piperidines and Leukemia-P388

[structure: see text] Two unprecedented C,C-linked dimeric indolizidine alkaloids, flueggenines A (1) and B (2), as well as their biosynthetic precursor (-)-norsecurinine, were isolated from the roots of Flueggea virosa. Their structures and absolute configurations were elucidated by spectroscopic methods, especially 2D NMR and CD spectral analyses, and supported by their unique biosynthetic pathway as proposed. Both 1 and 2 were tested against two tumor cell lines, and alkaloid 1 showed weak activity against the P-388 cell line.

Topics: Alkaloids; Animals; Azepines; Drug Screening Assays, Antitumor; Euphorbiaceae; Humans; Indolizines; Leukemia P388; Mice; Molecular Structure; Piperidines; Plant Roots; Plants, Medicinal

Two new 3-alkylpiperidine alkaloids, tetradehydrohalicyclamine A (2) and 22-hydroxyhalicyclamine A (3), have been isolated from a marine sponge Amphimedon sp. as cytotoxic constituents. Their structures were elucidated by spectroscopic analysis. Compounds 2 and 3 inhibited growth of P388 cells with IC50 values of 2.2 and 0.45 microg/mL, respectively.

Topics: Alkaloids; Animals; Antineoplastic Agents; Drug Screening Assays, Antitumor; Inhibitory Concentration 50; Japan; Leukemia P388; Mice; Mice, Inbred DBA; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Piperidines; Porifera; Tumor Cells, Cultured

Various 1-arylidene-2-tetralones 1 had been shown previously to possess moderate cytotoxic properties unaccompanied by murine toxicity. The objective of the present investigation was to undertake different molecular modifications of representative members of series 1 with a view to discerning those structural features leading to increased potencies. All compounds were evaluated using human Molt 4/C8 and CEM T-lymphocytes as well as murine P388 and L1210 leukemic cells. The Mannich bases 2, 4, 5 and 7 possessed increased potencies compared to the corresponding unsaturated ketones 1 and in general were potent cytotoxics having IC50 values in the 0.2-10 microM range. QSAR using the cytotoxicity data for 2a-e suggested that potency was positively correlated with the size of the substituents in the arylidene aryl ring. Compounds 2a-f were evaluated using a panel of approximately 53 human tumour cell lines and, when all cell lines were considered, were more potent than the reference drug melphalan. In particular, marked antileukemic activity was displayed. Molecular modeling was utilized in order to evaluate whether the shapes of the different compounds contributed to the varying potencies observed. Representative compounds demonstrated minimal or no inhibiting properties towards human N-myristoyltransferase (NMT) and did not bind to calf thymus DNA. This study has revealed a number of unique lead molecules as candidate anti-neoplastic agents serving as prototypes for future development.

Topics: Acyltransferases; Animals; Antineoplastic Agents; Cell Line, Tumor; Humans; Leukemia L1210; Leukemia P388; Leukemia, T-Cell; Mannich Bases; Mice; Piperidines; Structure-Activity Relationship; T-Lymphocytes; Tetralones

A previous investigation revealed that various 4-aryl-3-arylcarbonyl-1-ethyl-4-piperidinols and related vinylogs were cytotoxic to both murine and human tumour cell lines. In particular, 1a and 2a were identified as useful prototypic molecules. Structural modifications of 1a and 2a were accomplished leading to 1b-e and 2b-d which displayed cytotoxicity towards murine P388 and L1210 leukemic cells as well as human Molt 4/C8 and CEM T-lymphocytes. Among the new compounds, the greatest average potencies against these four cell lines were displayed by 1b and 2b, having approximately one quarter and one half of the potency of the reference drug melphalan, respectively. The synthesis and bioevaluation of three open chain analogues of 1b-d, namely 3a-c, did not reveal unequivocally whether this molecular modification led to increases in cytotoxicity or not. Compounds 2a-d were substantially more active than melphalan using a panel of human tumour cell lines. In addition, several compounds displayed selective toxicity to both colon and leukemic cancer cells. The 4-piperidinol 2d was active in the in vivo hollow fibre assay. This study revealed compounds with greater potency than 1a and 2a and it has confirmed that 1,3,4-trisubstituted-4-piperidinols and related compounds are novel groups of candidate antineoplastic and anticancer agents.

