Non-thiol farnesyltransferase inhibitors: evaluation of different AA(X)-peptidomimetic substructures in combination with arylic cysteine replacements

In the course of our studies on non-thiol farnesyltransferase inhibitors based on the 2, 5-diaminobenzophenone AAX-peptidomimetic substructure, we have developed the (4-nitrophenyl)butyryl (R(1)), the (2-naphthyl)acryloyl (R(2)), the 4-nitrocinnamoyl (R(3)), and the 5-(4-nitrophenyl)furylacryloyl (R(4)) groups as useful cysteine replacements. In this study, we combined these four groups with other AA(X)-peptidomimetic substructures (5-10: R = H) reported in the literature. The 5-(4-nitrophenyl)furylacryloyl moiety (R(4)) turned out to be the most useful non-thiol cysteine replacement yielding in all cases the most active inhibitors. By combination of this 5-(4-nitrophenyl) furylacryloyl moiety (R(4)) with the structurally simple AAX-peptidomimetics 4-aminobenzophenone (5) and 4-aminodiphenylsulfone (6) potent, readily accessible non-thiol farnesyltransferase inhibitors were obtained (IC(50) = 12 nMand 10 nM).     

MalignancyCase Report: Systemic Sarcoidosis Preceeding Acute Myeloid Leukemia

The authors report the case of a 59-year-old woman who developed acute myeloid leukemia nine months after the resolution of systemic sarcoidosis treated by corticosteroid therapy. This rare case poses the questions of the physiopathogenic mechanisms, particularly a granulomatous reaction to leukemic antigens or to cytokines or of the role of an infectious agent.     

The role of UV-B light in skin carcinogenesis through the analysis of p53 mutations in squamous cell carcinomas of hairless mice

Mutation spectra of the p53 gene from human skin carcinomas have been connected to solar UV radiation. For comparison we have characterized the mutation spectrum of the p53 gene in a very large sample of squamous cell carcinomas from hairless mice induced with UV of wavelength 280-320 nm (UV-B), which have substantiated the mutagenic effects of UV-B radiation in vivo. Tumors from hairless mice, random bred SKH:HR1 as well as inbred SKH:HRA strains, which are analyzed for mutations in the conserved domains of the p53 protein present a very specific mutation spectrum. The observed mutation frequency after chronic UV-B radiation in the p53 gene ranged from 54% (SKH-HRA) to 73% (SKH-HR1) among the 160 tumors analyzed. Over 95% of the mutations were found at dipyrimidine sites located in the non-transcribed strand, the majority were C-->T transitions and 5% were CC-->TT tandem double mutations. Four distinct UV-B mutation hot spots have been identified for the first time: two major ones at codons 267 (33%) and 272 (19%) and two minor ones at codons 146 (10%) and 173 (4%). The codon 267 hot spot consists of a CpG preceded by a pyrimidine, which confirms in vivo an important role for this UV-B mutable site in UV-B-induced skin tumors that is not found in other types of mouse tumors. Comparison with mutation spectra from human skin carcinomas fully validates the merits of the hairless mouse model for studying the molecular mechanisms of skin carcinogenesis. For example, the murine hot spot at codon 272 does have a full equivalent in human skin carcinomas. In contrast, the human equivalent of the murine codon 267 lacks the dipyrimidine site and therefore fails to be a pronounced hot spot in human skin carcinomas; however, this site is one of the major hot spots in human internal cancers (evidently not induced by UV radiation but probably by deamination of the 5 methyl cytosine).      

天然牛黄与培育牛黄的扫描电镜观察

天然牛黄(natural ox gallstone)为牛的胆结石,由于产量极少,供求困难,国内于1956年参照天然牛黄的主要成分制成人工牛黄(artificial ox gallstone),作为天然牛黄的代用品。从1974年以来,很多省区如吉林、广东、内蒙古等都先后进行了人工培育牛黄的试验,并试验成功培育牛黄(cultured ox gallstone)。其方法是用手术在牛胆囊内植入异物为核,促使胆汁成分的沉积与结石的形成,经过一段时间后,将异物取出,上面的沉积物即为培育牛黄。本文目的是探讨天然牛黄与培育牛黄的结构特征。     

Feigrisolides A, B, C and D, new lactones with antibacterial activities from Streptomyces griseus

Four new lactone compounds, named feigrisolides A to D (1 to 4), have been isolated from Streptomyces griseus. The chemical structures were determined by detail analysis of their spectroscopic data and chemical transformations. Structurally, the feigrisolides A (1) and B (2) are hepta-lactones, feigrisolide C (3) and D (4) are 16-membered macrodiolides. Biological studies showed that feigrisolide B (2) exhibited strong antibacterial, as well as medium cyctotoxic, and antiviral activities. Feigrisolides A (1), C (3) and D (4) are medium inhibitors of 3alpha-hydroxysteroid-dehydrogenase (3alpha-HSD) inhibiting activity.