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Only two spinach herbicides are currently available to producers, and with limited choices in herbicide mode of action (MOA), overuse of the current herbicides can result in dominance of uncontrolled weeds. Therefore, spinach producers need more herbicide options. Trials were conducted in processing spinach to evaluate the crop safety of dimethenamid-p (0.56 kg ai/ha), EPTC (2.94 to 3.40 kg ai/ha), or ethofumesate (0.84, 1.12 or 2.24 kg ai/ha) applied pre-emergent (PRE), and ethofumesate (0.09 or 0.18 kg ai/ha) applied early postemergent (EPOST) for potential use as alternatives to s-metolachlor (0.73 kg ai/ha) and cycloate (2.52 kg ai/ha). The control of London rocket was excellent with s-metolachlor, dimethenamid-p, and ethofumesate. Weed control with cycloate and EPTC was fair, and generally inferior to all others. Cycloate and s-metolachlor were safe to spinach, and only minor crop injury was observed with all other herbicides, except the high rate of ethofumesate PRE, which resulted in high levels of...

A 4-amido-pyrrolidone library that was intentionally synthesized as pairs of diastereomers was produced by solution-phase parallel syntheses and purified by an automated high-throughput purification system. A total of 2592 4-amido-pyrrolidinones were ultimately isolated as single diastereomers from a matrix of 1920 syntheses. After the four-step synthesis and HPLC purification, the average yield of a single diastereomer was 36.6%. The average chemical purity was >90%, and the average diastereomeric purity was >87%. The choice of chiral amines used to make amides with heterocyclic acid chlorides had a dramatic effect on success. Analysis of the relationship between amines used for synthesis and the diastereomeric separation showed that amides made from chiral 1,2-amino alcohols gave superior separation to amides from chiral morpholines. The presence of a hydrogen bond donor on the amide side chain seems to be required for a better diastereomeric separation.

Base-promoted cyclization of tert-butyl [2-(benzylideneamino)phenyl]acetate (13a) and subsequent C3-alkylation with allyl bromide affords 3-allyl-2-phenyl-2,3-dihydro-1H-indole-3-carboxylic acid, tert-butyl ester (15b) in high yield as a single diastereomer. This result is contrary to prior publications that describe failed cyclization of an analogous ethyl ester (ethyl [2-(4-methoxybenzylideneamino)phenyl]acetate) under strongly basic conditions. N-Acylation, olefin dihydroxylation, and tert-butyl ester cleavage affords the spirocyclic lactone 18 as a pair of diastereomers. Isolation and characterization of individual diastereomers 18a and 18b are described.

The N-alkylation of primary nitrophenylsulfonamides followed by removal of the nitrophenylsulfonamide moiety under nucleophilic conditions to provide secondary amines has become an established literature procedure. Application of this methodology with less reactive alkylating agents can give rise to side products resulting from a nitrogen to carbon transfer of the nitrophenyl ring. This side product predominates when tetrabutylammonium hydroxide is used in place of metal carbonate bases in the N-alkylation step.

Polymer-supported quench methodology has been used for parallel purification of combinatorial libraries of dihydropyridones and their derivatives. The dihydropyridone scaffold was assembled via a solution phase Lewis acid catalyzed, herero-Diels-Alder reaction. Further modifications allow for the rapid generation of subsequent aminopiperidine and acyl-aminopiperidine libraries utilizing a library from library approach.

Two solid-supported synthesis strategies for the preparation of 3-thio-1,2,4-triazoles are described. In the first, Rink amide resin is combined with Fmoc-protected ω-amino acids, acid hydrazides, and alkyl halides to provide diverse sets of starting materials from which numerous triazoles may be prepared. The second employs t-alkylcarbamateresin (Boc resin) which permits the use of additional pools of starting materials, including isothiocyanates and α- and ω-amino esters, resulting in triazoles with patterns of functional groups that are not possible from the initial route. The combination of multiple resins and resin attachment sites allows the preparation of a diverse library based upon the3-thio-1,2,4-triazole scaffold and avoids the pitfallof having a single linker functionality present at the same position in all library members. General synthetic procedures and representative products from each route are presented. A similarity analysis of representative sublibraries from each synthesis strategy concludes that variation of the solid-phase linker chemistry and attachment site can enhance molecular diversity of the combined triazole library.