Topics: Animals; Antineoplastic Agents; Chemical Phenomena; Chemistry, Physical; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Humans; Leukemia L1210; Leukemia P388; Magnetic Resonance Spectroscopy; Mannich Bases; Mice; Piperidines; Tumor Cells, Cultured

The syntheses of a series of 1-aryl-5-diethylamino-1-penten-3-one hydrochlorides 1 and 1-aryl-3-diethylamino-1-propanone hydrochlorides 4 were accomplished. Attempts to prepare the corresponding bis(5-aryl-3-oxo-4-pentenyl)ethylamine hydrochlorides 2 and bis(3-aryl-3-oxopropyl)ethylamine hydrochlorides 5 led to the formation of a series of 4-(beta-arylvinyl)-3-(beta-arylvinylketo)-1-ethyl-4-piperidi nol hydrochlorides 9 and 4-aryl-3-arylketo-1-ethyl-4-piperidinol hydrochlorides 11, most of which were converted subsequently into the corresponding quaternary ammonium salts 10 and 12, respectively. The structures of these compounds were determined by 1H NMR spectroscopy and confirmed by X-ray crystallography of representative molecules. Most compounds displayed significant cytotoxicity toward murine P388 and L1210 cells as well as human tumors. In general, Mannich bases containing olefinic bonds were more cytotoxic than the analogues without this functional group, while the piperidines 9 and 11 were more potent than the acyclic analogues 1 and 4, respectively. Correlations were noted between various physicochemical constants in the aryl rings and cytotoxicity. Compound 9d displayed promising in vivo activity against colon cancers. This study has revealed that the piperidines 9 and 11 constitute new classses of cytotoxic agents.

Topics: Animals; Antineoplastic Agents; Colonic Neoplasms; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Leukemia L1210; Leukemia P388; Mannich Bases; Mice; Molecular Conformation; Piperidines; Structure-Activity Relationship; Transplantation, Heterologous; Tumor Cells, Cultured

A series of 36 purine and purine analog derivatives have been synthesized and tested for their ability to modulate multidrug resistance in vitro (P388/VCR-20 and KB-A1 cells) and in vivo (P388/VCR leukemia). Compounds were compared to S9788, a triazine derivative which has already shown some activity during phase 1 clinical trials and also a limiting cardiovascular side effect possibly linked to its calcium channel affinity. The fact that active compounds increase adriamycin accumulation in the resistant KB-A1 cells, and not in the sensitive KB-3-1 cells, suggests they act predominantly by inhibiting the P-glycoprotein-catalyzed efflux of cytotoxic agents. No direct relation was found between the affinity for the phenylalkylamine binding site of the calcium channel and in vitro sensitization of resistant cells. In vivo, when administered po in association with vincristine (0.25 mg/kg), five compounds (3, 4, 9, 25, and 26), of very differing calcium channel affinities (Ki from 5 to 560 nM), fully restored (T/V > or = 1.4) the sensitivity of P388/VCR leukemia to vincristine.

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Calcium Channels; Doxorubicin; Drug Resistance, Multiple; Female; Leukemia P388; Leukemia, Experimental; Mice; Molecular Structure; Neoplasm Transplantation; Piperidines; Purines; Structure-Activity Relationship; Triazines; Tumor Cells, Cultured; Vincristine

Reaction of 1-(4-bromophenyl)-4,4-dimethyl-5-(1-piperidino)-1-penten-3-one hydrochloride (1f) with sodium 2-mercaptoethanesulphonate (mesna) gave rise to the thiol adduct. 3. Recrystallization of this compound led to the formation of the corresponding zwitterion 4f. A series of analogues of 4f were prepared and the structure of a representative compound was confirmed by X-ray crystallography. In general, the thiol adducts had similar activity towards P388 cells and human tumour cell lines as the precursor enones 1 although greater selectivity to malignant diseases was found with the thiol adducts. A stability study of representative compounds conducted by 1H NMR spectroscopy revealed that the thiol adducts decomposed in solution. In one case regeneration of the ketone was noted while for the other compounds, the decomposition products were not identified.

Topics: Animals; Antineoplastic Agents; Crystallography, X-Ray; Humans; Ketones; Leukemia P388; Magnetic Resonance Spectroscopy; Mannich Bases; Melphalan; Mesna; Mice; Molecular Conformation; Piperidines; Tumor Cells, Cultured

