Stereoisomeric Analogues Research Articles

Interleukin-1 beta stimulates nitrite production in the rat ovary: evidence for heterologous cell-cell interaction and for insulin-mediated regulation of the inducible isoform of nitric oxide synthase.

Recent studies suggest that endogenously generated nitric oxide (NO) may mediate the effects of cytokines in a variety of tissues. In an effort to determine whether NO generation mediates any of the intraovarian actions of interleukin-1 beta (IL-1 beta), we have looked for and characterized the accumulation of nitrite by IL-1 beta-treated, cultured whole ovarian dispersates. Application of IL-1 beta significantly enhanced basal nitrite release in a dose-, cell density- and time-dependent manner, the latter characterized by a lag time of about 20 h, suggestive of induction of NO synthase (NOS). Cellular NOS activity was also elevated by IL-1 beta. Sustained nitrite accumulation required continuous application of IL-1 beta. The maximally stimulating dose of IL-1 beta (50 ng/ml) produced a 10-fold increase in nitrite accumulation by 96 h of culture, an effect reduced 23% when cells were cultured in substrate (i.e., arginine)-free media. IL-1 beta-stimulated nitrite accumulation was reduced to control levels by the simultaneous application of an IL-1 beta receptor antagonist, thereby suggesting a specific receptor-mediated effect. Both the control and IL-1 beta-stimulated levels of nitrite accumulation were attenuated in a dose-dependent manner by inhibitors that favor the inducible form of NOS. In contrast, selective inhibitors of the constitutive form of NOS were significantly less potent. No inhibition was noted after application of an inactive stereoisomeric analogue. IL-1 beta-induced nitrite accumulation was shown to require cell-cell interaction between granulosa and theca-interstitial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Synthesis and Chirality of Novel Heterocyclic Compounds Designed for Crop Protection

More than 60% of the novel development products in agrochemistry, synthetic or of natural origin, contain heterocyclic ring systems. It will be shown that many modern formulations based on these new core structures can be used at very low application rates per hectare. In many cases these new structures are chiral. Synthetic investigations to produce enantiomerically pure products by stereoselective processes are discussed with examples A, B and C: 1 1-Substituted-imidazole-5-carboxylic acid derivatives were discovered as a new herbicidal class by the screening of pharmaceutical products. The R-enantiomer A proved to be a highly active inhibitor of the obtusifoliol-14-α-methyl-demethylase in the plant sterol metabolism. A pharmacophore substructure was proposed based on conformational analysis and was used to predict activities of stereoisomeric analogs. 2 A stereoselective synthesis of (2R,4S)-4-(2-ethyl-1,3-dioxolan-4-yl-methoxy)-phenyl-(3-fluoro-phenyl)-ether B, a 1,3-dioxolane type juvenile hormone mimic with two chiral centers, is described. A (-)-Camphor-10-sulfonamide served as a chiral auxiliary. 3 Synthetic methods to produce the post-emergence herbicide (+)-hydantocidin (ribantoin) C, a metabolite isolated from Streptomyces hygroscopicus, strain Tü 2474, with four contiguous stereogenic centers, are discussed. One reaction sequence features the Bucherer reaction and another highly stereoselective method, an intramolecular oxygen-bridged Vorbrüggen coupling, as key steps.

A topochemical approach to explain morphiceptin bioactivity.

A topochemical model to explain the bioactivity of morphiceptin (Tyr1-Pro2-Phe3-Pro4-NH2) was developed by taking account of accessible conformations around rotatable bonds which define relative spatial arrangements of opioid pharmacophores, the amine and phenolic groups of tyrosine and the aromatic ring of phenylalanine, necessary for receptor recognition. For this purpose, 1H-NMR measurements and computer simulations were extensively carried out on 10 stereoisomeric analogs related to morphiceptin: Tyr-Pro-(L and D)-Phe- (L and D)-Pro-NH2; Tyr-Pro-(L and D)-(NMe)Phe-(L and D)-Pro-NH2; Tyr-(NMe)Ala-Phe-D-Pro-NH2; and Tyr-Ala-Phe-D-Pro-NH2. These analogs are structurally close to one another but display various opiate potencies from highly active to inactive. The conformation of each rotatable bond has been specifically identified by measuring accessible space for the analogs, in which the difference in composition is observed in the specific site affecting only the conformation around the target bond. The most interesting characteristic of the model is a requirement of a cis amide bond linking residues 1 and 2. The model also requires the side chains in a trans conformation (chi 1 = 180 degrees) for the Tyr and Phe residues. The distances between the three pharmacophores, d1 (Tyr N to Tyr OH), d2 (Tyr N to the center of the aromatic ring of the third residue), and d3 (Tyr OH to the center of the aromatic ring of the third residue), were found to be approximately 8, approximately 7, and approximately 11-13 A, respectively. This model should aid in pharmaceutical design of peptide and nonpeptide ligands with opioid potencies.

