Studies on plant growth-regulating substances. XLIII. 2 -Chloro -3 -phenoxypropionitriles

A number of ring substituted 2-chloro-3-phenoxypropionitriles have been prepared and their plant growth-regulating activity has been assessed in the wheat coleoptile, pea segment and pea curvature tests, and also by spray treatments on tomato and dwarf French bean plants. The activities of these compounds are compared with those of previously studied 2-chloro-3-phenylpropionitriles and the results are discussed in terms of chemical structure/biological activity relationships and mode of action.     

Peroxidase activities in relation to plant height and grain weight in bread wheat (Triticum aestivum L.)

Summary The relationship of peroxidase activity with plant height and grain weight has been studied in seven different varieties of bread wheat belonging to diverse genotypes, and their F₁ crosses. The association between plant height and peroxidase activity was highly significant and negative. Based on the similarity index values of peroxidase isoenzymes, the seven wheat genotypes could be classified into two groups: the first group consisting of triple and quadruple dwarf varieties and the other of tall, single and double dwarf. A negative correlation between peroxidase activity and grain weight was also observed. However, the results of this study indicate a possibility of developing a dwarf plant type with low peroxidase activity and well filled grains.     

Studies on plant growth-regulating substances. XXX. The plant growth-regulating activity of substituted phenols

The growth-regulating activity of a number of substituted monophenols and related compounds has been assessed in the wheat cylinder, pea segment, pea curvature and tomato-leaf epinasty tests and the effect on activity of position, size and electronic nature of the substituents has been studied. The results indicate that, for high auxin activity, electron-attracting substituents, having certain steric properties must be substituted in the 2- and 6-positions. Furthermore, at least one of these ortho-substituents must be capable of intramolecular bonding with the hydrogen of the phenolic hydroxyl group. Any substituent in the para-position to the hydroxyl group leads to complete loss of activity and activity is reduced by meta-substitution. This new group of phenolic plant growth regulators is considered in relation to other synthetic auxins from the viewpoints of structural requirements for activity and current theories on mode of action.     

Studies on plant growth-regulating substances XXIX. The plant growth-retarding properties of certain ammonium, phosphonium and sulphonium halides

Wheat, pea and dwarf bean seedlings grown under controlled environmental conditions were used to assess the growth-retardant activity of members of series of chloro-substituted benzyl-, trimethyl- and tri-n-butyl- ammonium bromides. The influence on activity of trialkyl groupings other than tri-methyl and tri-n-butyl was also studied using compounds with the 4-chloro-benzyl ring structure. 3-Chloro- and 4-chloro-benzyltributylammonium bromides were the most effective compounds. The activity was similar to that of 2,4-dichlorobenzyltributylphosphonium bromide (Phosphon-D) and they showed little phytotoxicity. A series of chlorophenoxymethyltributylammo-nium and phosphonium salts were found to have lower activity than the corresponding chlorobenzyl derivatives. Allyldimethylsulphonium bromide retarded the growth of wheat seedlings but, like the aliphatic trimethylam-monium bromides tested, it was only slightly active in the pea-seedling test. The results are considered in relation to the chemical structure of the compounds studied. In particular, the influence of chlorine substitution in the ring of benzyltributylammonium salts on their growth-retardant activity is compared with the effect of similar substitution on the auxin activity of phenoxyacetic acids.     

Studies on plant growth-regulating substances

Nitrophenols structurally similar to 4-hydroxy-3-nitrobenzoic acid and 4-hydroxy-3-nitrobenzaldehyde have been examined for their ability to inhibit chloroplast development in linseed and oat seedlings, and their activity has been estimated quantitatively in specifically designed clover and Lemna bioassays. Twelve compounds were found to be active and activity is considered in relation to chemical structure. A nitro group in the 3-position and a hydroxyl group or ether linkage in the 4-position were found to be essential for activity whereas the nature of the functional group in the 1-position could vary considerably. Possibilities in which activity might arise from metabolism of the applied compound were investigated using excised wheat and pea tissue, and compounds with various groupings in the 1-position were shown to be converted to the corresponding active benzoic acid derivative.     

Evaluation of the Allelopathic Potential of Leaf,Stem, and Root Extracts of Ocotea pulchella Nees et Mart

Despite the increase in recent decades in herbicide research on the potential of native plants, current knowledge is considered to be low. Very few studies have been carried out on the chemical profile or the biological activity of the Brazilian savanna (Cerrado) species. In the study reported here, the allelopathic activity of AcOEt and MeOH extracts of leaves, stems, and roots from Ocotea pulchella Nees was evaluated. The extracts were assayed on etiolated wheat coleoptiles. The AcOEt leaf extract was the most active and this was tested on standard target species (STS). Lycopersicon esculentum and Lactuca sativa were the most sensitive species in this test. A total of eleven compounds have been isolated and characterized. Compounds 1 , 2 , 4 , and 6 have not been identified previously from O. pulchella and ocoteol ( 9 ) is reported for the first time in the literature. Eight compounds were tested on wheat coleoptile growth, and spathulenol, benzyl salicylate, and benzyl benzoate showed the highest activities. These compounds showed inhibitory activity on L. esculentum. The values obtained correspond to the activity exhibited by the extract and these compounds may therefore be responsible for the allelopathic activity shown by O. pulchella.     

