Recent advances in the development of steroid sulphatase inhibitors

Inhibition of steroid sulphatase is now an important target for the development of new drugs for the treatment of women with endocrine-dependent breast tumours. The first potent sulphatase inhibitor identified, oestrone-3-O-sulphamate (EMATE) proved, unexpectedly, to be oestrogenic. A number of strategies have therefore been adopted to design and synthesize a non-oestrogenic inhibitor. For this, a number of modifications have been made to the A and D rings of the oestrone nucleus. 2 Methoxyoestrone-3-O-sulphamate, while having similar in vitro and in vivo sulphatase inhibitory potency to that of EMATE, was devoid of oestrogenic activity when tested at 2 mg/kg in an ovariectomised rat uterine weight gain assay. 17-Deoxyoestrone-3-O-sulphamate was also a potent steroid sulphatase inhibitor and while it was devoid of oestrogenic activity when tested at 0.1 mg/kg, did stimulate uterine growth at 1.0 mg/kg. As an alternative approach to the use of steroid-based inhibitors a number of single ring, bicyclic non-fused ring, and two fused ring sulphamate analogues were designed, synthesized and tested for their ability to inhibit steroid sulphatase activity. In general, although the single ring and bicyclic non-fused ring sulphamate analogues could inhibit sulphatase activity, they were considerably less potent than EMATE. The mono- and bis-sulphamate derivatives of 5,7-dihydroxyisoflavone were relatively potent, inhibiting in vivo steroid sulphatase activity by 62 and 81% respectively at a single oral dose of 10 mg/kg. A study of the structure-activity relationship of a series of coumarin-based sulphamates has led to the development of a number of potent non-steroidal inhibitors, one of which has a similar potency to that of EMATE. The identification of potent steroid- and non-steroid-based sulphatase inhibitors will enable the therapeutic value of this therapy to be examined in the near future.     

Matrix metalloproteinase 2 (MMP-2) and tissue transglutaminase (TG 2) are expressed in periglandular fibrosis in horse mares with endometrosis

Periglandular arrangement of myofibroblasts, associated with the deposition of extracellular matrix (ECM), is a cardinal feature of endometrosis in mares. We hypothesized that a disturbance in the expression of matrix degrading enzymes such as matrix metalloproteinases (MMP's) and matrix cross-linking proteins might lead to an imbalance in deposition and degradation of extracellular matrix components and thereby accentuate degeneration. Therefore, distributions of MMP-2, capable of collagen IV and laminin degradation, and tissue transglutaminase (TG2), a cross-linker of extracellular matrix proteins, were investigated by means of immunohistochemistry on uterine biopsies of healthy mares and animals with endometrosis. It was illustrated that both proteins were present in fibrotic regions of affected endometria, and that they were in most cases colocalized. Periglandular MMP-2 expression was significantly associated with dilated and fibrotic uterine glands. Furthermore, MMP-2 and TG 2 were demonstrated in the stratum compactum of healthy and endometrotic endometria. Gelatin zymography proved that active and inactive pro-form of MMP-2 were present in all examined samples with significantly higher amounts of total and active MMP-2 in affected endometria. TG 2-activity, determined by an in situ assay, was found in cases of severe periglandular fibrosis. We suggest that both enzymes play a major role in changes that occur in ECM homeostasis in endometrial fibrotic regions.     

Biochemical characterization of the medaka (Oryzias latipes) orthologue for mammalian tissue-type transglutaminase (TG2)

Transglutaminase is an enzyme family responsible for post-translational modification such as protein cross-linking and the attachment of primary amine and/or deamidation of glutamine-residue in proteins. Medaka (Oryzias latipes), a recently established model fish, has similar functional proteins to those characterized in mammals. Previously, we found the apparent orthologues that correspond to human transglutaminases in medaka. In this study, regarding the medaka orthologue of human tissue-type transglutaminase (OlTGT), recombinant protein was expressed in an active form in bacteria cultured at low temperature. Using the recombinant protein, we biochemically characterized the enzymatic activity and also obtained a monoclonal antibody that specifically recognized OlTGT. Immunochemical analysis revealed that OlTGT was not expressed ubiquitously, unlike its mammalian orthologue, but in primarily limited tissues such as the eye, brain, spinal cord, and gas gland.     

Synthesis of potent water-soluble tissue transglutaminase inhibitors

Dipeptide-based sulfonium peptidylmethylketones derived from 6-diazo-5-oxo-L-norleucine (DON) have been investigated as potential water-soluble inhibitors of extracellular transglutaminase. The lead compounds were prepared in four steps and exhibited potent activity against tissue transglutaminase.     

