Toxicity of selected tremorgenic mycotoxins and related compounds to Spodoptera frugiperda and Heliothis zea

A series of tremorgenic mycotoxins and related compounds were tested for oral toxicity to the fall armyworm (Spodoptera frugiperda) and corn earworm (Heliothis zea) by incorporation of materials into artificial diets and examining mortality and weights after 7 days. Significant mortality to both insect species was caused with dihydroxyaflavinine and roseotoxin B, while significant mortality to H. zea was also caused by penitrem A at 25 ppm. After 7 days, weighs of larvae treated with 25 ppm penitrem A, roseotoxin B, and verruculogen were less than 50% of controls for both insect species. Weights of H. zea larvae treated with 25 ppb of penitrem A were less than 50% those of control larvae. Relative toxicities of the tremorgens and related compounds to insects compared to vertebrates are discussed.     

Toxicity of platinum compounds

Since the introduction of platinum-based combination chemotherapy, particularly cisplatin, the outcome of the treatment of many solid tumours has changed. The leading platinum compounds in cancer chemotherapy are cisplatin, carboplatin and oxaliplatin. They share some structural similarities; however, there are marked differences between them in therapeutic use, pharmacokinetics and adverse effects profiles [1-4]. Compared to cisplatin, carboplatin has inferior efficacy in germ-cell tumour, head and neck cancer and bladder and oesophageal carcinoma, whereas both drugs seem to have comparable efficacy in advanced non-small cell and small cell lung cancer as well as ovarian cancer [5-7]. Oxaliplatin belongs to the group of diaminocyclohexane platinum compounds. It is the first platinum-based drug that has marked efficacy in colorectal cancer when given in combination with 5-fluorouracil and folinic acid [8,9]. Other platinum compounds such as oral JM216, ZD0473, BBR3464 and SPI-77, which is a pegylated liposomal formulation of cisplatin, are still under investigation [10-13], whereas nedaplatin has been approved in Japan for the treatment of non-small cell lung cancer and other solid tumours. This review focuses on cisplatin, carboplatin and oxaliplatin.     

Toxicity of epoxy fatty acids and related compounds to cells expressing human soluble epoxide hydrolase

Soluble epoxide hydrolase (sEH) is suggested to alter the mode of action and increase the toxic potency of fatty acid epoxides. To characterize the structural features necessary for sEH-dependent epoxy fatty acid toxicity, 75 aliphatic compounds were assayed for cytotoxicity in the presence and absence of sEH. Three groups of aliphatic epoxide-diol pairs were described by their observed differential toxicity. Group I compounds were typified by terminal epoxides whose toxicity was reduced in the presence of sEH. Group II compounds were toxic in either their epoxide or diol form, but toxicity was unaffected by sEH. Group III compounds exhibited sEH-dependent toxicity and were therefore used to investigate the structural elements required for cytotoxicity in this study. The optimal structure for group III compounds appeared to be a fatty acid 18-20 atoms long (e.g., a carbon backbone plus a terminal heteroatom) with an epoxide positioned between C-7 and C-12. In the absence of sEH, replacement of epoxides with a vicinal diol was required for toxicity. While diol stereochemistry was unimportant, vicinal diol-induced toxicity exhibited fewer positional constraints to toxicity than sEH-dependent epoxide toxicity. Tested fatty acids and esters with neither an epoxide nor a vicinal diol were not toxic. These data support the hypothesis that long-chain epoxy fatty acid methyl esters are potential pro-toxins metabolized by sEH to more toxic diols. Furthermore, our results suggest that the endogenous compounds, leukotoxin methyl ester, 9,10(Z)-epoxyoctadec-12(Z)-enoic acid methyl ester, and isoleukotoxin methyl ester, 12, 13(Z)-epoxyoctadec-9(Z)-enoic acid methyl ester, are structurally optimized to elicit the observed effect.     

Toxicity and carcinogenicity of nickel compounds

The toxicity and carcinogenicity of nickel compounds are considered in three broad categories: (1) systemic toxicology, (2) molecular toxicology, and (3) carcinogenicity. The systemic toxicity of nickel compounds is examined based upon human and animal studies. The major organs affected are discussed in three categories: (1) kidney, (2) immune system, and (3) other organs. The second area of concentration is molecular toxicology, which will include a discussion of the chemistry of nickel, its binding to small and large molecular weight ligands, and, finally, its cellular effects. The third major area involves a discussion of the carcinogenicity and genotoxicity of nickel compounds. This section focuses on mechanisms, using studies conducted in vivo and in vitro. It also includes a discussion of the assessment of the carcinogenicity of nickel compounds.     

Toxicity and carcinogenicity of chromium compounds in humans

Chromium is a human carcinogen primarily by inhalation exposure in occupational settings. Although lung cancer has been established as a consequence of hexavalent chromium exposure in smokers and nonsmokers, some cancers of other tissues of the gastrointestinal and central nervous systems have also been noted. Except for a few reports from China, little is known about the health risks of environmental exposures to chromium. Likewise, there has been a lack of epidemiological studies of human exposure to hexavalent Cr by drinking water or ingestion, and it has been suggested that humans can perhaps tolerate hexavalent Cr at higher levels than the current drinking water standard of 50 ppb. This review highlights the most recent data on the induction of skin tumors in mice by chronic drinking-water exposure to hexavalent chromium in combination with solar ultraviolet light. This experimental system represents an important new animal model for chromate-induced cancers by ingestion of drinking water, and it suggests by extrapolation that chromate can likely be considered a human carcinogen by ingestion as well. The potential use of this animal model for future risk assessment is discussed.     

