II Inhibitors

Assignee Fujisawa Pharmaceutical Co., Ltd Utility Analgesic and Blood Platelet Inhibitor 

Invention Significance Nonsteroidal anti-inflammatory agents 

A solution of trifluoroacetoamidine (37.8 mmol) in 20 ml methyl alcohol was treated with 4-methoxyphenylhydrazine hydrochloride (27 mmol) followed by 3.77 ml triethylamine, then stirred 6 hours at ambient temperature, and concentrated. The residue was treated with 20 ml water and 50 ml EtOAc/THF, 9 1, and the organic layer isolated. The aqueous layer was re-extracted with 50 ml EtOAc/THF, 9 1, and combined extracts were washed with water and brine. The solution was then dried using MgS04, concentrated, and 108.2% yield residue isolated and used without further purification. 

The Step 1 product (3.95 mmol) dissolved in 10 ml dioxane was treated with pyridine (3.95 mmol) and 4-methoxybenzoyl chloride (3.95 mmol) dissolved in 3 ml dioxane, 

Analgesic Activity Effect on Adjuvant Arthritis in Rats 

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Electron Transport Between Photosystem I and Photosystem II Inhibitors. The interaction between PSI and PSII reaction centers (Fig. 1) depends on the thermodynamically favored transfer of electrons from low redox potential carriers to carriers of higher redox potential. This process serves to communicate reducing equivalents between the two photosystem complexes. Photosynthetic and respiratory membranes of both eukaryotes and prokaryotes contain stmctures that serve to oxidize low potential quinols while reducing high potential metaHoproteins (40). In plant thylakoid membranes, this complex is usually referred to as the cytochrome b /f complex, or plastoquinolplastocyanin oxidoreductase, which oxidizes plastoquinol reduced in PSII and reduces plastocyanin oxidized in PSI (25,41). Some diphenyl ethers, eg, 2,4-dinitrophenyl 2 -iodo-3 -methyl-4 -nitro-6 -isopropylphenyl ether [69311-70-2] (DNP-INT), and the quinone analogues,... 

Photosystem II Inhibitors. The PSII complex usually is assumed to be that stmctural entity capable of light absorption, water oxidation, plastoquiaone reduction, and generation of transmembrane charge asymmetry and the chemical potential of hydrogen ions (41). The typical PSII complex... 

Another application was investigated by Olson and coworkers (99HCA(82) 2432). 4-Substituted-A-alkyl- and A-aryl-l,2,5-thiadiazolidin-3-ones 247-249 were prepared and evaluated for their MHC class-II inhibitor activity. 

Some are mitosis inhibitors which affect microtubule function and hence the formation of the mitotic spindle, others are topoisomerase I and II inhibitors. 

Organ et al. from York University demonstrated that a diarylated IH-pyrazole-based library, based on the structure of the potent COX II inhibitor Celecoxib [4-(3-trifluoromethyl-5-(4-methylphenyl)-lH-pyrazol-l-yl)benzenesulfonamide], could be rapidly prepared using MAOS [59]. Microwave-accelerated Suzuki reaction on 4-(5-iodo-3-methyl-lH-pyrazol-l-yl)-benzenesulfonamide using heterogeneous Pd/C was the principal diversification step investigated (Scheme 41). The interest of the team in microwave... 

Carbonic anhydrase II inhibitors, IC50 = 0.6 nM (left) and 0.8 nM (right)... 

BOOS G, STOPPER H (2000) Genotoxicity of several clinically used topoisomerase II inhibitors. Toxicol Lett. 116 7-16. 

Quantitative Structure-Activity Reiationships of Heterocyciic Topoisomerase i and ii inhibitors... 

A series of 5H-indolo[2,3-b]quinoline derivatives (XVII) was synthesized by Kaczmarek et al. [70] as novel DNA topo II inhibitors. Using their data for topo Il-induced DNA cleavage by this compound series (XVII), Eq. 18 was derived (Table 14) ... 

In this chapter, an attempt has been made to present a total number of 20 QSAR models (12 QSAR models for topo I inhibitors and eight QSAR models for topo II inhibitors) on 11 different heterocyclic compound series (an-thrapyrazoles, benzimidazoles, benzonaphthofurandiones, camptothecins, desoxypodophyllotoxins, isoaurostatins, naphthyridinones, phenanthridines, quinolines, quinolones, and terpenes) as well as on some miscellaneous heterocyclic compounds for their inhibition against topo I and II. They have been found to be well-correlated with a number of physicochemical and structural parameters. The conclusion, from the analysis of these 20 QSAR, has been drawn that the inhibition of topo I is largely dependent on the hydrophobicity of the compounds/substituents. On the other hand, steric parameters (molar refractivity, molar volume, and Verloop s sterimol parameters) are important for topo II inhibition. 

Hansch C, Verma RP (2007) Quantitative Structure-Activity Relationships of Heterocyclic Topoisomerase I and II Inhibitors. 10 43-74 Herncindez-Mateo F, see Santoyo-Gonzdlez F (2007) 7 133-177 Holt H Jr, see Brown T (2006) 2 1-51... 

Hansch and Verma contribute to the quantitative structure-activity relationship (QSAR) analysis of heterocyclic topoisomerase I and II inhibitors. These inhibitors, known to inhibit either enzyme, act as antitumor agents and are currently used in chemotherapy and in clinical trials. 

Teniposide, a topoisomerase II inhibitor, is administered as an infusion over 30 to 60 minutes to prevent hypotension. The pharmacokinetics are described by a three-compartment model, with an a half-life of 0.75 hours, a (5 half-life of 4 hours, and a terminal half-life of 20 hours. Considerable variability in clearance of teniposide in children has been reported.17 Teniposide has shown activity in the treatment of acute lymphocytic leukemia, neuroblastoma, and non-Hodgkin s lymphoma. Side effects include myelosuppression, nausea, vomiting, mucositis, and venous irritation. Hypersensitivity reactions may be life-threatening. 

Gorbsky GJ 1994 Cell cycle progression and chromosome segregation in mammalian cells cultured in the presence of the topoisomerase II inhibitors ICRF-187 [(+)-l,2-bis(3,5-dioxopiperazinyl-l-yl)propane ADR-529] and ICRF-159 (Razoxane). Cancer Res 54 1042-1048... 

The potential properties of A. suaveolens Bl. has a source of topoisomerase II inhibitor is open for exploration. The plant probably elaborates aporphine alkaloids because aporphines are known to occur in the genus Artabotrys (2,3), Liriodenine and athero-spermidine from Artabotrys undnatus and artabotrine from Artabotrys zeylanicus abrogated the survival of cancer cells cultured in vitro (4). 

Examples of acridin alkaloids used in therapeutics as antineoplastic agents is amsacrine (Amsa P-D ), which is used for the treatment of acute leukemia in adults and malignant lymphomas, refractory to conventional therapy. Amsacrin is an intercalating agent and topoisomerase II inhibitor. 

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