Liver tissue engineering: Recent advances in the development of a bio-artificial liver

Orthotopic liver transplantation is the most common treatment for patients with end-stage liver failure. However, liver transplantation is greatly limited by a donor shortage. Liver tissue engineering may offer a promising strategy to solve this problem by providing transplantable, bioartificial livers. Diverse types of cells, biomaterials, and growth factor delivery systems have been tested for efficient regeneration of liver tissues that possess hepatic functions comparable to native livers. This article reviews recent advances in liver tissue engineering and describes cell sources, biomaterial scaffolds, and growth factor delivery systems that are currently being used to improve the regenerative potential of tissue-engineered livers.     

Recent advances in the discovery of zinc-binding motifs for the development of carbonic anhydrase inhibitors

Abstract

In addition to the sulfonamides and their isosteres, recently novel carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs) which act by binding to the metal ion from the active site were discovered. Based on the X-ray crystal structure of the CA II–trithiocarbonate adduct, dithiocarbamates, xanthates and thioxanthates were shown to potently inhibit α- and β-CAs. The hydroxamates constitute another class of recently studied CAIs both against mammalian and protozoan enzymes. Another chemotype for which CA inhibitory properties were recently reported is the salicylaldoxime scaffold. X-ray crystal structures were reported for CA II complexed with dithiocarbamates and hydroxamates, whereas the xanthates and salicylaldoximes were investigated by kinetic measurements and docking studies. The dithiocarbamates and the xanthates showed potent antiglaucoma activity in animal models of the disease whereas some hydroxamates inhibited the growth of Trypanosoma cruzii probably by inhibiting the protozoan CA.     

Recent advances in tissue stem cells

Science China Life Sciences - Stem cells are undifferentiated cells capable of self-renewal and differentiation, giving rise to specialized functional cells. Stem cells are of pivotal importance...     

Recent advances in the clinical application of aromatase inhibitors

Aromatase inhibitors have evolved over a period of 20 years to well tolerated agents that can effectively obliterate aromatase activity in postmenopausal women. Breast cancer is the predominant clinical application and here the newer agents have established themselves as the preferred second-line agent after tamoxifen in the treatment of advanced disease. Recent data indicate that they be more efficacious than tamoxifen and, therefore, may replace it as the first-line agent of choice in the near future. On-going clinical trials in the adjuvant setting and prospective prevention studies will elucidate whether these drugs have a yet greater role in breast cancer.     

Structure-activity relationship study of novel tissue transglutaminase inhibitors

Thieno[2,3-d]pyrimidin-4-one acylhydrazide derivatives were discovered as moderately potent inhibitors of TGase 2 (tissue transglutaminase) utilizing a fluorescence-based assay that measured TGase 2 catalyzed incorporation of the dansylated Lys derivative alpha-N-Boc-Lys-CH(2)-CH(2)-dansyl into the protein substrate N,N-dimethylated-casein. A SAR study revealed that the acylhydrazide thioether side-chain and the thiophene ring were critical to inhibitory activity.     

Recent advances in the development of bioelectronic nose

The olfactory system has the ability to discriminate and identify thousands of odorant compounds at very low concentrations. Recently, many researchers have been trying to develop artificial sensing devices that are based on the olfactory system. A bioelectronic nose, which uses olfactory receptors (ORs) as sensing elements, would benefit naturally optimized molecular recognition. Accordingly, ORs can be effectively used as a biological element in bioelectronic noses. Bioelectronic nose can be classified into cell-based and protein-based biosensors. The cell-based biosensor uses living cells that express olfactory receptors as the biological sensing elements and the protein-based biosensor uses the olfactory receptor protein. The binding of odorant molecules to the ORs can be measured using various methods such as piezoelectric, optic, and electric devices. Thus, bioelectronic nose can be developed by combining the biological sensing elements with these non-biological devices. The application of bioelectronic nose in a wide range of different scientific and medical fields is essentially dependent on the development of highly sensitive and selective biosensors. These sensor systems for the rapid detection of specific odorants are crucial for environmental monitoring, anti-bioterrorism, disease diagnostics, and food safety. In this article, we reviewed recent advances in the development of bioelectronic nose.     

Recent advances in bone tissue engineering scaffolds

Bone disorders are of significant concern due to increase in the median age of our population. Traditionally, bone grafts have been used to restore damaged bone. Synthetic biomaterials are now being used as bone graft substitutes. These biomaterials were initially selected for structural restoration based on their biomechanical properties. Later scaffolds were engineered to be bioactive or bioresorbable to enhance tissue growth. Now scaffolds are designed to induce bone formation and vascularization. These scaffolds are often porous, made of biodegradable materials that harbor different growth factors, drugs, genes, or stem cells. In this review, we highlight recent advances in bone scaffolds and discuss aspects that still need to be improved.     

