mannich-bases and Leukemia-P388

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

Various Mannich bases of chalcones and related compounds displayed significant cytotoxicity toward murine P388 and L1210 leukemia cells as well as a number of human tumor cell lines. The most promising lead molecule was 21 that had the highest activity toward L1210 and human tumor cells. In addition, 21 exerted preferential toxicity to human tumor lines compared to transformed human T-lymphocytes. Other compounds of interest were 38, with a huge differential in cytotoxicity between P388 and L1210 cells, and 42, with a high therapeutic index when cytotoxicity to P388 cells and Molt 4/C8 T-lymphocytes were compared. In general, the Mannich bases were more cytotoxic than the corresponding chalcones toward L1210 but not P388 cells. A ClusCor analysis of the data obtained from the in vitro human tumor screen revealed that the mode of action of certain groups of compounds was similar. For some groups of compounds, cytotoxicity was correlated with the sigma, pi, or molar refractivity constants in the aryl ring attached to the olefinic group. In addition, the IC50 values in all three screens correlated with the redox potentials of a number of Mannich bases. X-ray crystallography and molecular modeling of representative compounds revealed various structural features which were considered to contribute to cytotoxicity. While a representative compound 15 was stable and unreactive toward glutathione (GSH) in buffer, the Mannich bases 15, 18, and 21 reacted with GSH in the presence of the pi isozyme of glutathione S-transferase, suggesting that thiol alkylation may be one mechanism by which cytotoxicity was exerted in vitro. Representative compounds were shown to be nonmutagenic in an intrachromosomal recombination assay in yeast, devoid of antimicrobial properties and possessing anticonvulsant and neurotoxic properties. Thus Mannich bases of chalcones represent a new group of cytotoxic agents of which 21 in particular serves as an useful prototypic molecule.

Topics: Animals; Antineoplastic Agents; Cell Division; Chalcone; Crystallography, X-Ray; Drug Screening Assays, Antitumor; Humans; Leukemia L1210; Leukemia P388; Mannich Bases; Mice; Structure-Activity Relationship; T-Lymphocytes; 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 number of Mannich bases of alicyclic ketones containing one and two basic centres were prepared in order to evaluate the theory of sequential cytotoxicity and develop structure-activity relationships in these series of compounds. The compounds were evaluated in vitro against murine P388 D1 lymphocytic leukemia cells. The data generated supported the theory of sequential cytotoxicity and in general, compounds containing alicyclic rings of five and six carbon atoms possessed greater activity than the corresponding dodecyl analogues. Those Mannich bases containing dialkylamino groups were associated with greater cytotoxicity than related compounds possessing a basic heterocycle. Calculations of the atomic charges of the enone groups from selected compounds afforded some rationalization for the cytotoxic screening results.

Topics: Animals; Antineoplastic Agents; Ketones; Leukemia P388; Mannich Bases; Mice; Models, Molecular

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

Topics: Animals; Antineoplastic Agents; Humans; Leukemia P388; Mannich Bases; Mice; Tumor Cells, Cultured

The preparation of phenyl-ring substituted 4-morpholino-1-phenylthio-2-butanones 4a-e is described. These compounds were evaluated against P-388 leukemia and human cancer rhinopharynx KB cells in vitro; some compounds were found to exhibit activity against these cell lines.

Topics: Animals; Antineoplastic Agents; Butanones; Drug Screening Assays, Antitumor; Humans; KB Cells; Leukemia P388; Mannich Bases; Mice; Spectrophotometry, Infrared

Topics: Amines; Animals; Antineoplastic Agents; Chemical Phenomena; Chemistry; Leukemia P388; Mannich Bases; Mice

A novel series of bis-Mannich bases have been synthesized and evaluated against P388 lymphocytic leukemia in mice. Two compounds showed a perceptible beneficial response in this screen and all the compounds displayed marked murine toxicity. A representative compound inhibited respiration in mitochondria isolated from rat and mouse liver cells by 90% approximately at a dose of 2.5 mumol and it caused a small elevation in mouse liver glutathione equivalent concentrations at 5 mg/kg.

Topics: Animals; Antineoplastic Agents; Glutathione; Leukemia P388; Leukemia, Experimental; Male; Mannich Bases; Mice; Rats; Structure-Activity Relationship; Styrenes

A novel series of 5-(2-oxo-3-indolinylidene)thiazolidine-2,4-dione, having the 1- and 3-positions of the isatin and thiazolidine rings respectively, substituted by various Mannich bases, was prepared. Five compounds were evaluated for antileukemic activity against P388 lymphocytic leukemia in the mouse. The di-Mannich base with a dimethylamino component exhibited the highest activity of the tested compounds. Introduction of bromine into the aromatic moiety of isatin ring (position 5) increased the activity of the parent molecule to a smaller extent.

Topics: Amines; Animals; Antineoplastic Agents; Chemical Phenomena; Chemistry; Leukemia P388; Leukemia, Experimental; Mannich Bases; Mice; Mice, Inbred C57BL

A number of analogues of 3-dimethylamino-2-dimethylaminomethyl-1-(4-methoxyphenyl)-1-propanone dihydrochloride (IIa) and related compounds which showed activity against P388 lymphocytic leukemia were prepared, and of the 16 analogues, three met the criterion for activity in this screen. The toxicity of IIa was examined in rats and either a single dose of 25 mg/kg or nine daily doses of 12.5 mg/kg administered by the intraperitoneal route produced marked irritation and damage to the tissue with which it came into contact. Compound IIa did not show significant activity against eight other tumor systems.

Topics: Acetophenones; Animals; Antineoplastic Agents; Body Weight; Leukemia P388; Leukemia, Experimental; Male; Mannich Bases; Mice; Propiophenones; Rats; Rats, Inbred Strains

Topics: Amines; Animals; Antineoplastic Agents; Boron Compounds; Chemical Phenomena; Chemistry; Leukemia P388; Mannich Bases; Mice; Tetracyclines

Series of 3-dimethylamino-1-aryl-1-propanone hydrobromides (IV) and 3-dimethylamino-2-dimethylaminomethyl-1-aryl-1-propanone dihydrobromides (V) were synthesized. Evaluation of these derivatives against P-388 lymphocytic leukemia growth revealed that two compounds show promise as antineoplastic agents. Compounds of the V series were unstable in phosphate buffer (in contrast to series IV), and when the same nuclear substituent was present in both series of compounds, V was approximately 100 times more active than IV in both the stimulation and inhibition of respiration of mitochondria isolated from rat liver cells. Representatives from both series showed that respiration in mitochondria was affected by changing the pH of the aqueous buffer from 7.4 to 6.9 or 6.4 and by reducing the temperature from 37 degrees to 20 degrees. The compounds showed reactivity toward a biomimetic thiol.

Topics: Acetophenones; Animals; Antineoplastic Agents; Chemical Phenomena; Chemistry; Drug Stability; Female; In Vitro Techniques; Leukemia P388; Male; Mannich Bases; Mice; Mitochondria, Liver; Oxygen Consumption; Rats; Rats, Inbred Strains