Solution and solid phase synthetic methods leading to the rapid, stereocontrolled construction of highly functionalized fused bicyclic amino acid derivatives have been developed. The key step involves a unique application of the intramolecular Pauson-Khand cyclization for the construction of hexahydro-1H-[2]pyrindinone ring systems. Further modifications which demonstrate the potential for combinatorial library generation are also disclosed.

The preparation of polystyrene−divinylbenzene-supported derivatives of tris(2-aminoethyl)amine and methyl isocyanate are described. These polymeric reagents are used to quench excess reactants and remove known impurities from the crude reaction products obtained from the solution-phase, parallel syntheses of ureas, thioureas, sulfonamides, amides, and pyrazoles. In conjunction with the use of other polymeric reactants during the course of a reaction, the addition of polymer-supported quench reagent(s) at the conclusion of the reaction allows isolation of the desired product by a single filtration and evaporation of solvent. The mechanical simplicity and efficiency of this methodology make possible the rapid, parallel purification of crude reaction products obtained via solution-phase syntheses, regardless of whether the intended product is a single compound or a mixture of compounds, and hence offers an attractive alternative to solid-phase organic synthesis in the practice of combinatorial chemistry.

A series of 5-[[1-(4'-carboxybenzyl)imidazolyl]methylidene]hydantoins have been prepared and evaluated as in vitro and in vivo angiotensin II (Ang II) antagonists. Variation of substituents on the hydantoin ring leads to potent and selective Ang II antagonists with nanomolar IC50 values at the AT1 receptor and negligible affinity for the AT2 receptor. Preferred substituents include an n-butyl at R1 and an alkyl or heteroarylmethyl substituent at R2. The selection of the R2 substituent was guided in part by the calculation of its log P since a significant correlation was observed between CLOGP and AT1 binding affinity. The biphenyl tetrazole pharmacophore, common to a number of AT1 antagonists, could be replaced by, for example, a 4-carbomethoxyphenyl substituent resulting in potent Ang II antagonists both in vitro and in vivo. A representative compound of this series is 57, which reduced the mean arterial blood pressure of renal hypertensive rats by 40% at 30 mg/kg po and by 25% at 10 mg/kg po. In addition this compound was efficacious in the salt-deplete normotensive monkey model maximally decreasing blood pressure 27% at 10 mg/kg po. In summary, these compounds belong to a novel class of Ang II antagonists that lack the biphenyl tetrazole moiety yet display appreciable and long lasting oral activity.

Syntheses and structure-activity relationships for a series of substituted tetrahydroisoquinoline-3-carboxylic acid derivatives with AT2-specific angiotensin II receptor binding inhibitory activity are reported.

A novel series of nonpeptide angiotensin II (AII) receptor antagonists containing a 1H-pyrrol-1-yl moiety at the 4-position of the imidazole have been developed. The pyrrole group occupies the same lipophilic pocket at the receptor as the chloro group in DuP 753 (68) and EXP 3174 (69) and the pentafluoro group in DuP 532 (70), respectively. The impetus for its selection came from bioisosteric considerations based on hydrophobic and electronic substituent constants. An extensive study of the structure-activity relationships revealed several highly potent AII receptor antagonists. An acyl substitution at the 2-position of the pyrrole ring improved activity, most notably in the in vivo rat model. In addition, the 2-substituted pyrrole compounds improved chemical stability toward extremely facile decarboxylation reaction associated with unsubstituted pyrrole analogues, thus facilitating development of these agents. The IC50's of 18, 20, and 42 (< 1 nM) were better than the reference compounds 69 and 70, respectively. These compounds were selective AII antagonists that compete at the AT1 receptor and showed no affinity at the AT2 receptor at concentrations up to 10 microM. Upon intravenous administration in a normotensive rat model, compound 18 inhibited the AII-induced responses with ED50 of 6 micrograms/kg per min. In a renal hypertensive rat model, the antihypertensive potency of compound 18, at a dose of 10 mg/kg, was very similar to those 68 and 69, respectively. Compound 18 demonstrated a dose-related (3-30 mg/kg) decrease in blood pressure that was sustained for greater than 24 h. On the basis of its profile, compound 18, designated as CI-996, has been selected for in-depth studies. The design, synthesis, in vitro, and in vivo structure-activity relationships are described.

