Multiparameter toxicity assessment of novel DOPO-derived organophosphorus flame retardants.

Halogen-free organophosphorus flame retardants are considered as replacements for the phased-out class of polybrominated diphenyl ethers (PBDEs). However, toxicological information on new flame retardants is still limited. Based on their excellent flame retardation potential, we have selected three novel 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide (DOPO) derivatives and assessed their toxicological profile using a battery of in vitro test systems in order to provide toxicological information before their large-scale production and use. PBDE-99, applied as a reference compound, exhibited distinct neuro-selective cytotoxicity at concentrations ≥10 µM. 6-(2-((6-oxido-6H-dibenzo[c,e][1,2]oxaphosphinin-6-yl)amino)ethoxy)-6H-dibenzo[c,e][1,2]oxaphosphinine 6-oxide (ETA-DOPO) and 6,6'-(ethane-1,2-diylbis(oxy))bis(6H-dibenzo[c,e][1,2]oxaphosphinine-6-oxide) (EG-DOPO) displayed adverse effects at concentrations >10 µM in test systems reflecting the properties of human central and peripheral nervous system neurons, as well as in a set of non-neuronal cell types. DOPO and its derivative 6,6'-(ethane-1,2-diylbis(azanediyl))bis(6H-dibenzo[c,e][1,2]oxaphosphinine-6-oxide) (EDA-DOPO) were neither neurotoxic, nor did they exhibit an influence on neural crest cell migration, or on the integrity of human skin equivalents. The two compounds furthermore displayed no inflammatory activation potential, nor did they affect algae growth or daphnia viability at concentrations ≤400 µM. Based on the superior flame retardation properties, biophysical features suited for use in polyurethane foams, and low cytotoxicity of EDA-DOPO, our results suggest that it is a candidate for the replacement of currently applied flame retardants.

2'-deoxy-2'-α-fluoro-2'-ß-C-methyl 3',5'-cyclic phosphate nucleotide prodrug analogs as inhibitors of HCV NS5B polymerase: discovery of PSI-352938.

A series of novel 2'-deoxy-2'-α-fluoro-2'-ß-C-methyl 3',5'-cyclic phosphate nucleotide prodrug analogs were synthesized and evaluated for their in vitro anti-HCV activity and safety. These prodrugs demonstrated a 10-100-fold greater potency than the parent nucleoside in a cell-based replicon assay due to higher cellular triphosphate levels. Our structure-activity relationship (SAR) studies provided compounds that gave high levels of active triphosphate in rat liver when administered orally to rats. These studies ultimately led to the selection of the clinical development candidate 24a (PSI-352938).

Preparation and characterization of novel 4-bromo-3,4-dimethyl-1-phenyl-2-phospholene 1-oxide and the analogous phosphorus heterocycles or phospha sugars.

4-Bromo-3,4-dimethyl-1-phenyl-2-phospholene 1-oxide (3c) was first synthesized from 3,4-dimethyl-1-phenyl-2-phospholene 1-oxide (2c) by a bromo-radical substitution reaction occurred at C-4 position by N-bromosuccinimide and 2,2'-azobisisobutyronitrile. The novel phospha sugar analogue 3c exerted high anti-proliferative effect on U937 cells evaluated by MTT in vitro methods and was much more efficient than that of Gleevec, which is known as a molecule targeting chemotherapeutical agent. The substitution of 2-phospholenes at C-3 and C-4 position with methyl groups as well as 4-bromo substituent suggests a good anti-proliferative effect.

Potent anti-murine cytomegalovirus activity and reduced nephrotoxicity of ganciclovir cyclic phosphonate.

Ganciclovir cyclic phosphonate (SR3775) is a derivative of the R enantiomer (SR3773) of ganciclovir phosphonate (9-[((+/-)-1-hydroxymethyl-3-phosphono)propyloxymethyl]guanine), both of which are potent inhibitors of human ctyomegalovirus and murine cytomegalovirus (MCMV). Against wild-type and four drug-resistant strains of MCMV, SR3773 was 2.3- to 3-fold more potent than SR3775. SR3775 was about half as active as SR3773 against MCMV infections in severe combined immunodeficient mice. However, whereas SR3773 caused 20 to 30% destruction of renal tubules at 50 mg/kg of body weight per day (but exerted no toxicity at 25 mg/kg/day), SR3775 showed no deleterious renal effects at 600 mg/kg/day over 14 days. SR3775 has a therapeutic index at least 12 times higher than SR3773 in mice, making it a candidate for the treatment of human cytomegalovirus disease.