A new triazinoaminopiperidine derivative, Servier 9788 (S9788), was investigated for its ability to increase Adriamycin (ADR) accumulation and retention in two rodent (P388/ADR and DC-3F/AD) and three human (KB-A1, K562/R and COLO 320DM) cell lines displaying the P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) phenotype. Depending on the cell line S9788 was shown to be two to five times more active and five to 15 times more potent than Verapamil (VRP) in increasing ADR accumulation in resistant cells. ADR retention in KB-A1 cells maintained in a concentration of 10 microM S9788 was twice that in VRP-treated cells, and similar to that measured in the untreated sensitive KB-3-1 cells. Although 5 microM S9788 and 50 microM VRP gave the same values of ADR uptake in KB-A1 cells, S9788 was shown to induce a greater ADR retention following cell wash and post-incubation in resistance modifier- and ADR-free medium. Taking into account that S9788 had no effects on ADR accumulation and retention in sensitive KB-3-1 cells, it can be suggested that S9788 inhibits specifically the P-gp dependent ADR efflux, and in a manner less reversible than that observed with VRP. Moreover, [3H]azidopine photolabeling of P-gp, in P388/ADR plasma membranes, was completely inhibited by 100 microM S9788. Although S9788, as VRP, had no effect on the cell cycle of P388 cells, 5 microM S9788 increased 700-fold the efficacy of ADR to block P388/ADR cells in the G2+M phase of the cell cycle. Together, these results show that the sensitization, by S9788, of cell lines resistant to ADR is mainly due to an increase in ADR accumulation and retention, leading to an increase in the number of resistant cells blocked in the G2+M phase.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Azides; Carcinoma, Squamous Cell; Cell Cycle; Cell Membrane; Cells, Cultured; Colonic Neoplasms; Cricetinae; Cricetulus; Dihydropyridines; Doxorubicin; Drug Resistance; Flow Cytometry; Fluorescence; Humans; Kinetics; Leukemia P388; Leukemia, Myeloid, Acute; Lung; Membrane Glycoproteins; Mice; Piperidines; Sensitivity and Specificity; Triazines; Tritium; Tumor Cells, Cultured; Verapamil

S 9788, a new triazinoaminopiperidine derivative, was found to be a potent reversant of vincristine resistance in the in vivo murine leukemic P388/VCR model. In two treatment regimens (Q4D days 1, 5 and 9 and QD days 1-9), S 9788 enhanced the antitumor activity of vincristine in a dose-dependent manner, resulting in a complete circumvention of drug resistance for well-tolerated doses of S 9788. S 9788 was also effective in enhancing therapeutic effects of vincristine in the treatment of sensitive P388-bearing mice. These results strongly suggest that S 9788 may be a potential candidate for circumvention of multidrug resistance (MDR) in clinical practice.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation, Preclinical; Drug Resistance; Female; Leukemia P388; Mice; Mice, Inbred Strains; Piperidines; Triazines; Vincristine

S 9788 is a novel triazinoaminopiperidine derivative which does not belong to any of the classes of compounds known to reverse multidrug resistance (MDR). S 9788 was far more potent than verapamil (VRP) in reversing resistance to adriamycin (ADR) in the ADR-selected murine leukaemia cell lines P388/ADR-1 and P388/ADR-10, and the human chronic myelogenous leukaemia K562/R. Fold reversion with S 9788 (5 microM) was, respectively, 3.5, 5.4 and 11.3 times greater than that with VRP (5 microM). S 9788 was also a more potent reversant of ADR resistance in the intrinsically resistant human colon adenocarcinoma COLO 320DM (2.3 fold), and of vincristine (VCR) resistance in the human MDR1 gene-transfected squamous lung carcinoma line S1/tMDR1 (5.6 fold). The activity of S 9788 depended on both the MDR cell line and the cytotoxic agent. S 9788 (50-100 mg/kg/d) administered IP once a day on days 1-4 resulted in a dose-dependent increase in the chemotherapeutic effect of VCR (0.25 mg/kg/d) in P388/VCR - bearing mice and ADR (4 mg/kg/d) in P388/ADR - bearing mice. Increases in antitumor activity were (% T/C) of +20-34% in the P388/ADR model and + 50-78% in the P388/VCR model with respect to cytotoxic agent treatment alone. S 9788 appeared to be devoid of toxicity at its effective doses. The mechanism of action of S 9788 is unknown but S 9788 (0.5-10 microM) induced a dose-dependent increase in ADR accumulation in KB-Al cells and compared to verapamil its effect was twice as active and approximately seven times more potent. We conclude that S 9788 is a novel agent capable of reversing MDR in vitro and in vivo, and whose pharmacological profile warrants its selection as a candidate drug for eventual assessment in the clinic.

Topics: Animals; Antineoplastic Agents; Cell Line; Doxorubicin; Drug Interactions; Flow Cytometry; Humans; Leukemia P388; Mice; Piperidines; Triazines; Vincristine

A new antibacterial antibiotic tetrazomine was found from the fermentation broth of an actinomycete strain which was isolated from beach sand collected at Chichijima, Ogasawara Islands, Tokyo, Japan. The strain Y-09194L, was identified as Saccharothrix mutabilis subsp. chichijimaensis subsp. nov. The antibiotic exhibited broad antimicrobial activity against Gram-positive and Gram-negative bacteria in vitro. It also exhibited strong cytotoxic activity against P388 leukemia cells and showed antitumor activity against P388 leukemia. The apparent molecular formula of tetrazomine was determined as C24H34N4O5. It has a rare structure which consists of six rings including piperidine, piperadine, oxazole, and pyrrolidine.

Topics: Actinomycetales; Animals; Anti-Bacterial Agents; Fermentation; Leukemia L1210; Leukemia P388; Microbial Sensitivity Tests; Piperidines