Preparation, characterization, and antitumor activity of water-soluble aminoalkanol platinum(II) complexes

A new series of highly water-soluble aminoalkanol platinum(II) complexes have been synthesized and characterized by elemental analysis, conductance, IR, and 195Pt NMR. Preliminary in vitro and in vivo screening tests for antitumor activities of these complexes against L1210 murine leukemia were performed. In general, these compounds were far less cytotoxic than cisplatin and possessed only a moderate degree of antitumor activity.     

Synthesis and antitumor activity of duocarmycin derivatives: modification at the C-7 position of segment-A of A-ring pyrrole compounds

A series of the C7-substituted A-ring pyrrole derivatives of duocarmycin were synthesized, and evaluated for in vitro anticellular activity against HeLa S3 cells and in vivo antitumor activity against murine sarcoma 180 in mice. All of the C7-substituted A-ring pyrrole compounds decreased potency in vitro and in vivo. However, some showed strong antitumor activity with T/C values less than 0.3. Among them, the 7-formyl compound 5d showed remarkable potent in vivo antitumor activity and low peripheral blood toxicity, which were equal to 2c.     

Synthesis and biological evaluation of 2,7-Dihydro-3H-dibenzo[de,h]cinnoline-3,7-dione derivatives,a novel group of anticancer agents active on a multidrug resistant cell line

A series of anthrapyridazone derivatives with one or two basic side chains at various positions in the tetracyclic chromophore have been synthesized. The key intermediates in the synthesis are 2,7-dihydro-3H-dibenzo[de,h]cinnoline-3,7-diones 1, 12 and 15 monosubstituted at position 2 (4d, 16a-e), or 6 (2a-f) or disubstituted at positions 2 and 6 (4a-c) or 2 and 8 (17a-e) with appropriate alkylaminoalkylamines. All analogues showed in vitro cytotoxic activity against murine leukemia (L1210) and human leukemia (K562) cell lines. The compounds were also active against human leukemia multidrug resistant (K562/DX) cell line with resistance index (RI) in the range 1-3 depending on the compound's structure. Two of the most active in vitro compounds 4a and 11 were tested in vivo against murine P388 leukemia and displayed antileukemic activity comparable with that of Mitoxantrone. DNA-binding assays were performed and DNA affinity data were correlated with the structures of the compounds. The cytoplasmatic membrane affinity values (log k'(IAM)) have also been determined and the correlation with the resistance indexes discussed. The anthrapyridazones constitute a novel group of antitumor compounds that can overcome multidrug resistance.     

Specific binding of 2-amino-1,8-naphthyridine into a single guanine bulge as evidenced by photooxidation of GG doublet

Photoirradiation of 2-amino-1,8-naphthyridines in the presence of duplex DNA containing the GG doublet opposite a single bulge was examined. After hot piperidine treatment, DNA cleavage was observed preferentially at the GG opposite a single bulge. The cleavage efficiency was highly dependent on the nature of bulged base. The G cleavage at the GG opposite a single G bulge was exceptionally weak, suggesting an intercalative binding of 2-amino-1,8-naphthyridine chromophore into the GG step.     

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.     

Differences in the biological activity of TNF alpha and TNF beta correlate with their different abilities for binding to the target cells.

TNF alpha and TNF beta were compared regarding their binding to different types of target cells, cytotoxic/cytostatic activity against murine and human tumor cell lines as well as human capillary endothelial cells, their ability to induce differentiation in myeloid leukemia cell lines, and induction of hemorrhagic tumor necrosis and tumor regression as well as lethal toxicity in tumor-bearing mice. The results show considerable quantitative differences in the biological activity between TNF alpha and TNF beta depending on the type of target cell which has been used. TNF beta was 3 fold more cytotoxic than TNF alpha against murine L929 fibroblasts and 3-5 times more active concerning the induction of hemorrhagic tumor necrosis, complete tumor regression and more toxic in tumor-bearing mice. In contrast to this, TNF beta was markedly less cytotoxic against human capillary endothelial cells and the human mammary carcinoma cell line MCF7 and much less cytostatic against the human myeloid leukemia cell lines HL60 and U937. The lesser antiproliferative effect of TNF beta correlated with a lower ability for induction of differentiation in these cell lines. Competitive radioligand binding assays showed that TNF beta was about 4 fold more effective than TNF alpha in competing with 125I-labeled TNF alpha for the binding to murine L929 fibroblasts. But it was 15-20 times less effective in binding to the human MCF7 cells and the human myeloid leukemia cell lines HL60 and U937. This revealed that, at least for these targets, the differences in the biological activity between TNF alpha and TNF beta are due to different abilities for binding to the target cells. Possible mechanisms for these different binding abilities are discussed.     

