2-Tridecanone: A Naturally Occurring Insecticide from the Wild Tomato Lycopersicon hirsutum f.glabratum.

A nonalkaloid insecticide was isolated from the wild tomato Lycopersicon hirsutum f. glabratum and identified as 2-tridecanone, a compound 72 times more abundant in the wild tomato than in the cultivated tomato L. esculentum. Lepidopterous larvae (Manduca sexta and Heliothis zea) and aphids (Aphis gossypii) died when confined on 2-tridecanone-treated filter paper.

Novel degradation products from the treatment of salinomycin and narasin with formic acid.

Salinomycin and narasin (4-methylsalinomycin) upon treatment with HCO2H furnish the known furanone fragment 3 and the complementary but rearranged fragments 1 and 2 respectively. The structure of 1 has been established by X-ray analysis. Upon being heated under reflux in PhMe, 1 undergoes the retrograde aldol reaction to furnish alpha, gamma-dimethyl-2-furanbutanal (4). The furan moiety of 1 is more resistant to electrophilic substitution than expected, but it can be acylated by highly reactive reagents such as (CF3CO)2O and AcOSO2Me. Compounds 1 and 2, the acetyl and trifluoracetyl derivatives of the former, and the reduction products thereof have no significant anticoccidial activity.

1,3-Diamino-6,7-dimethoxyisoquinoline derivatives as potential alpha 1-adrenoceptor antagonists.

Treatment of 2-methyl-4,5-dimethoxybenzonitrile (3) with LDA followed by reaction with an N,N-disubstituted cyanamide provided a series of 1,3-diamino-6,7-dimethoxyisoquinolines (2), which were evaluated for alpha-adrenoceptor binding affinity and antihypertensive activity. 1-Amino-3-(dimethylamino)-6,7-dimethoxyisoquinoline (4) showed no significant affinity (Ki much greater than 10(-6) M) for alpha 1-adrenoceptors, while the corresponding 3-(2-furoylpiperazin-1-yl) analogue (8; Ki = 1.6 X 10(-7) M) was some 1000-fold less potent than prazosin. pKa data showed that N-2 protonation (34%) of 4 (pKa = 7.1) would occur at physiological pH, in agreement with X-ray crystallographic analysis of 8.HCl. Comparison of positive charge distribution following protonation of 4 with the corresponding quinoline and quinazoline cations confirmed N-1 protonation is required for these heterocyclic nuclei to bind efficiently to the alpha 1-adrenoceptor. Computer-assisted comparison of the X-ray structures of 8 and prazosin suggested that the 4.0 kcal/mol difference in alpha 1-adrenoceptor binding energies was largely due to salt-bridge formation (ca. 3.0 kcal/mol) between the protonated quinazoline and the receptor protein. None of the isoquinolines (2) proved to be effective antihypertensive agents in rats even when administered at relatively high doses (10 mg/kg). These results support the hypothesis that the antihypertensive activity of prazosin, doxazosin, and related derivatives derives solely from alpha 1-adrenoceptor blockade.

Synthesis, absolute configuration, and conformation of the aldose reductase inhibitor sorbinil.

The aldose reductase inhibitor 2,3-dihydro-6-fluorospiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5 '-dione was resolved into its enantiomers. Sorbinil, the S isomer, was found to be a better inhibitor of the enzyme in vitro and in vivo than the corresponding R isomer. X-ray data on sorbinil, which were used to determine its absolute configuration, are presented. NMR studies of sorbinil in solution indicate the existence of two conformers with a low energy barrier for interconversion.

5-Phenyl-3-ureidobenzazepin-2-ones as cholecystokinin-B receptor antagonists.

A series of 5-phenyl-3-ureidobenzazepin-2-one cholecystokinin-B (CCK-B) receptor antagonists was synthesized using Beckmann ring expansion of a suitable 4-phenyl-1-tetralone as a key step. Structure-activity relationship studies revealed the importance of the 5-phenyl group for potent and selective CCK-B affinity. Addition of an 8-methyl substituent and resolution provided the potent (CCK-B IC50 = 0.48 nM) CCK-B antagonist 4. The role of the 5-phenyl group as part of a "privileged structure" for high-affinity receptor antagonism is discussed.

