ABSTRACT
Design, synthesis and cytotoxicity of several known and novel biurets against human breast cancer T47D cell line in comparison to doxorubicin are described. Biurets incorporating 2-methyl quinoline-4-yl and benzo[d]thiazol-2-ylthio moieties showed higher cytotoxicity and decreased cell viability in a concentration- and time-dependent manner.
Subject(s)
Antineoplastic Agents/chemical synthesis , Biuret/chemistry , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/toxicity , Biuret/therapeutic use , Biuret/toxicity , Breast Neoplasms/drug therapy , Cell Line, Tumor , Female , Humans , Structure-Activity RelationshipABSTRACT
The aliphatic diisocyanate monomer 1,6-hexamethylene diisocyanate (HDI) is used as a building block for non-volatile polycondensation products, such as HDI-isocyanurate (HDI-IC) and HDI-biuret (HDI-BT). This paper describes the results from acute inhalation studies with these types of polyisocyanate aerosols in OF1 and C57BL/6J mice and in Wistar rats. The modifying role of different concentrations of residual HDI in HDI-BT on pulmonary irritation was also addressed. These data close data gaps for acute mouse inhalation studies in direct comparison with rats. The sensory irritant potency was examined in OF1 mice during a 3h nose-only exposure to the polyisocyanate aerosols. Concurrent with exposure, breathing patterns suitable to distinguish upper/lower respiratory tract irritation where examined. Functional measurements in barometric plethysmographs (Penh) addressed changes in respiratory function in C57BL/6J mice exposed for 6h up to 16h postexposure. These measurements revealed that these polyisocyanates elicit changes slow in onset suggestive of pulmonary irritation rather than upper airway irritation. This conclusion was supported by similarly exposed OF1 mice exposed to non-irritant, surface active respirable particles of amorphous silica. In C57BL/6J mice and Wistar rats, nose-only exposed for 6h to 10mg/m(3) of aerosolized HDI-BT HDI (0.1% or 2% residual HDI), the pulmonary irritation potency was comparatively assessed by bronchoalveolar lavage (BAL) on postexposure day 1. Similarly air-exposed animals served as concurrent controls. Most changes in BAL suggestive of acute pulmonary irritation were more pronounced in Wistar rats than in C57BL/6J mice. A conclusive dependence of BAL endpoints on the residual content of residual HDI monomer in the polyisocyanate was not found. The results of this study show that mice may be particularly suitable to functionally analyze at which location of the respiratory tract predominant irritation may occur. However, with regard to analysis of lower respiratory tract irritation, rats were demonstrated to be more susceptible than mice. In summary, this study supports the conclusion that data from rat inhalation studies with these types of isocyanates appear to be more conservative and less variable than the respective data from mice.
Subject(s)
Biuret/toxicity , Cyanates/toxicity , Irritants/toxicity , Polyurethanes/toxicity , Respiratory Distress Syndrome/chemically induced , Administration, Inhalation , Aerosols , Animals , Biuret/chemistry , Bronchoalveolar Lavage , Cyanates/chemistry , Drug Residues/chemistry , Drug Residues/toxicity , Inhalation Exposure , Irritants/chemistry , Isocyanates , Male , Mice , Mice, Inbred C57BL , Plethysmography , Polyurethanes/chemistry , Rats , Rats, Wistar , Species Specificity , Time Factors , Toxicity Tests, AcuteABSTRACT
Teratogenicity of 1,1,3-trimethyl-5-phenylbiuret (ST-281), a new anti-rheumatic agent, was evaluated in rabbits. ST-281 at doses of 0, 50, 100, 200 and 400 mg/kg/day were administered orally to pregnant NZW rabbits from day 6 to day 18 of pregnancy. Body weight and food consumption at the administration and the subsequent periods were significantly decreased in 400 mg/kg/day group, and 5 dams (41.7%) affected severely were dead. No remarkable changes were investigated in findings at near-term caesarean section in any dosed group including 400 mg/kg/day. In visceral and skeletal examinations, no significant increase in incidence of abnormal fetuses were observed. This report suggests that ST-281 has no embryotoxicity or teratogenicity in rabbits.