On the specificity of sialidase. Synthesis and properties of N5-acetyl-beta-D-neuraminoylpeptides - AcNeu-Gly-OH, AcNeu-Glu-OH, AcNeu-Phe-OH - and the corresponding alpha-ketosides

By means of the mixed anhydride procedure the benzyl alpha-ketoside of N5-acetyl-D-neuraminic acid was linked to L-glycine, L-glutamic acid and L-phenylalanine. Hydrogenolytic cleavage of the benzyl group resulted in the corresponding free N5-acetyl-beta-D-neuraminoylpeptides. This new class of compounds is no substrate for Vibrio cholerae sialidase. The enzyme does not split the benzyl alpha-ketosides of N5-acetyl-D-neuraminoylpeptides nor is its activity inhibited by these compounds. The results strongly support the assumption that in sialidase substrates the carboxy group must be located close to the ketosidic oxygen. N-(N5-acetyl-beta-D-neuraminoyl)-L-phenylalanine was readily hydrolysed by carboxypeptidase A from bovine pancreas.     

Synthetic and Antiviral Studies on Certain Acyclic Nucleosides of 5-Benzyl-6-Azauracil Derivatives

Abstract

Several 5-(4-substituted benzyl)-6-azauracils have been synthesized from the corresponding benzaldehydes. The 5-benzyl-6-azauracils were silylated with hexamethyldisilazane and then glycosylated with aliphatic halides, e.g., (2-acetoxyethoxy)methyl bromide and 1,3-dibenzyloxy-2-chloromethoxypropane, to give protected acyclic nucleosides which were deprotected to afford acyclonucleosides of 5-(4-substituted benzyl)-6-azauracils. None of the compounds exhibited significant antiviral activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in vitro.     

Synthesis of new 1-alkyl-, 1-benzyl-, and 1-aryloxyethyl-substituted 4,5-dichloroimidazoles and their antimicrobial,protistocidal, and fungistatic properties

Previously unknown 1-alkyl-, 1-benzyl-, and 1-aryloxyethylderivatives of dichloroimidazoles and products of their structural transformation were synthesized from 4,5-dichloroimidazole or 2-methyl-4,5- dichloroimidazole using alkyl, benzyl or aryloxyethyl halides. These N-substituted compounds were shown to have a weak antibacterial activity against some pathogenic gram-positive and gram-negative bacteria (Staphylococcus aureus and Escherichia coli). At the same time, some of the obtained compounds demonstrated a significant protistocidal activity against Colpoda steinii, which can exceed in strength the activity of clinically used veterinary drug Baycox. Moreover, these compounds showed a pronounced fungistatic effect.     

Studies on plant growth-regulating substances: XXXIII. The influence of ring substituents on the plant growth-regulating activity of phenylacetic acid

A comprehensive range of phenylacetic acids substituted with nitro, halogen, methyl, amino, hydroxyl and N-acetylamino groups have been synthesized and their growth-regulating activities assessed in the wheat cylinder, pea curvature and pea segment tests. The influence of substituents on molecular shape is shown to be more important in determining activity than their effects on electron distribution. Studies with 2,6-disubstituted phenylacetic acids have indicated that the most active compounds can attain a certain spatial configuration in which one surface of the molecule, including the plane of the ring system, is flat and the carboxyl group is above with its axis of rotation perpendicular to this surface. Positional requirements for growth-regulating activity in phenylacetic acids are shown to be less important than in the phenoxyacetic and benzoic acids.     

Studies on plant growth-regulating substances

The metabolism of certain 2,6-disubstituted phenols that possess high auxin activity in the pea segment, pea curvature and tomato-leaf epinasty tests, but are much less active in the wheat cylinder test, has been investigated in wheat, pea and tomato tissue. Metabolites were identified by thin-layer chromatography and a semi-quantitative assay method was developed. The low activity of 2,6-dihalogenophenols and inactivity of 2-halogeno-6-nitro-phenols and 3-halogeno-2-hydroxybenzonitriles in the wheat cylinder test was caused by rapid metabolic conversion of the compounds in this tissue to inactive compounds by a process involving hydroxylation of the aromatic ring in the para- position. No such inactivation occurred in pea and tomato tissues. Evidence for a novel detoxification of nitrophenols within both pea and wheat tissue was obtained; 2-bromo–6-nitrophenol was converted via 2-bromo-6-aminophenol to N-acetyl-2-bromo-6-aminophenol. Certain 3-halogeno-2-hydroxybenzaldehydes and corresponding aceto-phenones, although fulfilling the necessary structural and electronic criteria for auxin activity, are inactive. Metabolic studies indicate that this is because they are metabolized in wheat, pea and tomato tissues to compounds not possessing the structural requirements for auxin activity.     