Neuroleptic activity of chiral trans-hexahydro-gamma-carbolines.

A series of trans-8-fluoro-5-(4-fluorophenyl)-2,3,4,4a,5, 9b-hexahydro-1H-pyrido[4,3-b]indoles with various N-2 substituents has been prepared and tested for neuroleptic activity [( 3H]spiroperidol binding and amphetamine antagonism). Several members of this series showed exceptional in vivo potency, especially the hydantoin derivatives 27-30. Resolution into the enantiomers showed that neuroleptic activity is associated with the 4aS,9bS absolute configuration. These rigid neuroleptics have been correlated with other rigid neuroleptics [(+)-dexclamol, Ro 22-1319] and can serve to further define the topography of the dopamine receptor.

Hydantoin bioisosteres. In vivo active spiro hydroxy acetic acid aldose reductase inhibitors.

The hypothesis that clinical side effects of the aldose reductase inhibitor (ARI) sorbinil were related to its hydantoin ring led to a bioisosteric analysis and replacement of the hydantoin by a spiro hydroxy acetic acid moiety as in 40. These hydroxy acids, compared to hydantoins, showed a similar potency increase on chroman 2-methyl substitution, a similar orthogonal relationship of acidic to aromatic moieties, and similar ARI enantioselectivity. In this series the six-membered spiro hydroxy acetic acid anion array is a bioisostere for a spiro hydantoin anion and leads to ARIs with excellent in vivo activity. In vitro and in vivo activity was improved over 40 by chroman cis 2-methylation as in 4 and by aromatic 6,7-halogen substitution. Compounds with the best acute in vivo activity in rats were compared for chronic in vivo activity. The highest tissue levels and best chronic in vivo activities were found in the racemic 6,7-dichloro and 6-fluoro-7-chloro analogues 18 and 23. ARI activity was enantioselective for 58 and 60, the 2R,4R-enantiomers of 18 and 23. 7-Chloro-6-fluoro-cis-4-hydroxy-2(R)-methyl-chroman-4-acetic acid (60) was selected for phase 1 clinical trials and did not exhibit sorbinil-like hypersensitivity side effects.

Glucose transport-enhancing and hypoglycemic activity of 2-methyl-2-phenoxy-3-phenylpropanoic acids.

A series of 2-phenoxy-3-phenylpropanoic acids has been prepared which contains many potent hypoglycemic agents as demonstrated by assessing glucose lowering in ob/ob mice. Some compounds (32, 33, 59) normalize plasma glucose in this diabetic model at doses of approximately 1 mg/kg. The mechanism of action of these drugs may involve enhanced glucose transport, especially in fat cells, but the compounds do not stimulate GLUT4 translocation and do not increase the levels of GLUT1 or GLUT4 in vivo. Thus, these compounds may enhance the intrinsic activity of the glucose transporter GLUT1 or GLUT4. Some compounds also modestly decrease hepatocyte gluconeogenesis in vitro, but this is not likely to be a major contributor to the hypoglycemic effect observed in vivo. Likewise, a modest decrease in food consumption observed with some of these compounds was shown by a pair-feeding experiment not to be the primary cause of the hypoglycemia observed.

1-(3-cyano-2,3-dideoxy-beta-D-erythro-pentofuranosyl)thymine (cyanothymidine): synthesis and antiviral evaluation against human immunodeficiency virus.

1-(3-Cyano-2,3-dideoxy-beta-D-erythro-pentofuranosyl)thymine (cyanothymidine) (3a) has been prepared by an unambiguous route starting from D-xylose. The relative and absolute stereochemistry of 3a and its anomeric isomer 9 have been confirmed by NOE experiments and by X-ray diffraction analysis. In antiviral tests vs HIV 3a was shown to be inactive, a surprising result in view of a preliminary disclosure claiming potent anti-HIV activity. The activity previously assigned to 3a is believed to be due to contamination of that sample with the known antiviral nucleoside analogue 5b.

(1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol: a potent new neuroprotectant which blocks N-methyl-D-aspartate responses.