Effect of Selected Neuroleptic Agents and Stereo‐Isomeric Analogues on Virus and Eukaryotic Cells

Chlorpromazine, cis(Z)-chlorprothixene (Truxal), and the non-neuroleptic trans(E)-chlorprothixene and trans(E)-flupenthixol were studied in vitro for possible antiviral effect on Herpes simplex virus 2 and for toxic effect on human diploid fibroblasts. Based on an enzyme-linked immunosorbent assay (ELISA) antiviral activity was demonstrated for all the compounds in the concentration range 0.39 micrograms/ml-25 micrograms/ml. A cell-toxic effect was shown in the higher concentration range for all the compounds except cis(Z)-chlorprothixene. A cell-stimulatory effect was also detected at the lower concentration range (about 3.13 micrograms/ml) for all compounds. Thus both cell stimulation and antiviral effect can be found for the same agent within the same concentration range. The results point to the possibility of creating different antiviral drugs--which would also include a cell-stimulatory activity--among psychopharmacological drugs and their stereoisomeric analogues.

Molecular conformation of a D,L stereoisomeric analogue of valinomycin, cyclo[‐(L‐Val‐L‐Hyi‐L‐Val‐D‐Hyi)2‐(D‐Val‐L‐Hyi‐L‐Val‐D‐Hyi)‐

The crystal structure of a synthetic analogue of valinomycin, cyclo[-(L-Val-L-Hyi-L-Val-D-Hyi)2-(D-Val-L-Hyi-L-Val-D -Hyi)-] ([L-Val1, L-Val5]meso-valinomycin), C60H102N6O18, has been determined. Crystals grown from petroleum ether are orthorhombic, space group P2(1)2(1)2(1), with cell parameters a = 16.41(1), b = 18.76(1), c = 25.86(1) A, and Z = 4. The atomic coordinates for nonhydrogen atoms, except those of terminal carbons on one side chain, were refined in the anisotropic thermal motion approximation. The coordinate parameters of the H atoms were incorporated into the structure factor calculations at geometrically expected positions. Values of the standard and weighted R factors after refinement are 0.074 and 0.083, respectively. The crystal structure of the molecule is asymmetric and adopts a conformation with four 4----1 type and one 6----1 type intramolecular hydrogen bonds between amide nitrogens and carbonyl oxygens. Valinomycin binds potassium more than 100 times strongly than the D,L stereoisomeric analogue, as a result of a different spatial orientation of potentially interacting carbonyl groups.

Synergy between a non-neuroleptic thioxanthene stereo-isomer and penicillin in vivo.

Some neuroleptic drugs of the phenothiazine and thioxanthene groups have an antimicrobial effect in vitro. This is also true for neuroleptically inactive stereo-isomeric analogs of the thioxanthenes e.g. trans(E)-clopenthixol (t-CPT). In a murine pneumococcus peritonitis model t-CPT demonstrated a slight, but non-significant antibacterial effect in doses of 0.3-0.9 mg per mouse, while higher doses seemed to enhance the bacterial virulence. If combined with subtherapeutic doses of penicillin, a significantly higher survival rate was obtained compared with either drug given alone. In vitro studies demonstrated a similar synergistic effect. These results indicate that at least one non-neuroleptic thioxanthene stereo-isomer has an antibiotic potential also in vivo. The mechanism of action is not known.

THE ANTIBIOTIC EFFECT OF THE ANTI‐DEPRESSIVE DRUG FEMOXETINE AND ITS STEREO‐ISOMERIC ANALOGS ON DIARRHOEA PRODUCING ENTEROBACTERIACEAE

The present investigation has been undertaken to illustrate the antibacterial effect on 20 diarrhoea producing enterobacteriaceae of an anti-depressive drug available as femoxetine and its three analogs. It has been shown that the stereo-isomeric trans forms of femoxetine are more than twice as active as the cis forms and inhibited all the strains below 400 microgram/ml (1.2 mM). The two cis compounds only inhibited 11 and 9 of the 20 strains respectively in the investigated area 100 microgram/ml - 800 microgram/ml (0.3 mM - 2.4 mM). Our investigations point out that the bacterial cell has a target for psychopharmacologically active agents. Thus the known psychopharmaca and their stereo-isomeric analogs may represent a pool of potentially new antimicrobial drugs. Furthermore the bacterial model may be useful as a model system in the study of the interaction of neuropharmacological agents and other membrane active compounds with biological membranes.

The antibacterial effect of selected phenothiazines and thioxanthenes on slow-growing mycobacteria.

