Facile synthesis of acid-labile polymers with pendent ortho esters

This work presents a facile approach for preparation of acid-labile and biocompatible polymers with pendent cyclic ortho esters, which is based on the efficient and mild reactions between cyclic ketene acetal (CKA) and hydroxyl groups. Three CKAs, 2-ethylidene-1,3-dioxane (EDO), 2-ethylidene-1,3-dioxolane (EDL), and 2-ethylidene-4- methyl-1,3-dioxolane (EMD) were prepared from the corresponding cyclic vinyl acetals by catalytic isomerization of the double bond. The reaction of CKAs with different alcohols and diols was examined using trace of p-toluenesulfonic acid as a catalyst. For the monohydroxyl alcohols, cyclic ortho esters were formed by simple addition of the hydroxyl group toward CKAs with ethanol showing a much greater reactivity than iso-propanol. When 1,2- or 1,3-diols were used to react with the CKAs, we observed the isomerized cyclic ortho esters besides the simple addition products. Biocompatible polyols, that is, poly(2-hydroxyethyl acrylate) (PHEA) and poly(vinyl alcohol) (PVA) were then modified with CKAs, and the degree of substitution of the pendent ortho esters can be easily tuned by changing feed ratio. Both the small molecule ortho esters and the CKA-modified polymers demonstrate the pH-dependent hydrolysis profiles, which depend also on the chemical structure of the ortho esters as well as the polymer hydrophobicity.     

Britton Chance (1913-2010)--from sailing to biophysics and biochemistry and back

A short CV of Britton Chance, an outstanding American biophysicist and biochemists, who has passed away in November 2010, is presented. Chance invented and applied in biochemical research fast recording of difference spectra during chemical reactions. Due to this technique he discovered and studied formation of enzyme-substrate complexes as exemplified by the peroxidase reaction. He also described spectral changes of electron carriers of mitochondrial respiratory chain that accompany transition from the resting to the active (phosphorylating) states. Applying vibrating platinum electrode, he recorded changes in the rate of oxygen uptake by isolated mitochondria in resting and phosphorylating states and defined the so-called respiratory states, called after his name. He was the first to describe formation of reactive oxygen species by mitochondria. Britton Chance was a devoted yachtsman and won a gold medal for the United States in sailing at the 1952 Olympic Games in Helsinki.     

Progress in the prevention of breast cancer: concept to reality

In 1936, Professor Antoine Lacassagne suggested that breast cancer could be prevented by developing drugs to block estrogen action in the breast. Jensen discovered the physiologic target, the estrogen receptor, that regulates estrogen action in its target tissues and Lerner discovered the first nonsteroidal antiestrogen MER25. However, the success of tamoxifen as a treatment of breast cancer opened the door for the testing of the worth of tamoxifen to reduce breast cancer incidence in high-risk women. In 1998, Fisher showed that tamoxifen could reduce breast cancer incidence by 50%. Nevertheless, only half the women who develop breast cancer have risk factors other than age, so what can be done for women without risk factors? The recognition that nonsteroidal antiestrogens have the ability to modulate estrogen action selectively has advanced the design and development of new drug for multiple diseases. Tamoxifen and raloxifene maintain bone density and raloxifene is now used to prevent osteoporosis and is being tested as a preventive for coronary heart disease and breast cancer. The drug group is now known as selective estrogen receptor modulators (SERMs) and the challenge is to design new agents for multiple applications. If the 20th century was the era of chemotherapy, the 21st century will be the era of chemoprevention.     

Poly (delta-L-ornithine)

Poly (delta-L-Orn) is an example of an iso-polypeptide (i.e. variant of the usual poly a-peptide chain), where the a-carboxyl and delta-amino groups of ornithine are used in polymerization while the a-amino groups form the side chain. A procedure for the synthesis of this iso-polypeptide is described. Circular dichroism studies of poly (delta-L-Orn) and its Na-Boc derivative suggest that these polymers might adopt a conformation in solution similar to the beta-pleated sheet.     