Syntheses of radiolabeled, fluorescent and biotinyl probes with highly selective affinity for the angiotensin AT 2 receptor are described. The binding affinities at AT 2 and AT 1 receptors are reported.

A synthesis of 6-amino-7-cyclohexyl-3,5-heptanediol 1 (CDH) and related amino 1,3-diols involving a nucleophilic ring opening of N-acyl activated lactams is described. Stereochemical proof of the 1,3-diol moiety is also presented.

Les reactions electrophiles de l'oxazol-2-yllithium et la synthese de bis-oxazolyl methanol sont reportees

Structure-activity relationships are reported for a novel class of 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid derivatives that displace 125I-labeled angiotensin II from a specific subset of angiotensin II (Ang II) binding sites in rat adrenal preparations. This binding site is not the Ang II receptor mediating vascular contraction or aldosterone release, but, rather, is one whose function has not yet been fully elucidated. It has been identified in a number of tissues and has a similar affinity for Ang II and its peptide analogues as does the vascular receptor. The non-peptide compounds reported here are uniquely specific in displacing Ang II at this binding site and are inactive in antagonizing Ang II at the vascular receptor or in pharmacological assays measuring vascular effects. PD 123,319 (79), one of the most potent compounds, has an IC50 of 34 nM. Certain of these compounds may have utility in the definition and study of Ang II receptor subtypes.

Les reactions electrophiles de l'oxazol-2-yllithium et la synthese de bis-oxazolyl methanol sont reportees

New derivatives of the naturally occurring amino acid 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid (spinacine) are reported. These include amide, ester, 5-alkyl and acyl, and regiospecific N im -alkyl and aralkyl derivatives. Synthesis via the Pictet-Spengler reaction of N im -substituted histidines is described. Cyclic hydantoin derivatives of spinacines are included

(C18H27NO)12n · (C10H10)n · (C8H8)87n) (Polymer-supported initiator of living free radical polymerization; core support for the preparation of Rasta resins.1-4) Alternate Name: TEMPO-methyl resin. Solubility: Insoluble in all solvents. Swells in aprotic solvents such as dichloromethane, chloroform, tetrahydrofuran, toluene, and N,N-dimethylformamide. Form Supplied in: Sand-colored, spherical polymer beads (75–192 μM, 1.0–1.86 mmol g−1). Analysis of Reagent Purity: Elemental analysis. Preparative Methods: Prepared by reaction of Merrifield's resin with the sodium salt of 1-hydroxy-2,2,6,6-tetramethylpiperidine in N,N-dimethylformamide (∼6 equiv) at room temperature.1 Purification: Wash repeatedly with a variety of solvents including water, methanol, N,N-dimethylformamide, dichloromethane, and hexanes; then dry at reduced pressure.1 Handling, Storage, and Precautions: Store at 0–20 °C. TEMPO-methyl-polystyrene resin does not require any special handling precautions other than avoiding conditions that crush the polymer beads.

Merrifield resin is converted to a solid-supported free radical initiator by reacting with the TEMPO-Na. Heating TEMPO-methyl resin with a variety of functionalized styrene and acrylate monomers gives larger resin beads via living free radical polymerization. We have coined the term Rasta resin to describe resin beads prepared in this fashion. The process can be described as a solvent-free suspension polymerization. It is particularly well suited for preparation of resin beads from monomers which contain electrophilic groups that would be destroyed upon suspension polymerization in water. Rasta resins have a novel macromolecular architecture wherein long straight chain polymers bearing reactive functional groups emanate from the phenyl groups of a cross-linked polystyrene core. With judicious choice of co-monomers and polymerization strategy, the solvent affinity, loading capacity, and distance of functionality from the cross-linked core may be controlled giving beads with properties that are tailored to specific uses as synthesis supports and scavenging resins.