(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (20, CP-101,606) has been identified as a potent and selective N-methyl-D-aspartate (NMDA) antagonist through a structure activity relation (SAR) program based on ifenprodil, a known antihypertensive agent with NMDA antagonist activity. Sites on the threo-ifenprodil skeleton explored in this report include the pendent methyl group (H, methyl, and ethyl nearly equipotent; propyl much weaker), the spacer group connecting the C-4 phenyl group to the piperidine ring (an alternating potency pattern with 0 and 2 carbon atoms yielding the greatest potency), and simple phenyl substitution (little effect). While potent NMDA antagonists were obtained with a two atom spacer, this arrangement also increased alpha 1 adrenergic affinity. Introduction of a hydroxyl group into the C-4 position on these piperidine ring resulted in substantial reduction in alpha 1 adrenergic affinity. The combination of these observations was instrumental in the discovery of 20. This compound potently protects cultured hippocampal neurons from glutamate toxicity (IC50 = 10 nM) while possessing little of the undesired alpha 1 adrenergic affinity (IC50 approximately 20 microM) of ifenprodil. Furthermore, 20 appears to lack the psychomotor stimulant effects of nonselective competitive and channel-blocking NMDA antagonists. Thus, 20 shows great promise as a neuroprotective agent and may lack the side effects of compounds currently in clinical trials.

The discovery of (2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1- azabicyclo[2.2.2]-octan-3-amine as a novel, nonpeptide substance P antagonisst.

We describe the structure-activity relationship development of a series of quinuclidines which culminated in the first potent, selective, nonpeptide substance P (SP) antagonist, (2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxy-phenyl)methyl]-1- azabicyclo[2.2.2]octan-3-amine, 3 (CP-96,345). Compound 3 is a potent displacer of [3H]SP binding in human IM-9 cells and blocks SP-induced and capsaicin-induced plasma extravasation, as well as SP-induced salivation in the rat in vivo. This compound may both help to further our understanding of the interactions of small molecules with peptide receptors and serve to evaluate the therapeutic potential of a SP antagonist.

(3R,4S)-3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol: a conformationally restricted analogue of the NR2B subtype-selective NMDA antagonist (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)- 1-propanol.

(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606, 1) is a recently described antagonist of N-methyl-D-aspartate (NMDA) receptors containing the NR2B subunit. In the present study, the optimal orientation of compounds of this structural type for their receptor was explored. Tethering of the pendent methyl group of 1 to the phenolic aromatic ring via an oxygen atom prevents rotation about the central portion of the molecule. Several of the new chromanol compounds have high affinity for the racemic [3H]CP-101,606 binding site on the NMDA receptor and protect against glutamate toxicity in cultured hippocampal neurons. The new ring caused a change in the stereochemical preference of the receptor-cis (erythro) compounds had better affinity for the receptor than the trans isomers. Computational studies suggest that steric interactions between the pendent methyl group and the phenol ring in the acyclic series determine which structures can best fit the receptor. The chromanol analogue, (3R,4S)-3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1- yl]chroman-4,7-diol (12a, CP-283,097), was found to possess potency and selectivity comparable to CP-101,606. Thus 12a is a new tool to explore the function of the NR2B-containing NMDA receptors.

An approach to the skeleton of the securinega alkaloids. The total synthesis of (+/-)-securinine.

[structure: see text]. The concise total synthesis of securinine in nine steps from readily available starting materials is described. Key steps of the synthesis include an addition of a silyloxyfuran to an in situ generated iminium ion and a novel ring closing metathesis reaction.

Design of novel cholecystokinin-B receptor ligands based on the 'double-ring system' approach.

A structurally novel series of cholecystokinin-B (CCK-B) receptor ligands has been designed and synthesized based on the 'double ring system' theory of receptor recognition. Compounds 2b-cis and 2g-cis from this 1-amino-2-benzyltetralin series show modest CCK-B receptor affinity, with IC50 values of 48.5 nM and 39.0 nM, respectively. The results are discussed in the context of ongoing efforts to identify the CCK-B receptor binding site for nonpeptide ligands.

Discovery of CP-96,345 and its characterization in disease models involving substance P.

