Effect of organic mercury on the electrical resistance of phosphatidylserine bilayers.

Acidic phospholipids have been shown to form complexes with methyl mercury chloride, at physiological pH, in vitro. To check if this interaction had any effect on the physical properties of membranes made with these lipids, the specific resistance of phosphatidylserine bilayers was monitored, as a function of time, in the absence and in the presence of methyl mercury chloride in the bathing solution. While the resistance of the bilayer remained constant in the absence of the toxic, it dropped an average of 17% in four hours in the presence of 100 microM methyl mercury chloride. Such observations suggest that the physical integrity of these membranes is modified by the interaction with organic mercury. This result may be relevant to the observed degeneration of nerve membranes in Minamata disease.

In vitro and in vivo activity of 1-aryl-3-(2-chloroethyl) urea derivatives as new antineoplastic agents.

A few 1-aryl 3-(2-chloroethyl)ureas (CEU) were synthesized and screened in vitro for their cytotoxicity. Some of these derivatives were assayed for their mutagenicity, their in vivo toxicity and their antineoplastic activity. Methyl 4-(p-(3-(2-chloroethyl) ureido) phenyl) butyrate, 4-methyl and 4-tertbutyl (3-(2-chloroethyl) ureido) phenyl) butyrate, 4-methyl and 4-tert-butyl (3-(2-chloroethyl) ureido) benzene had an ID50 of 28, 20 and 4 microM respectively when tested on LoVo cells, while chlorambucil (CBL) and CCNU had an ID50 of 21 and 45 microM. These 3 chloroethyl urea derivatives were not toxic when injected i.p. at doses up to 220 mg/kg, whereas chlorambucil was already toxic at 18.5 mg/kg. The survival time of BDF1 mice bearing L1210 leukemia tumors was significantly enhanced by intraperitoneal injections of CBL and CEU. The most cytotoxic derivative (tert-butyl derivative) gave the best antineoplastic activity with a median survival time 1.77 times that of the control at 10 mg/kg/day and was not toxic, whereas CBL at this concentration enhanced survival time by a factor of 1.6 and presented important side effects. The 4-tert-butyl (3-(2-chloroethyl) ureido) benzene and the methyl 4-(p-(3-(2-chloroethyl) ureido) phenyl) butyrate showed no mutagenicity when assayed on TA-97, TA-98, TA-100 and TA-102, four strains of S. thyphimurium, while CBL had a weak effect on TA-102 and CCNU was highly mutagenic on TA-100 and TA-102.

1-Aryl-3-(2-chloroethyl) ureas: synthesis and in vitro assay as potential anticancer agents.

1-Aryl-3-(2-chloroethyl) ureas and 1-aryl-3-nitroso-3-(2-chloroethyl) ureas, derived from 4-phenylbutyric acid and alkylanilines, were synthesized and their cytotoxicity was evaluated on human adenocarcinoma cells in vitro. Methyl 4-[p-[3-(2-chloroethyl)ureido]-phenyl]butyrate, 4-methyl [3-(2-chloroethyl)ureido]benzene, and 4-butyl[3-(2-chloroethyl)ureido]benzene were found to be at least as cytotoxic as 4-[p-[bis-(2-chloroethyl)amino]phenyl]butyric acid (chlorambucil), while their N-nitroso derivatives were inactive.

Fluorescence determination of microconcentrations of chlorambucil after photoactivation.

A fluorescence assay is described which measures the alkylating activity of chlorambucil or its isocyanate derivative after photoactivation in the presence of dimethyl sulfoxide. This assay has a lower limit of sensitivity of 100 ng/mL and RSD of less than 10% for chlorambucil. The method requires less than 5 micrograms of alkylating agent and the fluorophore produced is stable for at least 24 h.