Syntheses of novel antitumor dihydroxanthone derivatives with inhibitory activity against DNA topoisomerase II.

A series of methoxycarbonyl group modified nidulalin A analogs were synthesized to improve stability against esterases. The amide derivatives showed cytotoxic activity along with inhibitory activity against DNA topoisomerase II. Among the analogs, amide 9a exhibited antitumor activity in Colon 26 murine tumor model.     

Design and synthesis of 2-(3-alkylaminophenyl)-6-(pyrrolidin-1-yl)quinolin-4-ones as potent antitumor agents

2-(3-Alkylaminophenyl)-6-(pyrrolidin-1-yl)quinolin-4-ones 1–3 were synthesized and screened for anti-proliferative activity against three human cancer cell lines, as well as the normal cell line Detroit 551. All of the synthesized target compounds 1–3 demonstrated potent cytotoxic activity against the cancer cell lines, but weak inhibitory activity toward the normal cell line. 2-(3-Methyl aminophenyl)-6-(pyrrolidin-1-yl)quinolin-4-one (1), one of the potent compounds in vitro, was also tested in an in vivo Hep3B xenograft nude mice model, and its significant anticancer activity was reconfirmed. Therefore, compound 1 merits further investigation as an antitumor clinical trial candidate and potential anticancer agent.     

Synthesis and cytotoxic activity of benzo[c][1,7] and [1,8]phenanthrolines analogues of nitidine and fagaronine

Fagaronine and nitidine are natural benzo[c] phenanthridinium alkaloids, which display antileukemic activity. Both act as topoisomerase I and topoisomerase II inhibitors. The objective of the present study was to prepare noncharged isosters of these compounds, with replacement of the aromatic A ring by a pyridine ring, present in other topoisomerase I inhibitors. Various 7,8- and 8,9-dimethoxy and metylenedioxy benzo[c][1,7] and [1,8]phenanthrolines were readily synthesized by benzyne-mediated cyclization of the corresponding substituted N-(2-halobenzyl)-5-quinolinamines or 5-isoquinolinamines. In both series, compounds bearing oxygenated substituents at positions 8 and 9 exhibited cytotoxic properties towards L1210 murine leukemia cells, which may result from their capacities to intercalate into DNA. Topoisomerase I inhibition was observed for all active compounds.     

Potential new antitumor agents from an innovative combination of camphorato, a ramification of traditional Chinese medicine, with a platinum moiety

Eight new camphorato platinum complexes have been synthesized and evaluated for their in vitro cytotoxicity against HL-60 human leukemia, 3AO human ovarian carcinoma, BEL-7402 human hepatocarcinoma, and A549 human lung carcinoma cell lines. Most complexes showed good cytotoxic activity against the above-selected cell lines. Among the complexes, two compounds were assayed for their in vivo antitumor activity against LS-174T human colon carcinoma cells implanted in mice. One complex exhibited not only higher in vivo antitumor activity, but also less toxicity than oxaliplatin when it was administered intravenously at a dose of 6 mg/kg three times.     

Influence of substituent modifications on the binding of 2-amino-1,8-naphthyridines to cytosine opposite an AP site in DNA duplexes: thermodynamic characterization

Here, we report on a significant effect of substitutions on the binding affinity of a series of 2-amino-1,8-naphthyridines, i.e., 2-amino-1,8-naphthyridine (AND), 2-amino-7-methyl-1,8-naphthyridine (AMND), 2-amino-5,7-dimethyl-1,8-naphthyridine (ADMND) and 2-amino-5,6,7-trimethyl-1,8-naphthyridine (ATMND), all of which can bind to cytosine opposite an AP site in DNA duplexes. Fluorescence titration experiments show that the binding affinity for cytosine is effectively enhanced by the introduction of methyl groups to the naphthyridine ring, and the 1:1 binding constant (10⁶ M⁻¹) follows in the order of AND (0.30) < AMND (2.7) < ADMND (6.1) < ATMND (19) in solutions containing 110 mM Na⁺ (pH 7.0, at 20°C). The thermodynamic parameters obtained by isothermal titration calorimetry experiments indicate that the introduction of methyl groups effectively reduces the loss of binding entropy, which is indeed responsible for the increase in the binding affinity. The heat capacity change (ΔC_p), as determined from temperature dependence of the binding enthalpy, is found to be significantly different between AND (−161 cal/mol K) and ATMND (−217 cal/mol K). The hydrophobic contribution appears to be a key force to explain the observed effect of substitutions on the binding affinity when the observed binding free energy (ΔG_obs) is dissected into its component terms.     