A novel series of potent and selective EP(4) receptor ligands: facile modulation of agonism and antagonism

A novel series of EP(4) ligands, based on a benzyl indoline scaffold, has been discovered. It was found that agonism and antagonism in this series can be easily modulated by minor modifications on the benzyl group. The pharmacokinetic, metabolic and pharmacological profiles of these compounds was explored. It was found that these compounds show good pharmacokinetics in rat and are efficacious in pre-clinical models of pain and inflammation.     

Studies on plant growth-regulating substances XXVI. Isatic and anthranilic acids

The plant growth-regulating activities of isatic acid and twenty-six of its derivatives, together with the twenty-seven corresponding anthranilic acids, have been assessed in the wheat cylinder, the pea segment and the pea curvature tests. Activity was sustained by substitution in the 4- and 5-positions of isatic acid but decreased by substitution in the 3- and 6-positions. In the anthranilic acid series, the parent acid was inactive but the introduction of a large grouping (bromine or iodine) into the 5-position conferred activity. The 3,6- and 5,6-dichloro and the 3,6-dibromo acids were also active; compounds substituted in the 4-position to the carboxyl group or disubstituted in the 3,5-positions, were, as expected, inactive. In metabolism experiments on wheat and pea tissues with isatic and 5-chloroisatic acids the corresponding anthranilic acid was formed, together with an unidentified non-acidic metabolite in each case. There was no evidence that the growth regulating activity of isatic acids was related to this breakdown and it is concluded that the acids possess activity per se. The results are briefly discussed in terms of recent theories relating chemical structure to plant growth-regulating activity.     

Synthesis, QSAR and anti-HIV activity of new 5-benzylthio-1,3,4-oxadiazoles derived from α-amino acids

2-(1-[(4-Chloro/methylphenylsulfonylamino)alkyl]-5-thioxo-4,5-dihydro-1,3,4-oxadiazoles (4a-e) were synthesized, in four steps, via the sulfonyl derivatives of l-amino acids (l-alanine, l-methionine and l-phenylalanine) 1a-e, the esters 2a-e, the hydrazides 3a-e and finally the cyclization to 4a-e. Alkylation of 4a-e with 1.0 mole eq. of substituted benzyl halides furnished S-benzyl derivatives 5a-t, while 1.1 mole eq. yielded major 5a-t and minor amount of 6a-d. Alternatively, treatment of 4a-e with 2.0 mole eq. of substituted benzyl halides furnished 6a-d only. The structures of 5b and 5l were further confirmed by single crystal X-ray analysis. Compounds 5a-t and 6a-d showed no selective inhibition against HIV-1 and HIV-2 replication in MT-4 cells. However, 5f and 5j-5q exhibited some inhibitory activity against both types with EC(50) values (>11.50 - >13.00 μg/mL). These results suggest that the structural modifications of these compounds might lead to the development of new antiviral agents. The quantum structure-activity relationship of these novel structural congeners is discussed.     

Halogenolysis of para-substituted benzyl cobaloximes. Part II.

The reaction of benzyl cobaloximes with halogens (Cl₂ or Br₂) in chloroform or acetic acid forms benzyl halides and benzyl ethers of dimethylgly- oximes by an oxidative dealkylation mechanism.     

Studies on plant growth-regulating substances

A report of an alkoxypurine showing cytokinin activity is presented. This compound, 6-benzyloxypurine, has been tested in three tests and in two of these, a wheat leaf senescence and a young coleoptile test, the compound is as active as benzyladenine or kinetin. Although it is much less effective on molar basis than these compounds in a tobacco tissue culture test, it is as active at its optimum concentration. In addition to promoting cell division the presence of 6-benzyloxypurine leads to morphological differentiation within the tobacco stem tissue, and whole plants have been grown without altering the nutrient medium.     

