1,8-naphthyridine-3-carbonitrile as a new class of serotonin 5-HT3 receptor antagonists.

A series of novel 2-(4-substituted piperazin-1-yl)-1,8-naphthyridine-3-carbonitrile 6 were prepared by microwave irradiation and conventional heating. The intermediate, 2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile 3, was prepared from 2-aminonicotinaldehyde 1 and ethyl cyanoacetate 2 in the presence of piperidine under solvent free condition. The synthesized compounds were evaluated for 5-HT3 antagonisms in longitudinal muscle-myenteric plexus (LMMP) preparation from Guinea pig ileum against 5-HT3 agonist, 2-methyl-5-HT. Among the compounds tested, 2-(4-allylpiperazin-1-yl)-1,8-naphthyridine-3-carbonitrile 6d showed most favorable 5-HT3 receptor antagonism in the Guinea pig ileum.

Animals↗

PubMed2006

2-Amino-5,7-dimethyl-1,8-naphthyridine as a fluorescent reagent for the determination of nitrite.

A new fluorescent reagent 2-amino-5,7-dimethyl-1,8-naphthyridine (ADMND) was proposed for the determination of trace nitrite. The reaction is based on the diazotization of naphthyridine amine with nitrite to form a diazonium salt that hydrolyzed when boiling to give hydroxyl group substituted naphthyridine. Fluorescence quenching degree of ADMND by nitrite ion is linear in the nitrite concentration range of 1 x 10(-7) to 2.5 x 10(-6)mol l(-1) with a detection limit of 4.06 x 10(-8)mol l(-1). Reaction and determination acidity for nitrite is the same which made the method much simpler compared with the widely accepted fluorescence method with DAN as a fluorescence reagent.

Anions↗

PubMed2003

5H-Dibenzo[c,h]1,6-naphthyridin-6-ones: novel topoisomerase I-targeting anticancer agents with potent cytotoxic activity.

5H-Dibenzo[c,h]1,6-naphthyridine-6-ones can exhibit potent antitumor activity. The effect of varied substituents at the 5-position of 5H-8,9-dimethoxy-2,3-methylenedioxydibenzo[c,h]1,6-naphthyridine on relative cytotoxicity and topoisomerase I-targeting activity was evaluated. Potent TOP-1-targeting activity is observed when the 5-position is substituted with either a 2-(N,N-dimethylamino)ethyl group, as in 3a, or a 2-(pyrrolidin-1-yl)ethyl substituent, 3c. In contrast, the addition of a beta-methyl group or a beta-hydroxymethyl group to compound 3a, as in 3b and 3j, results in a loss of significant TOP1-targeting activity. While the presence of a 3-(N,N-dimethylamino)propyl substituent at the 5-position or a methyl(2-tetrahydrofuranyl) group allows for retention of TOP1-targeting activity, the 2-(4-methyl-1-piperazinyl)ethyl analogue, 3d, did not exhibit significant activity. Replacement of the N,N-dimethylamino group of 3a with either C(2)H(5) or OH, as in 3f and 3h, respectively, also had a negative impact on both cytotoxicity and TOP1-targeting activity. Treatment of 3a with LAH gave the 5,6-dihydrodibenzo[c,h]naphthyridine, 4a. This dihydro derivative has approximately 2/3 the potency of 3a as a TOP1-targeting agent. Compounds 3a, 3b, 3h, 3i, and 4a were evaluated for antitumor activity in the human tumor xenograft model using athymic nude mice. The non-estrogen responsive breast tumor cell line, MDA-MB-435, was used in these assays. Compound 3a proved to be effective in regressing tumor growth in vivo when administered either by ip injection or orally 3x week at a dose of 2.0mg/kg. Compound 4a when administered orally 5x weekly at a dose of 40 mg/kg also suppressed tumor growth.

Animals↗

PubMed2003

Spectroscopic and theoretical studies of derivatives of 1,6- and 1,7-naphthyridines.