The aim of the present investigation was to illustrate the antibacterial effect of various phenothiazine and thioxanthene derivatives on mycobacteria in vitro. It was demonstrated that clopenthixol is about twice as potent as chlorpromazine (CPZ) and levomepromazine-maleate is about half as potent as CPZ, measured by the inhibitory effect on the growth of the mycobacterial strains. Measured in the same way the stereoisomeric compounds of flupenthixol are shown to be more potent than the stereo-isomeric compounds of clopenthixol and chlorprothixen. The two last-named compounds are equal in potency. The stereo-isomeric analogs of the thioxanthene derivatives are equal in antibacterial potency against the slow-growing mycobacteria. The mycobacterial strains investigated show no difference in sensitivity between the cis (Z)--and and trans (E)--compounds of the thioxanthenes. It seems particularly promising that also the more resistant mycobacteria other than Mycobacterium tuberculosis, e.g. M. avium and M. intracellulare, are sensitive in the concentration range investigated. Considered as a whole, these results might be a stimulus to investigate the antimicrobial effect of the thioxanthenes in vivo.

Studies on structure-activity relationships of FK-156, an immunostimulating peptide, and related compounds. I. Synthesis of stereoisomeric analogues of FK-156.

Five stereoisomeric analogues, 2-6, of FK-156 (1), an immunostimulating microbial metabolite, have been synthesized and screened for immunostimulating activity. The results indicate that the D-configuration of glutamic acid and L-configuration of diaminopimelic acid at the site combining with other amino acids are essential, while the configurations of lactic acid and alanine are of little importance for the biological activity of the FK-156 series.

Antiviral activity of antilipidemic compounds on herpes simplex virus type 1.

Two antilipidemic compounds, clofibrate and procetofene, inhibited the replication of herpes simplex virus type 1 (HSV-1) in African green monkey kidney cells. Clofibrate, at a concentration of 400 mumol/liter caused a 63% reduction (P < 0.001) in HSV-1 yield and at 100 mumol/liter caused a 62% reduction (P < 0.001) in plaque formation. Two stereoisomeric analogs of clofibric acid, (-)- and (+)-desmethyl clofibric acid, also caused a significant inhibition of HSV-1 replication. Procetofene at 5 mumol/liter caused a 56% reduction (P < 0.001) in HSV-1 plaques and at 10 mumol/liter caused a significant reduction (P < 0.001) in both viral yield (42 to 54%) and plaque formation (65%). Procetofene also inhibited the development of HSV-1 plaques. A concentration of 5 mumol/liter resulted in a 26% reduction (P < 0.001) in plaque diameter. Because of their nonspecific inhibitory effect on the uptake of cellular macromolecular precursors for nucleic acid and protein biosynthesis, these antilipidemic compounds may exert their antiviral activity by affecting one or more key metabolic host cell pathways.

Studies on abscisic acid. Part XIV. Synthesis and physiological activity of methyl 6',6'-didemethyl abscisate and new chiral analogs.

Methyl 6', 6'-didemethyl abscisate (5) was synthesized and assayed to elucidate the physiological activity of methyl substituents on the cyclohexene ring of abscisic acid (ABA). During this study two new chiral stereoisomeric analogs 6 and 7 were synthesized from l- and d-carvone. The rice seedling assay and germination assay of garden radish showed that 6'-methyl groups of ABA were not important in biological activity and that 5'-isopropenyl analogs 6 and 7 were inactive.

L-glucosylceramide: synthesis, properties, and resistance to catabolism by glucocerebrosidase in vitro.

Procedures for the synthesis and radioactive labeling of L-glucosylceramide are described. This compound is a stereoisomeric analogue of D-glucosylceramide which occurs in nature and accumulates in pathological quantity in the organs and tissues of patients with Gaucher disease. The properties of L-glucosylceramide that have been examined so far have been found to be indistinguishable from those of the naturally occurring glycolipid. However, L-glucosylceramide is completely refractory to enzymatic hydrolysis by purified placental glucocerebrosidase and enzyme(s) present in whole tissue extracts. It is anticipated that L-glucosylceramide will be a uniquely useful substance for exploring pathogenetic processes in animal analogues of Gaucher disease.

Progestational activity of stereoisomeric progesterone-analogues following oral administration in amenorrhoea.

ABSTRACT A stereoisomeric analogue of progesterone, 9β,10α-pregn-4-ene-3,20-dione (retro-progesterone) and a 6-dehydro derivative, 9β,10α-pregna-4,6-diene-3,20-dione (6-dehydro-retro-progesterone) were studied for their progestational activity in 26 artificial cycles induced in 17 amenorrhoic women.1 It was found that 6-dehydro-retro-progesterone is a highly potent orally active progestational agent in the human subject. Daily doses of 10 mg of this compound given orally for 10 days induced a definite secretory transformation of the endometrium. The histological appearance of the endometrium following treatment with this compound could not be distinguished from that seen in normal cycles. Both compounds studied were excellently tolerated; no toxic side-effects were observed.