Rational design,synthesis and biological evaluation of thiadiazinoacridines: a new class of antitumor agents

A series of potential DNA-binding antitumor agents, 3-[omega-(alkylamino)alkyl]-6-nitro-thiadiazino[3,4,5-kl]acridines 12 and 1,3-di[omega-(alkylamino)alkyl]-6-nitro-thiadiazino[3,4,5-kl]acridines 13, has been prepared by cyclization with SOCl(2) of 1-[[omega-(alkylamino)alkyl]amino]-9-imino-4-nitro-9,10-dihydroacridines 16 or 1-[[omega-(alkylamino)alkyl]amino]-9-[omega-(alkylamino)alkyl]imino-4-nitro-9,10-dihydroacridines 17, respectively. The non-covalent DNA-binding properties of 12, 13 have been examined using a fluorometric technique. In vitro cytotoxic potencies of these derivatives toward six tumor cell lines, including human colon adenocarcinoma (HT29) and human ovarian carcinoma (A2780 sensitive, A2780cisR cisplatin-resistant, CH1, CH1cisR cisplatin-resistant, and SKOV-3) cells, are described and compared to that of reference drugs. In vivo antitumor activity of some selected derivatives, endowed with relevant cytotoxic activity against murine leukemia P388 are reported. The 3-[2-(dimethylamino)ethyl]-6-nitro-2,7-dihydro-3H-2 lambda(4)-thiadiazino[3,4,5-kl]acridin-2-one (12d) has been identified as a new lead in the development of anticancer tetracyclic acridine derivatives.     

Novel heterocyclic family of phenyl naphthothiazole carboxamides derived from naphthalimides: synthesis, antitumor evaluation, and DNA photocleavage

A new heterocyclic family of (2-(dimethylamino)ethyl)-2-substituted phenylnaphtho[2,1-d]thiazole-5-carboxamides modified from naphthalimides was designed, synthesized, and quantitatively evaluated as antitumor agents and photonucleases. All these compounds were found to be more cytotoxic against P388 than against A549. B(3) (m-NO(2)) was found to be the strongest inhibitor for P388 with IC(50) of 1.49 microM, while B(2) was the most cytotoxic compound against A549 with IC(50) of 12 microM. B(4) (p-CH(3)), the most efficient DNA photocleaver, showed detectable DNA cleavage at 0.5 microM and total cleavage from form I to 100% form II at 50 microM. The photocleaving mechanism was changed with the modification to be via superoxide anion and radical.     

Synthesis, characterization, and antitumor activity of 1,2-bis(diphenylphosphino) ethane platinum(II) and palladium(II) complexes

A number of 1,2-bis(diphenylphosphino)ethane monomeric platinum(II) and palladium(II) complexes have been synthesized in light of their potential antitumor activity. The metal center is coordinated with a number of carboxylate anions in the cis-configuration. These complexes have been characterized by elemental analysis, conductivity measurement, and various spectroscopic techniques [IR and 195Pt NMR]. In vivo screening tests for activity of these complexes were performed against the L1210/0 murine leukemia cancer model, but none displayed a significant level of antitumor activity.     

4-Substituted 4-(1H-1,2,3-triazol-1-yl)piperidine: Novel C7 moieties of fluoroquinolones as antibacterial agents

A series of 4-substituted 4-(1H-1,2,3-triazol-1-yl)piperidine building blocks was synthesized and introduced to the C7 position of the quinolone core, 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid, to afford the corresponding fluoroquinolones in 40–83% yield. The antibacterial activity of these new fluoroquinolones was evaluated using a standard broth microdilution technique. Among them, the quinolone 1-cyclopropyl-6-fluoro-7-(4-(4-formyl-1H-1,2,3-triazol-1-yl)piperidin-1-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (34.15) exhibited comparable antibacterial activity against quinolone-susceptible and multidrug-resistant strains, especially to Staphylococcus aureus and Staphylococcus epidermidis, in comparison with ciprofloxacin and vancomycin.     