Optimization of a 2-step reaction sequence was accomplished in 3-4 days, with over 200 different reaction conditions evaluated. Combinatorial arrays were performed using the optimized conditions to synthesize 590 new compounds which were tested for inhibition against N-His (D381E) ICE. Thirty-five compounds showed at least a tenfold improvement in activity compared to an initial standard.

The preparation and characterization of a homologous series of solid phase synthesis resins for anchoring amines via a Boc-like linker are described. The scope and limitations of these resins are explored with respect to procedures for attachment and cleavage of a variety of primary amines, secondary amines, and alpha-amino esters.

Mutational activation of ras has been found in many types of human cancers, including a greater than 50% incidence in colon and about 90% in pancreatic carcinomas. The activity of both native and oncogenic ras proteins requires a series of post-translational processing steps. The first event in this process is the farnesylation of a cysteine residue located in the fourth position from the carboxyl terminus of the ras protein, catalyzed by the enzyme farnesyltransferase (FTase). Inhibitors of FTase are potential candidates for development as antitumor agents. Through a high-volume screening program, the pentapeptide derivative PD083176 (1), Cbz-His-Tyr(OBn)-Ser(OBn)-Trp-DAla-NH2, was identified as an inhibitor of rat brain FTase, with an IC 50 of 20 nM. Structure-activity relationships were carried out to determine the importance of the side chain and chirality of each residue. This investigation led to a series of potent FTase inhibitors which lack a cysteine residue as found in the ras peptide substrate. The parent compound (1) inhibited the insulin-induced maturation of Xenopus oocytes (concentration : 5 pmol/oocyte), a process which is dependent on the activation of the ras pathway.

Angiotensin II (ANG II) produces its physiological effects via interaction with its specific receptors that are distributed among a number of different tissues.1–4 The wide variety of receptor locations as well as their varying affinity for angiotensin peptidic fragments5,6 in the presence or absence of dithiothreitol (DTT) allowed some authors to speculate about ANG II receptor subtypes.7 Indeed, some authors referred to different affinity states,8–10 the ability of ligands to bind competitively versus noncompetitively,11–13 and to different signal transduction pathways14–17 to validate their case. However, it was not until the recent discovery of selective ligands that this receptor heterogeneity was clearly established.18–28 Since the AT1 receptor subtype29 mediates a variety of therapeutically important events, in particular, vascular smooth muscle contraction, there has been little effort directed toward the design and synthesis of AT2-specific ligands. However, as losartan (DuP 753)30–33 and numerous other AT1-selective antagonists34–33 progress through the clinical departments44–46 of pharmaceutical companies, one is left to consider the clinical consequence of AT2 receptor activation. Although at present there have been very few functional correlates identified with the AT2 receptor, it would seem reasonable to expect the role of the AT2 receptor to be revealed during the long-term administration of AT1 antagonists, as a consequence of elevated ANG II levels.

Publisher Summary Traditional approaches to cancer management have involved cytotoxic intervention at the level of DNA replication. While cytotoxic anti-cancer drugs have shown limited efficacy against rapidly growing tumor cells, there remains a critical need for the development of agents targeted against more refractory, slow growing, and solid tumors. The 1990s have witnessed a revolution, in the understanding of signaling pathways, which are important to the growth of normal and neoplastic cells. Whether a cell divides or stops dividing depends, to a great extent, on its ability to respond to membrane localized growth stimuli. Among the numerous oncogene or protooncogene encoded proteins that serve as signal transducers in the pathway from the outer membrane to the nucleus, perhaps none are as central as the Ras protein. A distinguishing biochemical feature of the members of the Ras superfamily has their ability to bind guanine nucleotides, with high affinity, and their ability to hydrolyze bound guanosine triphosphate (GTP) to guanosine diphosphate (GDP) and phosphate. Ras serves, as a molecular switch, for cellular growth and differentiation, by cycling, between an active, GTP-bound form, and an inactive, GDP-bound form. Selectivity for oncogenic Ras relative to normal Ras would be a desirable property of a pulmonary function testing (PFT) inhibitor, because Ras is expressed in virtually all tissues, and plays a critical role in normal cellular proliferation.