Poly(germaniumpolycarbodiimides)

Poly(metalpolycarbodiimides) were obtained from cyanamide or dilithium cyanamide and di-, tri- or tetra-chlorogermanes by dehydrochlorination, transmetallation or exchange GeCl/GeN reactions. The preparation was extended to mesityldichlorostibane. Metal polyhalides develop a high tendency to generate poly(metalcarbodiimide) cryptands in spite of the linear molecular shape of the carbodiimide links. In these oligomeric structures, the reactivity of the metal nitrogen bond towards protic reagents is preserved and allows the confirmation of their structure by chemical investigations.     

Molecular Mobility in Poly(butyl methacrylate) and Poly(methyl methacrylate)

Molecular mobility is studied in poly(butyl methacrylate) and poly(methyl methacrylate) (PMMA) with molecular dynamics simulations in order to understand the effect of the α–β crossover on the β relaxation activation energy and co-operativity. In the high frequency range investigated, the estimated β process activation energy is decreased as compared to the low frequency value. This deviation is stronger in poly(n butyl methacrylate) (PnBMA) than in PMMA. The intra-molecular co-operativity related to the β process is also higher in PnBMA than in PMMA. These results could be related to the relative position of the simulation temperature range and of the extrapolated α–β crossover temperature.     

Protein phosphatase 4--from obscurity to vital functions

Protein phosphatase 4 (Ppp4) is a ubiquitous serine/threonine phosphatase in the PPP family that is now recognised to regulate a variety of cellular functions independently of protein phosphatase 2A (PP2A). Regulatory subunits (R1 and R2) have been identified in mammals that interact with the catalytic subunit of Ppp4 (Ppp4c) and control its activity. Ppp4c-R2 complexes play roles in organelle assembly; not only are they essential for maturation of the centrosome, but they are also involved in spliceosomal assembly via interaction with the survival of motor neurons (SMNs) complex. Several cellular signalling routes, including NF-kappaB and the target of rapamycin (TOR) pathways appear to be regulated by Ppp4. Emerging evidence indicates that Ppp4 may play a role in the DNA damage response and that Ppp4c-R1 complexes decrease the activity of a histone deacetylase, implicating Ppp4 in the regulation of chromatin activities. Antitumour agents, cantharidin and fostriecin, potently inhibit the activity of Ppp4. Orthologues of mammalian Ppp4 subunits in Saccharomyces cerevisiae confer resistance to the anticancer, DNA-binding drugs, cisplatin and oxaliplatin.     

Biological Activities of Oligonucleotides Linked to Poly(L-Lysine)

Abstract

We have developped a method to couple oligonucleotides to poly(L-lysine). This tool has been tested with anti m-RNA synthetic oligodeoxyribonucleotides and 2′-5′(A)_n and allows oligonucleotides to enter intact cells.     

多ADP-核糖聚合酶家族

分离鉴定多功能的核基质蛋白及核基质结合蛋白是目前核基质研究的一个重要领域。通过与转录因子、核基质结合元件以及DNA间相互作用,核基质结合蛋白在DNA复制、转录、加工修饰等细胞内事件中起着支持和调节的作用。多ADP-核糖聚合酶[poly(ADP—ribose)polymerase,PARP]是一种高度保守的核基质结合蛋白,在多种活动例如基因组损伤修复、细胞凋亡、信号转导、基因表达调控中都发挥着调节的功能。PARP的潜在生物学功能已越来越引起国内外研究人员的关注。     

Poly(ADP-ribosylation) and apoptosis

Poly(ADP-ribosylation) is a post-translational modification playing a relevant role in DNA damage recovery, DNA replication and viral integration. Several reports also suggest a modulation of this process during cell death by apoptosis. The aim of this review is to discuss the possible involvement of poly(ADP-ribosylation) during apoptosis, by dealing with general considerations on apoptosis, and further examining the correlation between NAD consumption and cell death, the regulation of poly(ADP-ribose) metabolism in apoptotic cells, the effect of poly(ADP-ribose) polymerase inhibition on cell death occurrence and the use of enzyme cleavage as a marker of apoptosis. Finally, the future prospects of the research in this area will be addressed.