Synthesis, cytotoxic and antiviral activity of uracils containing 5-(1-hydroxy-2-haloethyl)- and 5-(1-methoxy-2-haloethyl) substituents.

5-(1-Hydroxy-2-haloethyl)- (4), 5-(1-methoxy-2-haloethyl)- (5) and 5-(1-hydroxy-2-methoxyethyl)uracils (6) (see Figure 2 for structures) were synthesized to investigate the effect of the C-5 substituents on cytotoxic and antiviral activity. The bromo compounds (4b and 5b) exhibited greater cytotoxic activity than the chloro or iodo analogues in the in vitro L1210 assay. Replacement of the hydroxyl substituent of 4b (bromo) and 4c (iodo) by a methoxyl substituent (5b-c), or substitution of their halogen substituents by methoxyl (providing 6) increased the potency. However, the cytotoxic activity of all the compounds was weak, the most active (6) producing a 45% decrease in cell survival at a concentration of 50 micrograms/ml, as compared with a 97% decrease when the reference standard (melphalan) was tested at 1 microgram/ml. They were inactive antiviral agents against herpes simplex virus type 1 (HSV-1) infected Vero cells at 10 micrograms/ml; in the same test, the reference standard (acyclovir) exhibited an ID50 of 0.01 micrograms/ml.

Synthesis of 5-[1-hydroxy(or methoxy)-2-bromo(or chloro)ethyl]-2'-deoxyuridines and related halohydrin analogues with antiviral and cytotoxic activity.

A series of new 5-(1-hydroxy-2-haloethyl)-2'-deoxyuridines (3, 6, 8) were synthesized in 60-70% yields by addition of HOX (X = Br, Cl, I) to the vinyl substituent of the respective 5-vinyl-2'-deoxyuridines (2, 5, 7). Treatment of 3a,b with methanolic sulfuric acid afforded the corresponding 5-(1-methoxy-2-haloethyl)-2'-(deoxyuridines (4a,b). The 5-(1-hydroxy-2-chloroethyl) (3b), 5-(1-methoxy-2-bromoethyl) (4a), 5-(1-hydroxy-2-bromo-2-(ethoxycarbonyl)ethyl) (6a), and 5-(1-hydroxy-2-iodo-2-(ethoxycarbonyl)ethyl) (6b) derivatives exhibited in vitro antiviral activity (ID50 = 0.1-1 microgram/mL range) against herpes simplex virus type 1 (HSV-1). 5-(1-Hydroxy-2-bromo-2-(ethoxycarbonyl)-ethyl)-2'-deoxyuridine (6a) was the most active cytotoxic agent in the in vitro L1210 screen exhibiting an ED50 of 11 micrograms/mL relative to melphalan (ED50 = 0.15 micrograms/mL).

Some pharmacological activities of novel adenine-related compounds isolated from a marine sponge Agelas mauritiana.

Agelasimine A and agelasimine B, two novel compounds related to adenine, have been isolated from the orange sponge, Agelas mauritiana, and have been tested for a variety of biological activities. Both compounds inhibited proliferation of cultured L1210 leukemia cells at nanomolar concentrations with accumulation in the G1 stage of the cell cycle. However, no prolongation of life was observed in mice bearing P388 leukemia treated with these compounds. In the rat isolated aorta, micromolar concentrations of agelasimines were very effective in inhibiting contractions elicited by potassium chloride but had little or no effect on responses for prostaglandin F2 alpha and had modest effects on the responses to noradrenaline and significant effects on 5-hydroxytryptamine. Agelsamines A and B appeared to be equipotent in causing relaxation in rabbit jejunum and bovine coronary artery, and they also inhibited nucleoside transport into rabbit erythrocytes in micromolar concentrations.

Synthesis and cytotoxic activity of pyridylthio, pyridylsulfinyl, and pyridylsulfonyl methyl acrylates.

Nineteen 2-pyridylthio (2), 2-pyridylsulfinyl (3) or 2-pyridylsulfonyl (4) derivatives of (Z)-methyl acrylate were synthesized in order to investigate the effect of the oxidation state of the sulfur atom, and the position and nature of pyridyl substituents on cytotoxic activity. Analogous sulfinyl and sulphonyl derivatives were equipotent, and more potent than analogous thio derivatives, in an vitro L1210 screen. In most cases, incorporation of nuclear trifluoromethyl and chloro substituents at various positions of the pyridyl ring of the sulfinyl derivatives (compounds 3b-3h) decreased activity relative to the unsubstituted sulfinyl 3a (ED50 0.43 micrograms/ml). Compounds 3b, 3d and 3i exhibited weak antineoplastic activity in an in vivo P388 screen at a dose of 5 mg/kg.

Synthesis and cytotoxic activity of tetrahydropyridylidene-2- and -4-sulfonamides.

1,2,3,4-Tetrahydropyridylidene-4-sulfonamides, 1,2,3,4-tetrahydropyridylidene-2-sulfonamides, and 1,2,3,6-tetrahydropyridylidene-2-sulfonamides, of structures 10, 12 and 14, respectively (given in Table I), were synthesized in order to investigate the effect of nuclear substituents and the position of the sulfonamido group on cytotoxicity. The relative potency order was 12 greater than 10 greater than 14. Compounds possessing an R1 CONEt2 substituent were more potent than those possessing a R1 CN substituent. The nature of the aryl(alkyl)-sulfonamido substituent was a determinant of activity, the relative potency order being 4-chlorophenyl greater than phenyl, 4-methoxy- or 4-nitrophenyl greater than methyl. 1-Methyl-4-tert-butyl-5-diethylaminocarbonyl-1,2,3,4-tetrahydro pyridylidene- 2-(4-chlorophenyl)sulfonamide (12c) was the most active cytotoxic agent, exhibiting an ED50 of 5.4 micrograms/ml in the L1210 in vitro screen.

Synthesis and cytotoxic activity of 1-(3-oxoprop-1-enyl)-2-pyridones.

1-(3-Oxoprop-1-enyl) derivatives of nuclear substituted 2-pyridones (7a-i), 2-pyridinethione (7j), 1-isoquinolone (9), and the 1,4-dihydropyridine (11) have been synthesized and tested for biological activity. The 2-pyridones (7) and the 1-isoquinolone (9) were all active cytotoxic agents as determined in the in vitro L1210 screen, exhibiting activity in the ED50 0.5-3.5 micrograms/ml range. The nature and position of nuclear substituents present in 7 and 9 did not alter activity significantly. The unsubstituted (7a) and 5-ethoxycarbonyl-2-pyridones (7g), and the 1-isoquinolone derivative (9) were active antineoplastic agents (%T/C = 133-135) in vivo exhibiting activity comparable to 5-fluorouracil.