Recent advances on the development of bacterial poles

In rod-shaped bacteria, a surprisingly large number of proteins are localized to the cell poles. Polar positioning of proteins is crucial to many fundamental cellular processes. Formation of the pole occurs at the time of a prior cell division event and involves coordination of the cell division machinery with septal placement of newly-synthesized peptidoglycan. Development of polar peptidoglycan and outer membrane depends on the formation of the cytokinetic FtsZ ring at midcell. By contrast, positioning of at least two polar proteins depends on signals independent of both the assembly of the FtsZ ring and the synthesis of septal and polar peptidoglycan. We propose a model for distinct but interrelated developmental pathways for polar cell envelope synthesis and positional information recognized by polar proteins.     

Recent advances in the biocontrol of Orobanche (broomrape) species

Parasitic broomrapes (Orobanche spp.) are majoruncontrolled weeds in the Mediterranean regions of Europe and the NearEast causing major losses to vegetable, grain legume, and sunflowercrops. Selective herbicides alone cannot provide persistent, season-longcontrol of these parasites, and much methyl bromide is used for theircontrol, where affordable. Thus they are excellent targets forbiocontrol. The recent progress by the COST 816 Orobancheworking group in this area is reviewed herein. Natural infestation bythe fly Phytomyza orobanchia of seed capsules of Orobanchecrenata parasitising faba bean halved Orobanche seedproduction while inundative releases of adults reduced it to 5%of viable seeds. The fungi Fusarium arthrosporioides E4a andF. oxysporum E1d, as well as strains of bacteria were isolatedfrom diseased, juvenile, Orobanche flower stalks. They arepathogenic to O. aegyptiaca, O. crenata and O. ramosaon most vegetable crops. A F. oxysporum f. sp.orthoceras was specifically pathogenic to O. cumana onsunflowers. All were used in various experiments with a modicum ofsuccess. Methods were developed to formulate isolated mycelia, whichcould eventually allow the use of transgenic hypervirulent pathogens inasporogenic (deletion) mutants (as a failsafe against spread).Mycotoxins were also isolated from different Fusarium and otherfungal species that kill Orobanche, and are being consideredfor direct use, or to augment other strategies. All threeFusarium spp. used have been transformed with gusand/or gfp genes allowing tracing their movement in theenvironment, and opening the way to future transformations tohypervirulence.     

Recent advances in the synthesis of 2-deoxy-glycosides

Glycosides of 2-deoxy-sugars, monosaccharides in which the hydroxyl group at C-2 is replaced with a hydrogen atom, occur widely in natural products and therefore have been the subject of intense synthetic activity. The report summarizes recent advances in this area, with a particular focus on work published since an earlier review on the topic, in 2000 (Marzabadi, C. H.; Franck, R. W. Tetrahedron2000, 56, 8385-8417).     

Recent progress in development of aromatase inhibitors

In postmenopausal women with breast cancer, aromatase, which is the enzyme converting androstenedione to estrone and testosterone to estradiol, is the rate-limiting step in estrogen biosynthesis. The currently available aromatase inhibitor, aminogluethimide, effectively blocks estrogen production and produces tumor regressions in patients previously treated with tamoxifen. This drug, however, produces frequent side effects and blocks steroidogenic steps other than the aromatase enzyme. Thus, newer aromatase inhibitors with greater potency and specificity are under intense study. More than 20 such compounds have recently been developed. In several clinical trials, 4-hydroxyandrostenedione, given parenterally, has been highly active and specific for aromatase inhibition in patients with breast cancer. In two large recent studies, one-third of heavily pretreated women experienced objective tumor regression with this therapy. CGS 16949A, a newer agent, is also Phase II clinical trials. This compound is an imidazole derivative with nearly 1000-fold greater potency than aminoglutethimide. An initial Phase I study compared the potency of 0.6–16 mg daily in 12 postmenopausal women and found maximal suppression of urinary and plasma estrogens with 2 mg daily. The degree of inhibition was similar to that induced by aminoglutethimide or by surgical adrenalectomy. No CNS, hematologic or biochemical toxicity was observed. A larger Phase II study in 54 patients confirmed this high degree of potency of CGS since a plateau effect was observed at the 1.8, 2 and 4 mg daily doses. The endocrine effects were not absolutely specific as a blunting of ACTH-stimulated but not basal aldosterone levels were observed. This and other emerging aromatase inhibitors offer promise as pharmacologic methods to inhibit estrogen production specifically and without side effects.