The solvatochromism in 8-hydroxy-1,6-naphthyridin-5(6H)-one-7-carboxylic acid methyl ester (1), 5-hydroxy-1,7-naphthyridin-8(7H)-one-6-carboxylic acid methyl ester (2), and 4-hydroxy-2-methyl-1(2H)-isoquinolone-3-carboxylic acid methyl ester (3), has been studied in solvents of different polarity and hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) ability. The relative stabilities of isomers for these naphthyridine derivatives and their interaction with the solvent are reported. Two intramolecular hydrogen-bonded structures contribute to the ground state of compound 1. Temperature effects on the absorption bands were recorded to analyse the possible equilibrium between covalent and zwitterionic forms. The formation of zwitterionic species was observed only in HBD solvents, from which is inferred the solvent assistance in the proton transference. AM1 and PM3 semi-empirical calculations were used in support of the proposed interpretations.

Dimethyl Sulfoxide↗

PubMed2000

3-(3,5-Dimethoxyphenyl)-1,6-naphthyridine-2,7-diamines and related 2-urea derivatives are potent and selective inhibitors of the FGF receptor-1 tyrosine kinase.

A series of 3-aryl-1,6-naphthyridine-2,7-diamines and related 2-ureas were prepared and evaluated as inhibitors of the FGF receptor-1 tyrosine kinase. Condensation of 4,6-diaminonicotinaldehyde and substituted phenylacetonitriles gave intermediate naphthyridine-2,7-diamines, and direct reaction of the monoanion of these (NaH/DMF) with alkyl or aryl isocyanates selectively gave the 2-ureas in varying yields (23-93%). For the preparation of more soluble 7-alkylamino-2-ureas, a number of protecting groups for the 2-amine were evaluated (phthaloyl, 4-methoxybenzyl) following selective blocking of the 7-amine (trityl), but these were not superior to the (required) 2-tert-Bu-urea group itself. Direct alkylation of the anion of the (unprotected) 7-amino group with excess 4-(3-chloropropyl)morpholine in DMF gave low (10%) yields of the desired product, but alkylation of the 7-acetamido anion, followed by mild alkaline hydrolysis, raised this to 64%. 3-Phenyl analogues were nonspecific inhibitors of isolated c-Src, FGFR, and PDGFR tyrosine kinases, whereas 3-(2,6-dichlorophenyl) analogues were most effective against c-Src and FGFR, and 3-(3,5-dimethoxyphenyl) derivatives showed high selectivity for FGFR alone. A water-soluble (7-morpholinylpropylamino) analogue retained high FGFR potency (IC(50) 31 nM) and selectivity. Pairwise comparison of the 1, 6-naphthyridines and the corresponding known pyrido[2,3-d]pyrimidine analogues showed little differences in potency or patterns of selectivity, suggesting that the 1-aza atom of the latter is not important for activity. A 7-acetamide derivative inhibited the growth of FGFR-expressing tumor cell lines and was particularly potent against HUVECs (IC(50) 4 nM). This compound was also a very potent inhibitor of HUVEC microcapillary formation (IC(50) 0.01 nM) and Matrigel invasion (IC(50) 7 nM) and showed significant in vivo antitumor effects in a highly vascularized mammary adenocarcinoma 16/c model at nontoxic doses. The compounds are worthy of further evaluation as antiangiogenesis agents.

Animals↗

PubMed1992

Novel cAMP PDE III inhibitors: 1,6-naphthyridin-2(1H)-ones.

Two series of medorinone (3) analogs were prepared by modifications at C(2) and C(5). The C(2)-series was prepared from 2-chloro-5-methyl-1,6-naphthyridine (4) by replacement of the chloro group with various nucleophiles. The C(5)-series was prepared from 5-acyl-6-[2-(dimethylamino)-ethenyl]-2(1H)-pyridinone (11), 5-bromo-1,6-naphthyridin-2(1H)-one (17), and 1,3-diketones 19 and 27. 1,6-Naphthyridin-2(1H)-ones are novel inhibitors of cAMP PDE III. Modification of the carbonyl group of 3 or N-methylation at N(1) resulted in a dramatic loss of enzyme activity. Absence of the C(5)-methyl group of medorinone (3) or its shift to C(3) or C(7) also resulted in reduced activity. Substitution at C(3) also diminished activity. However, substitution at C(5) by a wide variety of substituents led to improvement of enzyme activity and several C(5)-substituted analogs were more potent than milrinone.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1984

Pyridonecarboxylic acids as antibacterial agents. 2. Synthesis and structure-activity relationships of 1,6,7-trisubstituted 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids, including enoxacin, a new antibacterial agent.