Studies with CP-96,345, a potent, selective, orally active, nonpeptide NK1 receptor antagonist, have provided considerable insight into SP pharmacology. Rather than being a primary neurotransmitter, SP prolongs the nociception produced by other neurotransmitters. By controlling endothelial permeability, SP plays a major role in inflammation and inflammatory aspects of asthma, possibly by regulating the access of neutrophils to an inflammatory site. These results indicate potential therapeutic applications for SP antagonists in the treatment of chronic pain, inflammation, and inflammatory aspects of asthma, and signal a new era in the clinical management of these important diseases.

Carolinoside: a phytosteroidal glycoside from Solanum carolinense.

The glycoside of a new class of phytosteroids has been isolated from Solanum carolinense. The steroidal aglycone (carolinone) is alkylated at C-3 and is identified as C-[(2,4,5-trideoxy-3-keto-4,5-dehydro)-pentulopyranosyl]-(5----3)- (13,14- seco-14 beta,17 alpha-dihydroxy) estrogen. The hydrolytic labile glycosyl moiety is identified as O-(beta-D-glucopyranosyl) (1----1)-[L-(2,6-dideoxy-3-C-methyl)- arabinopyranose]. The linkage of this disaccharide in the steroidal glycoside (carolinoside) is shown to be O-(alpha-pentulopyranosyl)- (1----4)-O-(beta-L-arabinopyranosyl)-(1----1)-D-glucopyranose. Carolinoside occurs at concentrations of 10(-7)-10(-6) M in leaf tissue and was shown to be the host plant specific feeding induction factor for Manduca sexta.

Structure of the natural antibiotic ionophore CP-54,883.

The structural formula of the novel antibiotic ionophore CP-54,883 is deduced by systematic reduction from its 13C and 1H NMR spectra. The molecule consists of a polyether ring network and side chain terminated by an aromatic ring containing a phenoxy and two chlorine substituents. Based partly on an assumed analogy to corresponding regions of the similar structure nigericin-A1, the configurations about the sixteen asymmetric carbons are also derived. A belated crystal structure determination confirms, with the exception of one configuration assumed from nigericin-A1, the conclusions drawn, and shows that the anionic charge is in the phenoxy group, rather than the carboxylic acid function.

UK-69,753, a novel member of the efrotomycin family of antibiotics. II. Structure determination and biological activity.

A novel antibiotic, UK-69,753, has been isolated from a submerged fermentation of Amycolatopsis orientalis strain N731-15. UK-69,753 has been assigned the structure 1 using spectroscopic means, primarily by NMR analysis. UK-69,753 is a glycoside of factumycin (A40A), a previously reported member of a small group of antibiotics related to aurodox and efrotomycin. UK-69,753 was shown to have potent activity both in vitro and in vivo against the swine pathogen Treponema hyodysenteriae.

The structures of atpenins A4, A5 and B, new antifungal antibiotics produced by Penicillium sp.

The structures of atpenins A4, A5 and B, new antifungal antibiotics produced by Penicillium sp., have been deduced to be I, II and III, respectively, on the basis of spectroscopic and 1H and 13C NMR spectral data. The molecular structure of atpenin A4 with absolute configurations was finally confirmed to be 2'S,4'S,5'S-5,6-dimethoxy-4-hydroxy-5'-chloro-2',4'- dimethyl-1'-oxoheptyl-2-hydroxypyridine (I') by the single crystal X-ray crystallographic analysis. The absolute configurations of atpenins A5 and B were also expected to be 2'S,4'S,5'R-II (II') and 2'S,4'R-III (III'), respectively.

CP-84,657, a potent polyether anticoccidial related to portmicin and produced by Actinomadura sp.

A new polyether antibiotic CP-84,657 (C45H78O14) was isolated by solvent extraction from the fermentation broth of Actinomadura sp. (ATCC 53708). Following purification by column chromatography and crystallization, the structure of CP-84,657 was elucidated by spectroscopic (NMR and MS) methods. The absolute stereochemistry was determined by a single crystal X-ray analysis of the corresponding rubidium salt. CP-84,657 is among the most potent anticoccidal agents known, effectively controlling the Eimeria species that are the major causative agents of chicken coccidiosis at doses of 5 mg/kg or less in feed. It is also active in vitro against certain Gram-positive bacteria, as well as the spirochete, Treponema hyodysenteriae.