Novel water-soluble analogues retaining potent antitumor activity of RA-VII, a cyclic hexapeptide from Rubia plants

Deoxybouvardin (3) was reacted with 2-dialkylaminoethyl chloride salts to produce analogues 4a-h. All analogues retained antitumor activity against P388 leukemia in mice, and analogue 4c showed more promising antitumor activity than RA-VII (1) against the P388 leukemia, B16 melanoma and colon adenocarcinoma 26 murine tumor models. The hydrochloride salt of 4c is soluble in water.     

Synthesis of some new [1,2,4]triazolo[3,4-b][1,3,4]thiadiazines and [1,2,4]triazolo[3,4-b][1,3,4] thiadiazoles starting from 5-nitro-2-furoic acid and evaluation of their antimicrobial activity

New series of fused 1,2,4-triazoles such as, 6-(aryl)-3-(5-nitrofuran-2-yl)-5,6-dihydro-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 4-8, 6-(alkyl/aryl amino)-3-(5-nitrofuran-2-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 9-13 and 6-(4-substituted phenyl)-3-(5-nitrofuran-2-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines 14-18 have been synthesized via the reaction of 4-amino-5-(5-nitrofuran-2-yl)-4H-1,2,4-triazole-3-thiol 3 with various reagents such as hetero aromatic aldehydes, alkyl/aryl isothiocyanates and 4-substituted phenacyl bromides, respectively. The structures of the newly synthesized compounds have been confirmed on the basis of elemental analysis and spectral studies. The newly synthesized triazolo derivatives have been investigated for their in vitro antibacterial activity. Most of the tested compounds showed interesting antibacterial activity against Staphylococcus aureus. Furthermore, the most potent antibacterial compounds 11-13 were evaluated for their in vitro cytotoxic activity against human cancer cell lines. It was found that compounds 11 and 13 showed higher cytotoxicity against Hep-G2 cell line as compared to standard.     

Synthesis and selective tumor targeting properties of water soluble porphyrin-Pt(II) conjugates

We have designed and synthesized a series of novel water soluble porphyrins and their platinum(II) conjugates, cis-[(Por)Pt(dmso)X], where Por=5-(4-pyridyl)-10,15,20-tris(4-sulfonatophenyl)porphyrin) (PyTPPS) or 5-[4-(3-aminopropyl)pyridiniumyl]-10,15,20-tris(4-sulphonatophenyl)porphyrin (PyTPPS-NPn), X=2Cl, 1,1-cyclobutanedicarboxylic acid, oxalate, or malonate. Their biodistribution in tumor bearing mouse was examined along with their antitumor activity against murine leukemia L1210 cell line. The representative complex 1 exhibited a significant accumulation in tumor tissue with a tumor/muscle ratio of 7 after 24 h post injection. The antitumor activity of the title compounds was marginal (T/C: 95-117%), but it was found that platinum(II) coordination to the porphyrin periphery did not affect the tumor accumulating properties of the porphyrin permitting further derivatization for efficient delivery of the Pt(II) antitumor agent.     

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.     

Synthesis of 7-oxo-7H-naphtho[1,2,3-de]quinoline derivatives as potential anticancer agents active on multidrug resistant cell lines

Following our earlier finding that tetracyclic anthraquinone analogs with a fused pyridone ring exhibit cytotoxic activity toward multidrug resistant tumor cells, a series of new potential antitumor agents, 7-oxo-7H-naphtho[1,2,3-de]quinoline derivatives (3, 6-8, 10-12, 14, 15, and 18), bearing one or two basic side chains and various substituents at the pyridone ring, have been synthesized. The compounds have been obtained from 1-amino-4-chloroanthraquinone or 1-aminoanthraquinone by cyclization with diethyl malonate and the subsequent reactions of the key intermediates 2, 4, and 17. The compounds exhibited cytotoxic activity toward sensitive human leukemia cell line HL-60 and against its resistant sublines HL-60/VINC (MDR1 type) and HL-60/DX (MRP1 type).