The title compounds having nitro, amino, cyano, chloro, or fluoro as the C-6 substituent were prepared. Introduction of the chloro and cyano groups at C-6 was accomplished by the Sandmeyer reaction of 6-amino-1,8-naphthyridine derivatives 9 via their 6-diazonium salts. The reaction was extended to the synthesis of the 6-fluoro analogues, involving the Balz-Schiemann reaction of the diazonium tetrafluoroborate. Furthermore, a series of the 1-ethyl, 1-vinyl, 1-(2-fluoroethyl), and 1-(difluoromethyl) analogues of 7-substituted 6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids was prepared. 1-Pyrrolidinyl and, particularly, N-substituted or unsubstituted 1-piperazinyl groups were introduced as the C-7 variants. As a result of this study, 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1, 8-naphthyridine-3-carboxylic acid (named enoxacin, originally AT-2266) was found to show the most broad and potent in vitro antibacterial activity, an excellent in vivo efficacy on systemic infections, and a weak acute toxicity. Structure-activity relationships of compounds with variations of substituents at C-1, C-6, and C-7 are also discussed.

Animals↗

PubMed1988

Quinolone antibacterial agents. Synthesis and structure-activity relationships of 8-substituted quinoline-3-carboxylic acids and 1,8-naphthyridine-3-carboxylic acids.

A series of 7,8-disubstituted 1-cyclopropyl-6-fluoroquinoline-3-carboxylic acids, 7-substituted 1-cyclopropyl-6-fluoro-1,8-naphthyridine-3-carboxylic acids, and 10-substituted 9-fluoropyridobenzoxazine-6-carboxylic acids has been prepared and evaluated for antibacterial activity. The side chains examined at the 7-position (benzoxazine 10-position) included piperazinyl (g), 3-aminopyrrolidinyl (a), 3-(aminomethyl)pyrrolidinyl (b), and alkylated 3-(aminomethyl)pyrrolidinyl (c-f). Variations at C-8 of the quinolone ring system included hydrogen, nitro, amino, fluorine, and chlorine. The relative enhancement of in vitro activities by the side chains on the 8-hydrogen quinolone and 1,8-naphthyridine against Gram-negative organisms was a greater than b greater than g greater than c-f. The activity imparted to the substituted quinolone nucleus by the 8-substituent was in the order F greater than Cl greater than naphthyridine greater than H greater than benzoxazine greater than NH2 greater than NO2. These trends were retained in vivo.

Animals↗

PubMed2002

Synthesis and structure-activity relationships of novel 7-substituted 1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylic acids as antitumor agents. Part 1.

In an attempt to search for clinically useful antitumor agents, we have discovered that a series of 1,7-disubstituted-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids possessed moderate cytotoxic activity. We investigated the structure-activity relationships in this series of compounds by changing N-1 and C-7 positions and the core ring structure itself and evaluated the synthesized compounds against several murine and human tumor cell lines. These modifications led us to the following findings. (1) The 2-thiazolyl group at the N-1 position of the naphthyridine structure is the best substituent for antitumor activity. (2) Regarding core ring structure, the naphthyridine derivative is the most active followed by pyridopyrimidine analogue. (3) At the C-7 position, aminopyrrolidine derivatives are more effective than other amines or thioether derivatives. Finally, the trans-3-amino-4-methoxypyrrolidinyl derivative (43j) and the 3-amino-3-methylpyrrolidinyl derivative (43f) as well as 3-aminopyrrolidinyl derivative (AT-3639, 1) were determined to be effective in in vitro and in vivo antitumor assays, and their activity was comparable to that of etoposide.

Animals↗