Enkephalin-degrading enzyme inhibitors. Crucial role of the C-terminal residue on the inhibitory potencies of retro-hydroxamate dipeptides

The retro-inversion of the amide bond in kelatorphan and analogs, the first series of complete inhibitors of enkephalin metabolism, led to compounds highly efficient only against the neutral endopeptidase 24-11 (NEP). In order to increase the recognition of the aminopeptidase N (APN) and dipeptidylaminopeptidase (DAP), without loss of affinity for NEP, the malonyl group of these retro-inhibitors was replaced by diversely substituted succinyl moieties. All the molecules synthesized are highly efficient NEP inhibitors with Ki's in the 0.2-1 nM range, indicating that NEP possesses a relatively large and not very selective S'2 subsite. In contrast, inhibition of DAP activity is crucially dependent on the size and the position of the substituent in the succinyl moiety. Inhibitory potencies in the nanomolar range are obtained with compounds containing a benzyl group in the alpha-position related to the retro amide bond. Finally, a relatively modest inhibition of APN was observed with Ki's in the 0.5-1 microM range for compounds with benzyl or cyclohexyl group in P'2 position. However, these data demonstrate that efficient and complete inhibition of enkephalin degradation can be obtained with hydroxamate dipeptides containing a retro amide bond. The analgesic potency of the most active inhibitors was measured using the hot plate test in mice. Significant antinociceptive responses were obtained but these effects were rather weaker than those expected from the in vitro inhibitory potencies of these compounds on the three enkephalin-degrading enzymes.     

Cyclic retro-inverso dipeptides with two aromatic side chains. I. Synthesis.

A series of cyclic retro-inverso dipeptides--2-[(4-hydroxy)benzyl]-5-benzyl-4,6(1H,2H,3H,5H)-pyrimidinedi one (c[mPhe-gTyr]), 2-benzyl-5-[(4-hydroxy)benzyl]-4,6(1H,2H,3H,5H)-pyrimidinedione (c[mTyr-gPhe]), and 2-benzyl-5-amino-5-[(4-hydroxy)benzyl]-4,6(1H,2H,3H,5H)-pyrimidinedione (c[(alpha-amino)mTyr-gPhe])--were synthesized in order to define the minimum structural requirements for binding affinity with opiate receptors and biological activity. Although the first two compounds lack a free amine proposed to be necessary for receptor recognition, the c[mPhe-gTyr] and c[mTyr-gPhe] analogues serve as model molecules in conformational studies of the target analogue, c[(alpha-amino)mTyr-gPhe]. The cis- and trans-c[(alpha-amino)mTyr-gPhe] contain all the functional groups such as the amine and phenolic groups in the tyrosine, and the aromatic group in the phenylalanine, necessary for opiate activity. In addition, the c[(alpha-amino)mTyr-gPhe] analogues possess similar geometries to the Tyr-Pro part of morphiceptin (Tyr-Pro-Phe-Pro-NH2) whose high mu-receptor activity is attributed to conformations with the Tyr-Pro amide bond in a cis conformation because the peptide bonds assume a cis conformation. However, both analogues are inactive in the guinea pig ileum and the mouse vas deferens assays. This may result from wrong orientation of the benzyl group of the gPhe residue with respect to the (alpha-amino)mTyr residue. Conformational studies of these molecules using 1H-nmr spectroscopy and molecular mechanics calculations will be reported in the following paper. Results of conformational analysis should provide information about backbone-side-chain interactions in the retro-inverso peptide chains since all the fundamental structural elements of the retro-inverso peptides are included in these model systems even though the peptide bonds must assume a cis conformation.     

Geminivirus-based shuttle vectors capable of replication in Escherichia coli and monocotyledonous plant cells

Shuttle vectors have been constructed that are able to replicate in either Escherichia coli or plant cells. They contain the ColE1 origin of replication and parts of the wheat dwarf virus genome, a geminivirus infecting a variety of species of monocotyledonous plants. Such plasmids are able to replicate in E. coli and wheat cells. The plasmids can be rescued in E. coli and show no changes during their passage through plant cells. Such an E. coli/plant cell shuttle vector system could be used for the amplification of foreign genes in plant cells, for studies on DNA rearrangement or the isolation of plant transposons.     

Studies on plant growth-regulating substances. XL. 2-Chloro-3-phenylpropionitriles

The complete series of chloro-, dichloro-, methyl-, dimethyl- and chloro-methyl-ring substituted 2-chloro-3-phenylpropionitriles and several related compounds have been prepared. Their auxin activities have been assessed in the wheat coleoptile, pea segment and pea curvature tests, and the results, which are discussed in relation to molecular structure, support the suggestion by other workers that the observed activity is due to rapid uptake of the nitriles by the plant tissues, followed by metabolism to the corresponding phenylacetic acid. The high growth promoting activity of 2-chloro-3-(3-chloro-2-methyl-phenyl)propionitrile (orthonil) is confirmed but 2-chloro-3-(2,3-dichloro-phenyl)propionitrile and 2-chloro-3-(2,3-dichlorophenyl)butyronitrile are shown to be the most active members of the series.