Synthesis and biological activities of chloroethylurea, methylurea, and nitrosourea analogues of N-deacetylmethylthiocolchicine.

A series of urea and nitrosourea analogues of N-deacetylmethylthiocolchicine (1) has been synthesized, and their antineoplastic and antiviral activities were evaluated. The objective for combination of two active moieties, such as thiocolchicine and nitrosourea, into one molecule was the generation of compounds with potential improved biological and pharmacological properties. The ED50 for 2, 3, 4, and 5 was 1.6, 1.2, 3.3, and 1.8 X 10(-8) M for L1210 cells and 3.0, 2.7, 2.9, and 2.6 X 10(-8) M for S-180 cells, respectively. The synthesis and cytotoxic and antiviral properties of these compounds are discussed.

Preparation and anticoagulant activity of trimethylsilyl heparin in Carbowax.

Trimethylsilyl heparin, when administered intraduodenally or intragastrically to rats, did not increase intestinal absorption and, consequently, the clotting times were not influenced. However, suspension of sodium heparin in Carbowax 200 prolonged the whole blood clotting time at a dose of 50 mg/kg when given intraduodenally or intragastrically to rats.

4-amino-6-(trichloroethenyl)-1,3-benzenedisulfonamide, a new, potent fasciolicide.

The synthesis and fasciolicidal activity of 4-amino-6-(trichloroethenyl)-1,3-benzenedisulfonamide are reported. A single dose of 15 mg/kg was effective in removing over 90% of immature Fasciola hepatica from sheep (6 weeks after infection) and calves (8 weeks after infection). A 2.5 mg/kg dose removed over 90% of mature (16 weeks old) liver fluke from sheep. Single oral doses up to 400 mg/kg were tolerated by sheep without gross toxic symptoms.

Alkylthiocolchicines and N-deacetyl-alkylthiocolchicines and their antileukemic activity.

A series of alkylthiocolchcines (methyl, ethyl, n-butyl, n-hexy, n-octyl, and pinanyl) was prepared from colchicine by treatment with the appropriate alkyl mercaptan and p-toluenesulfonic acid. Some of these compounds (methyl-, ethyl-, and n-butylthiocolchicines) were deacetylated in good yields with 2 N hydrochloric acid in methanol. These compounds were tested for their antileukemic activity in an in vitro assay against L-1210 (mouse leukemia). Preliminary results showed that methylthiocolchicine is more active and the other alkylthiocolchicines are much less active than colchicine. N-Deacetyl-methylthiocolchicine is as active as colchicine.

Synthesis and evaluation of N-deacetyl-N-glycosylalkylthiocolchicines as antileukemic agents.

A series of N-deacetyl-N-glycosylalkylthiocolchicines (glucosyl, galactosyl, mannosyl, ribosyl, and arabinosyl) was prepared by heating N-deacetylalkylthiocolchicines with the appropriate monosaccharides in methanol. Some compounds (glucosyl-, mannosyl-, and ribosylalkylthiocolchicines) were per-O-acetylated in dry pyridine with acetic anhydride. The compounds were tested against leukemia L-1210 and P-388 systems. Preliminary results showed that the antileukemic activity of the glycosyl compounds in vitro is similar to that of the N-deacetylalkylthiocolchicines used for their preparation. However, the presence of a glycosyl moiety in the molecule gives the advantage of greater solubility in water. Of the results obtained to date in lymphoid leukemia screening in vivo, five glycosyl compounds showed promising activity levels and have now reached confirmed active status.

Supra-additive toxic interaction of nicotine with antihistamines, and enhancement by the proconvulsant pentylenetetrazole.

Antihistamines are being increasingly administered in combination with various other agents, with adverse drug reactions the frequent result. The present study consisted of two experiments. Experiment 1 examined the toxicological response of rats to nicotine tartrate (0.0, 2.0, 4.0, and 8.0 mg/kg) in combination with either of two H1-histamine receptor antagonists, the ethylene diamine tripelennamine HCl (0.0, 16.0, 32.0, and 64.0 mg/kg) or the aminoethyl ether diphenhydramine HCl (0.0, 32.0, 64.0, and 96.0 mg/kg). Adult female rats received intraperitoneal injections when housed 12 per cage and toxicological response (number dead per group) was assessed 24 hours post-treatment. The results showed that over the dose ranges employed, and when given alone, nicotine was completely non-lethal, tripelennamine was virtually non-lethal and diphenhydramine was toxic only at the highest dose (5 of 12, at 96.0 mg/kg). However, when nicotine and the antihistamines were delivered in combinations, the toxicological response was markedly altered. Tripelennamine in combination with nicotine yielded supra-additive interaction, with the degree of potentiation being a simple linear function of nicotine within each dose of tripelennamine. The interaction between nicotine and diphenhydramine was more complicated, with certain dose combinations yielding supra-additivity, yet with others yielding antagonism. It was suggested that seizure-precipitated cardiopulmonary collapse was the immediate cause of death, plausibly mediated by central mechanisms. As such, Experiment 2 examined the influence of adding the proconvulsant pentylenetetrazole (PTZ) (0.0, 10.0, and 20.0 mg/kg) to nicotine (0.0, 2.0, 4.0, and 8.0 mg/kg)-tripelennamine (0.0 and 32.0 mg/kg) combination treatments. Effects were assessed both at 1.0 and 24.0 hours post-injection.(ABSTRACT TRUNCATED AT 250 WORDS)