Antianaphylactic benzophenones and related compounds

The synthesis and biological properties of 85 benzophenones and related compounds are described. The majority of the compounds inhibit the release of leukotrienes (LT) C4 and D4 in vitro from sensitized guinea pig chopped lung. In addition, some of the compounds inhibited the release of LTs from passively sensitized human chopped lung and protected guinea pigs from the effects of anaphylaxis in a modified Herxheimer test.     

Ureylene anticonvulsants and related compounds

The results from a previous study led to the postulate that a number of aryl semicarbazones displaying anticonvulsant activity in the maximal electroshock (MES) screen interacted at both a hydrophobic and a hydrogen bonding areas on a specific binding site. These two parts of the binding site may be referred to as areas A and B, respectively. In order to circumvent the possible problems of the carbimino group in semicarbazones, such as toxicity and acid lability, some related ureylenes were considered. Initial evidence suggested that a second lipophilic group in the molecule was advantageous; this group may interact at area C on the proposed binding site. Most of the compounds prepared with a view to interacting at areas A, B and C showed protection in mice against MES induced seizures. Of particular interest were the compounds 1d, j which contained an alpha-methylbenzyl group attached to the N1 atom of the ureylenes which afforded good protection in the MES screen. The areas A and C at which lipophilic moieties were considered to interact were capable of accommodating groups of different sizes as measured by their solvent accessible surface areas. A number of compounds were active when given orally to rats and devoid of neurotoxicity at the doses utilized. Several compounds including 1d, f, j, 2d are useful prototypic molecules for subsequent development of further novel anticonvulsants.     

Preparation of menisdaurigenin and related compounds

Journal of Natural Medicines - Menisdaurin (1), a cyano glucoside, was first isolated in 1978 from Menispermum dauricum (Menispermaceae) and named after the plant. It has been also isolated from...     

阿哌沙班及有关物质的合成

目的合成凝血因子Xa抑制剂阿哌沙班及其有关物质,有关物质可作为阿哌沙班的质量控制的对照品。方法以4,5,6,7-四氢-1-(4-甲氧基苯基)-7-氧代-6-(4-硝基苯基)-1H-吡唑并[3,4-c]吡啶-3-羧酸乙酯(6)为起始原料,经还原、酰胺化、环合、氨解反应得到阿哌沙班,同时合成4个阿哌沙班有关物质。结果与结论所得阿哌沙班HPLC检测纯度为99.6%,总收率为43.8%(以化合物6计)。合成的阿哌沙班以及4个阿哌沙班有关物质,结构经MS、1H-NM R确认。     

Cytotoxic 4'-aminochalcones and related compounds

A series of 4'-aminochalcones 1 and related maleamic acids 2 and Schiff bases 3 were designed and synthesized as candidate cytotoxic agents. The atomic charges on different atoms of representative compounds were calculated. Evaluation of the enones 1-3 against human Molt 4/C8 and CEM T-lymphocytes as well as murine P388 and L1210 leukemic cells revealed that approximately 40% of the IC50 values generated were less than 10 microM. In some cases cytotoxicity was correlated with the Hammett sigma values of the aryl substituents and less frequently with the aryl Hansch pi values. Evidence was obtained that in general these compounds displayed selective toxicity for certain malignant cells and were well tolerated in mice. This study has revealed various directions whereby the project may be amplified in the future with a view to finding compounds with increased cytotoxicity to tumour cells.     

Nitrogen pyramidal amides and related compounds

A planar amide bond is a fundamental linkage in the structures of peptides and proteins. The rigid planarity of the amide linkage, due to a conjugation between carbonyl and amine groups, may be requisite for encoded protein folding and many other biological processes. Non-planar amides in the ground state will decode the significance of the planarity and rigidity of the amide linkage. We show here that simple amides of 7-azabicyclo[2.2.1]heptane, free from steric bias, including parent N-benzoyl 7-azabicyclo[2.2.1]heptane, are nitrogen-pyramidal amides in the crystalline state. We can suggest that pyramidalized amide nitrogen is a general feature and intrinsic to the 7-azabicyclo[2.2.1]heptane motif. Low rotational barriers of the amide C-N bond in a series of N-benzoyl amides of 7-azabicyclo[2.2.1]heptane, compared to monocyclic amides, may imply that ground-state nitrogen pyramidalization of the former amides also exist in solution. The 7-azabicyclo[2.2.1]heptane motif also favors nitrogen pyramidalization of sulfonamides and N-nitrosoamines, which can lead to pharmacophores after appropriate modification.     

Antitrypanosomal naphthylisoquinoline alkaloids and related compounds

In view of the need to develop new drugs against human African trypanosomiasis, a series of naturally occurring naphthylisoquinoline alkaloids, axially chiral acetogenic products derived from tropical plants, have been investigated for their activity against Trypanosoma brucei brucei TC 221. Likewise compounds corresponding to the two molecular portions, the naphthalene and the isoquinoline parts were tested, as well as molecules related to the central biaryl core of the alkaloids. Among all compounds tested, the natural, genuine alkaloids themselves, in particular dioncophylline B with its biaryl system and a moderate number of free hydroxy functions, showed the highest activities. Our results demonstrate that naphthylisoquinoline alkaloids constitute an interesting novel class of antitrypanosomal compounds worth further optimization.     

Microbial hydroxylation of novobiocin and related compounds

A new soil actinomycete (UC 5762, NRRL 11111) was found to transform novobiocin to 11-hydroxynovobiocin. The product was isolated by solvent extraction and column chromatography, and identified by IR, UV, 1H NMR and 13C NMR spectroscopy. Related structures (8,9-dihydronovobiocin, novobiocic acid and chlorobiocin) were similarly transformed to their corresponding C-11 hydroxylated analogues. The microbial process is superior to chemical (selenium dioxide) oxidation which yielded a mixture of 11-hydroxy- and 11-oxonovobiocin.