Inhibitors, synthetic

A new generation of antiinflammatory agents having immunosuppressive activity has been developed. The appearance of preclinical and clinical reports suggest that these are near entry to the pharmaceutical market. For example, tenidap (CP-66,248) (12) has been demonstrated to inhibit IL-1 production from human peripheral blood monocytes in culture (55). Clinically, IL-1 in synovial fluids of arthritic patients was reduced following treatment with tenidap. Patients with rheumatoid or osteoarthritis, when treated with tenidap, showed clinical improvement (57,58). In addition to its immunological effects, tenidap also has an antiinflammatory profile similar to the classical NSAIDs (59). Other synthetic inhibitors of IL-1 production are SKF 86002 (20) andE-5110 (21) (55). 

Inhibition of Metastasis by Protease Inhibitors. Cancer metastasis can be inhibited by either synthetic or naturally occurring protease inhibitors. Thus, various synthetic inhibitors of serine proteases have been found to prevent tumor cell invasion through amniotic membranes in vitro and to inhibit cancer metastasis in vivo [for reviews, see Aznavoorian et al. (A4) and Duffy (D6). In... 

Besides the synthetic inhibitors, a variety of natural compounds is known to inhibit the CP. One of these natural inhibitors, lactacystin, was discovered by its ability to induce neurite outgrowth in a murine neuroblastoma cell line. Incubation of cells in the presence of radioactive lactacystin leads to the labelling of the yS5 subunit (Fenteany et al. 1995) and to irreversible inhibition of the CP. As shown by X-ray analysis, the inhibitor is covalently attached to subunit fS5 by an ester bond with the N-terminal ThrlO (Groll et al. 1997) (see Figure 10.7A). The subunit selectivity of lactacystin can be attributed to its dimethyl group, which mimics a valine or a leucine side chain and closely interacts with Met45 in the hydrophobic SI pocket of subunit j85. 

Lachner M, O Carroll D, Rea S, Mechtler K Jenuwein T (2001) Methylation of histone H3 lysine 9 creates a binding site for HPl proteins. Nature 410 116-120 Lau OD, Kundu TK, Soccio RE, Ait-Si-Ali S, KhaUl EM, Vassilev A, Wolffe AP, Nakatani Y, Roeder RG, Cole PA (2000) HATs off selective synthetic inhibitors of the histone acetyltransferases p300 and PCAF. Mol Cell 5 589-595... 

Saito A, Yamashita T, Mariko Y, Nosaka Y, Tsuchiya K, Ando T, Suzuki T, Tsurao T, Nakanishi O (1999) A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors. Proc Natl Acad Sci USA 96(8) 4592-4597 Schneider R, Bannister AJ, Myers FA, Thorne AW, Crane-Robinson C, Kouzarides T (2004) Histone H3 lysine 4 methylation patterns in higher eukaryotic genes. Nature 6 73-77 Schwartz BE, Ahmad K (2005) Transcriptional activation triggers deposition and removal of the histone variant H3.3. Genes Dev 19 804-814... 

Synthetic Inhibitors of Bacterial and Mammalian Interstitial Collagenases... 

Fig. 9.10 Inhibitors of brassinin oxidase/ dehydrogenase, the phytoalexins cyclobrassinin (32) and camalexin (33) and synthetic inhibitors 34 and 35...

Enzyme inhibitors are chemicals that may serve as a natural means of controlling metabolic activity by reducing the number of enzyme molecules available for catalysis. In many cases, natural or synthetic inhibitors have allowed us to unravel the pathways and mechanisms of intermediary metabolism. Enzyme inhibitors may also be used as pesticides or drugs. Such materials are designed so that they inhibit a specific enzyme that is peculiar to an organism or a disease state. For example, a good antibiotic may inhibit a bacterial enzyme, but it should have no effect on the host person or animal. 

Substances known as intercalators, such as rifamycin and actinomycin D (bottom) are deposited in the DNA double helix and thereby interfere with replication and transcription (B). As DNA is the same in all cells, intercalating antibiotics are also toxic for eukaryotes, however. They are therefore only used as cytostatic agents (see p. 402). Synthetic inhibitors of DNA topoisomerase II (see p. 240), known as gyrase inhibitors (center), restrict replication and thus bacterial reproduction. 

Pharmacology Trimetrexate, a 2.4-diaminoquinazoline, nonclassical folate antagonist, is a synthetic inhibitor of the enzyme dihydrofolate reductase. The end result is disruption of DNA, RNA, and protein synthesis, with consequent cell death. Pharmacokinetics Clearance was 38 15 ml /min/m and volume of distribution at steady state (Vdgs) was 20 8 L/m. The plasma concentration time profile declined... 

Corticosteroids Glucocorticoids Mineralocorticoids Corticosteroid antagonists Receptor antagonists Synthetic inhibitors... 

Sturzebecher J, Sturzebecher U, Yieweg H, Wagner G, Hauptmann J, Markwardt F. Synthetic inhibitors of bovine factor Xa and thrombin comparison of their anticoagulant efficiency. Thrombosis Res 1989 54 245-252. 

The preliminary modeled structures of the synthetic inhibitors described in this review were constructed and energy minimized by the author using HyperChem (1995, Hypercube, Inc., Release 4.5). Docking of these inhibitors to the active site of Factor Xa was accomplished by the author using the x-ray coordinates of native Factor Xa [4] and INSIGHT II (Biosym Technologies, Inc.) and the approach outlined in Section 6. 

As a non-phagocytosable, non-protein stimulus detergents have been used, especially digitonin but also sodium dodecyl sulfate Fatty acids which elicit the burst include myristate and arachidonateActive lectins include concanavalin A and phytohemagglutinin the specific synthetic inhibitor, alpha methyl... 

Stereoscopic ribbon structure of the HIV-1 protease with the synthetic inhibitor Sequinivircc bound in the active site. One of the two identical subunits (top) is shaded darker than the second (bottom). When mutated, the amino acid side chains shown in ball-and-stick form with residue numbers shown for the top subunit led to drug-resistant viruses. Courtesy of Alex Wlodawer, National Cancer Institute.01... 

---