In vitro dermal absorption of flame retardant chemicals.

Flame retardant chemicals may be used in furniture fabric in the future to reduce the flammability of the fabric. As a part of the process to evaluate the potential for exposure to these chemicals, this study examined the in vitro dermal absorption of two flame retardant chemicals. The chemicals were [14C]decabromodiphenyl oxide (DBDPO) and [14C]tris-(1,3-dichloro-2-propyl)phosphate (TDCP). Skin from the adult hairless female mouse (SKH1) was removed and mounted in flow-through diffusion cells. The chemicals, at three dose levels (DBDPO: 6, 30 and 60 nmol; TDCP: 20, 100 and 200 pmol), were applied in a volatile vehicle (tetrahydrofuran for DBDPO; acetone for TDCP) to the skin. Fractions of receptor fluid, pumped below the skin, were collected over a 24-h period. The skin was washed with solvent (tetrahydrofuran for DBDPO; ethanol for TDCP) to remove unabsorbed chemical 24 h after application. The receptor fluid, skin wash and skin were analyzed for chemical-derived radioactivity. The skin from the high-dose group of both chemicals, and the receptor fluid from TDCP high-dose samples, were analyzed for parent compound and metabolites by HPLC. The 24-h cumulative percent of the dose of DBDPO in the receptor fluid was very low (0.07-0.34%). The applied dose of DBDPO detected in the skin ranged from 2 to 20%. The lowest dose of DBDPO had the highest percentage of the dose (20%) in the skin. The major portion of the applied dose was removed by washing the skin 24 h after application of DBDPO, and ranged from 77 to 92%. HPLC analysis of homogenate extract prepared from the high-dose of DBDPO-treated skin showed the presence of DBDPO and a minor unknown peak. TDCP was readily detected in the receptor fluid; 39-57% of the applied dose of TDCP was in the receptor fluid by 24 h. The solvent wash removed 11-25% of the dose from the skin and 28-35% remained in it. HPLC analysis of the skin homogenate extract and receptor fluid extract from the TDCP high-dose treated samples showed the presence of parent compound and a minor unknown peak. TDCP more readily penetrated hairless mouse skin and diffused into the receptor fluid than DBDPO. TDCP has a lower molecular weight and log octanol:water partition coefficient than DBDPO. The differences in the physico-chemical properties of these two chemicals most likely explains their dissimilar absorption through hairless mouse skin.

Interferon induction by mismatched analogues of polyinosinic acid . polycytidylic acid [(Ix,U)n.(C)n].

Interruption of the (I)n strand of (I)n.(C)n by unpaired bases [(U)] yielded mismatched analogues, (Ix,U)n.(C)n which were still effective as inducers of interferon, provided the I:U ratio (x) was equal or greater than 10. In highly sensitive interferon-induction systems such as primary rabbit kidney cells and human skin fibroblasts superinduced with cycloheximide and actinomycin D, (I10,U)n.(C)n and (I50,U)n.(C)n proved nearly as active as (I)n.(C)n. By virtue of their increased susceptibility to degradation by nucleases, (Ix,U)n.(C)n complexes with 10 less than or equal to x less than or equal to 50 may be expected not to persist as long in biological fluids as (I)n.(C)n, hence to induce fewer side effects.

Improved synthesis and in vitro antiviral activities of 5-cyanouridine and 5-cyano-2'-deoxyuridine.

In order to evaluate the influence of the cyano group on the antiviral activity of pyrimidine deoxyribonucleosides, a moderate yield, unified approach to the synthesis of both 5-cyanouridine and 5-cyano-2'-deoxyuridine was developed. Thus, treatment of the appropriate acetylated 5-bromouracil nucleoside with NaCN or KCN in Me2SO at 90-110 degrees C gave, after deblocking, 35-45% yields of the corresponding 5-cyanouracil nucleosides. 5-Cyanouridine was devoid of significant activity against vaccinia virus, herpes simplex-1, and vesicular stomatitis virus, but 5-cyano-2'-deoxyuridine, while lacking activity against herpes simplex, showed significant inhibition of vaccina virus; for instance, 5-cyano-2'-deoxyuridine inhibited vaccinia virus replication at concentrations 10-20 times that required for inhibition by the known antivirals, 5-iodo-2'-deoxyuridine and 1-(beta-D-arabinofuranosyl)adenine. Replacement of the 5-halogeno substituents of pyrimidine deoxyribonucleosides thus decreases, but does not abolish, antiviral activity.

Novel heterocyclic nitrofurfural hydrazones. In vivo antirypanosomal activity.

Hydrazine derivatives of several pyrazolo[1,5-alpha]pyrimidines (A), pyrazolo[1,5-alpha]-1,3,5-triazines (B), s-triazolo[1,5-alpha]pyrimidines (C), and imidazo[1,2-alpha]pyrimidines (D) were synthesized and condensed with 5-nitrofurfural in order to obtain the corresponding nitrofurfural hydrazones of each heterocycle (1d-14d). Each compound was screened for in vitro activity against Trypanosoma cruzi. The compounds were then tested in vivo against experimental infections of T. cruzi in laboratory (C3H/He strain) mice. An interesting structure-activity relationship was uncovered, revealing that 5-methyl-7-(5-nitrofurfurylidenehydrazino)pyrazolo[1,5-alpha]pyrimidine (2d) greatly increased the mean survival time (IMST) of mice with terminal infections. Subtle alterations in the structure of 2d, such as the substitution of a 5-hydrogen for the 5-methyl group (1d) or the substitution of the 3-hydrogen by the water-soluble 3-sulfonic acid (3d) or 3-sodium sulfonate (4d), resulted in a drastic loss of in vivo and in vitro activity.