Neuropathy target esterase inhibitors: 2-alkyl-, 2-alkoxy-, and 2-(aryloxy)-4H-1,3,2-benzodioxaphosphorin 2-oxides.

The standard probes used earlier to study neuropathy target esterase (NTE) are N,N'-diisopropyl phosphorofluorodiamidate (mipafox), diisopropyl phosphorofluoridate (DFP), 2-(2-methylphenoxy)-4H-1,3,2-benzodioxaphosphorin 2-oxide (2-CH3C6H4O-BDPO) (the neurotoxic metabolite of tri-o-cresyl phosphate), and dipentyl 2,2-dichlorovinyl phosphate (DDP) with I50s for hen brain enzyme of 7000, 700, 29, and 3 nM, respectively. NTE phosphorylated by DFP and DDP is proposed to undergo alkylation on aging, and this probably also occurs with 2-CH3C6H4O-BDPO. Optimized probes for NTE should meet the following specifications: highest potency achievable; rapid aging perhaps associated with alkylation; preferably a phosphonate so there are only two leaving groups. An attempt was made to achieve these goals in the 4H-1,3,2-benzodioxaphosphorin 2-oxide series by synthesis of 49 analogs systematically varied in the 2-alkyl, 2-alkoxy, or 2-(aryloxy) substituent. Special precautions are required in synthesis of BDPO derivatives because of their potential hazard on human exposure. Thirty of these compounds had NTE I50s lower than 3 nM. Representative high-potency NTE inhibitors in each series are [2-substituent,I50 (nM) for hen and human brain NTE, respectively]: octyl, 0.25 and 0.18; nonyloxy, 0.89 and 0.98; 4-propylphenoxy, 0.82 and 0.77. In comparing these compounds, although the octyl analog is the most potent in vitro NTE inhibitor, the propylphenoxy compound is the most effective in vivo NTE inhibitor and delayed neurotoxicant in hens. These benzodioxaphosphorins are improved probes for investigations on NTE phosphorylation and alkylation in relation to delayed neurotoxicity.

[Toxicity and antitumor activity of the antibiotic rubomycin and dipin in combination with diuretics (diacarb)]. / Toksichnost' i protivoopukholevaia aktivnost' antibiotika rubomitsina i dipina pri sochetanii ikh s diuretikami (diakarbom)

Rubomycin or dipin in combination with diacarb had higher toxicity and antitumor activity as compared to administration of the cytostatic agents alone to mice with transplanted lymphosarcoma, strain L10-1. The chemotherapeutic indices of the combinations did not differ or were somewhat lower as compared to the same indices of the cytostatic agents used alone.

Extreme toxicity from combustion products of a fire-retarded polyurethane foam.

The products from nonflaming combustion of wood and a trimethylol-propane-based rigid-urethane foam that was not fire-retarded produced elevated carboxyhemoglobin levels but no abnormal neurological effects. However, when this type of foam contained a reactive phosphate fire retardant, the combustion products caused grand mal seizures and death in rats. The toxic combustion product responsible for the seizures has been identified as 4-ethyl-1-phospha-2,6,7-trioxabicyclo(2.2.2.)octane-1-oxide.

Bicyclic phosphorus esters: high toxicity without cholinesterase inhibition.

4-Isopropyl-2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane 1-oxide has a mouse intraperitoneal lethal dose, 50 percent effective, of 0.18 milligram per kilogram of body weight. Related compounds used by many chemical researchers are also highly toxic. Brain acetylcholinesterase inhibition is not involved in their mode of action. The structural similarity of these compounds to adenosine 3',5'-monophosphate (cyclic AMP) is of interest.