A series of chalcones was evaluated as antimitotic agents. One of these, (E)-1-(2,5-dimethoxyphenyl)-3-[4-(dimethylamino)phenyl]-2-methyl-2-pr open- 1-one) (73), was found to be an effective antimitotic agent at a concentration of 4 nM in an in vitro HeLa cell test system. When evaluated in experimental tumor models in vivo, this compound exhibited antitumor activity against L1210 leukemia and B16 melanoma.

A number of bis(benzyl)polyamine analogs were found to be potent inhibitors ofboth chloroquine-resistant and chloroquine-sensitive strains of the human malaria parasite Plasmodiumfalciparum in vitro (IC50 values = 0.2-14MM).Administration of one of the compounds, MDL 27695, which is N,N'-bis{3-[(phenylmethyl)aminolpropyl}-1,7-diaminoheptane (C6H5CH2NH(CH2)3NH(CH2)7NH(CH2)3NHCH2C6HS), at 10-15 mg/kg i.p. three times per day for 3 days in combination with 2% x-difluoromethylornithine (DFMO; eflornithine) (1). Radical departure from the chemical classes of compounds effective in the past is needed to circumvent the problems of cross-resistance between drugs. We have studied an approach to the chemotherapy of malaria that involves the disruption of the biosynthesis and/or intracellular function of the polyamines-putrescine, spermidine, and spermine.The polyamines are important regulators of growth and differentiation in a wide variety of cell types including parasitic protozoa (2). a-Difluoromethylomithine (DFMO; eflornithine), an irreversible inhibitor of the first enzyme in polyamine biosynthesis, ornithine decarboxylase, inhibits the proliferation of a number of human-infective parasites, including P. falciparum (3,4). We have recently shown that DFMO also inhibits the growth of Plasmodium berghei in mice but does not cure these infections (5).Another approach to interference with polyamine biosynthesis and function, which has been applied successfully in cancer cells (6), takes advantage of the ability of the natural polyamines (7,8) and nonphysiological polyamine analogs (9, 10) to suppress ornithine decarboxylase activity in the cell and also possibly to block the intracellular function of the natural polyamines by displacing them from critical binding sites, such as appear to be present on DNA (11). In this approach, it is preferred that the polyamine analogs not subserve the normal physiological roles of putrescine, spermidine, and spermine, because then they would simply replace the natural polyamines and growth inhibition would not occur. We now report on a series of bis(benzyl)polyamine analogs that have marked antimalarial activity against both chloroquine-sensitive and chloroquine-resistant P. falciparum in vitro and, when administered in combination with DFMO, cure murine malaria. Trager and Jensen (14). Maintenance cultures, in 25-cm2 flasks at 370C, contained a 6% suspension of human (type 0+) erythrocytes in RPMI 1640 medium supplemented with 10% human serum, 25 mM Hepes, and 0.2% NaHCO3 with a gaseous phase of 90% N2/5% 02/5% CO2. Cultures were fed daily with fresh medium and were subcultured twice weekly by 10-to 20-fold dilutions with fresh human erythrocytes. MATERIALS AND METHODSMicrotiter Cultures for Drug Testing. Drug testing in vitro was carried out using standard procedures (15). In the 96-well microtiter cultures P.falciparum (FCR-3/Gambia strain) was at a starting parasitemia of =0.5% in a 1% suspension of erythrocytes in a total volume of 0.2 ml. Test compounds were dissolve...

The synthesis of a series of novel polyamine analogues is reported. The DNA binding of these compounds and a variety of other polyamines were compared with their IC50 values against HeLa cell. There seemed to be no apparent correlation between the DNA binding and toxicity against HeLa cells.

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A series of tetraamines derived from 1,8-diaminooctane was prepared and tested as antitumor agents. The reaction of 1,8-diaminooctane with acrylonitrile gave N,N'-bis(cyanoethyl)-1,8-diaminooctane, which was reduced to tetraamine 20. Alkylation of the terminal nitrogen atoms of the tetra-Boc derivative of this compound by methyl or ethyl halide followed by removal of the Boc groups gave the bis(alkyl)polyamines 26a and 26b, respectively. These three compounds exhibit promising antitumor activity in the mouse L1210 leukemia model. Coadministration of a polyamine oxidase inhibitor potentiated the antitumor activity.