Five renin inhibitors were cocrystallized with endothiapepsin, a fungal enzyme homologous to renin. Crystal structures of inhibitor-bound complexes have provided invaluable insight regarding the three-dimensional structure of the aspartic proteinase family of enzymes, as well as the steric and polar interactions that occur between the proteins and the bound ligands. Beyond this, subtleties of binding have been revealed, including multiple subsite binding modes and subsite interdependencies. This information has been applied in the design of novel potent renin inhibitors and in the understanding of structure-activity relationships and enzyme selectivities.

A series of renin inhibitors containing ester side chains at the P2 subsite are potent inhibitors of primate renin. Derivatives containing the diol isostere (ACDMH) at P1-P1' were the most potent inhibitors. Moderate selectivity for renin was observed relative to the closely related aspartic proteinase cathepsin D. The prototype compound, 4 (PD 132002), inhibited pepsin only weakly. In both high-renin normotensive and high-renin renal hypertensive monkeys, 4 produced substantial reductions in blood pressure after oral administration of 30 mg/kg. The maximum drop in blood pressure observed (24 +/- 4 mmHg) in the renal hypertensive monkey model was comparable to the drop produced by an intravenous infusion of saralasin at a maximally effective dose. Both the magnitude and duration of the oral antihypertensive effect of 4 is greater than that produced by enalkiren, CGP-38560, or CP-80794 by direct comparison in the same hypertensive monkey model. The malonate ester derivatives were prepared as ca. 65:35 mixtures of epimers. The kinetics of epimerization of 4 were investigated in detail, and it was shown to equilibrate rapidly at physiological pH (t1/2 less than 2 min). Fractional crystallization was employed to obtain the individual diastereomers in greater than 98% purity, which were indistinguishable in terms of their activity in vitro or in vivo, presumably due to rapid epimerization under the testing conditions.

Statine (STA, 8) and its cyclohexyl analog (ACHPA, 9) are obtained by a stereospecific synthesis via tetramic acid chemistry. Amides of STA and ACHPA, useful for the synthesis of antihyperten-sive renin inhibitors, are prepared directly from the intermediate activated lactams 7 by nucleophilic ring opening with amines.

Statine (STA, 8) and its cyclohexyl analog (ACHPA, 9) are obtained by a stereospecific synthesis via tetramic acid chemistry. Amides of STA and ACHPA, useful for the synthesis of antihyperten-sive renin inhibitors, are prepared directly from the intermediate activated lactams 7 by nucleophilic ring opening with amines.

The mass spectral fragmentation of a series of 10 mitosene analogs is described. Major pathways arise through decomposition of the substituents in the 1 and 10 positions and are unaffected by the substituent in the 7 position. The base peak in the spectrum, in most cases, is represented by the basic mitosene ring. The patterns are general for this series of compounds and may have application in elucidating the structure of the DNA alkylation sites involved in reactions with mitosenes or natural mitomycins.

Oxindole is converted to its dianion by treatment with two equivalents each of n-BuLi and TMEDA. Alkylations with a number of common electrophiles define the scope of synthetically useful transformations leading to 3-monosubstituted and 3,3-disubstituted oxindoles.

Alkylation -deprotection de phenacyl-1 histidinates de methyle N-proteges; obtention d'alkyl-3 imidazolyl-5alanines

When Dryden read the manuscript of William Congreve's Old Bachelor in 1692, he pronounced it the best “first play” that he had ever seen. Dryden's appreciation of Congreve's first play has been seconded by later critics. Dr. Jonson, for instance, found the comedy “the work of very powerful and fertile faculties; the dialogue ... quick and sparkling, the incidents such as seize the attention, and the wit so exuberant that it ‘o'er-informs its tenement.‘” Macaulay pronounced it “inferior indeed” to Congreve's “other comedies, but, in its line, inferior to them alone.” The dialogue, continued Macaulay, “resplendent with wit and eloquence ... preserves a certain colloquial air, a certain indescribable ease, of which Wycherley had given no example and which Sheridan in vain attempted to imitate.”