Sanji Hagishita

Potent cytotoxic metabolites from a Leptosphaeria species. Structure determination and conformational analysis

Abstract New cytotoxic epipolysulfanyldioxopiperazine dimers, leptosins K (4), K1 (5) and K2 (6), have been isolated from a strain of Leptosphaeria sp. originally isolated from the marine alga Sargassum tortile. Their stereostructures, with a different configuration from that of leptosins A-C, have been elucidated by spectral and X-ray analyses and some chemical transformations. X-Ray and NMR and NOE spectral analyses of 4 revealed that it exists in a mixture of four conformers, of which two each closely resemble, in a single crystal, and in a single conformer in solution. NOE experiments of 5 and 6 demonstrated that they exist in a mixture of two conformers slowly exchanging in CDCl3.

Absolute stereostructures of novel cytotoxic metabolites, penostatins A–E, from a Penicillium species separated from an Enteromorpha alga

Abstract Penostatins A – E have been isolated from a strain of Penicillium sp. originally separated from the marine alga Enteromorpha intestinalis , and their absolute stereostructures and conformations have been established on the basis of spectral analyses and some chemical transformations. All the compounds except for penostatin D exhibited significant cytotoxicity against cultured P388 cells.

Leptosins O-S, Cytotoxic Metabolites of a Strain of Leptosphaeria Sp. Isolated from a Marine Alga

Leptosins O (1), P (2), Q (3), R (4) and S (5) have been isolated from a strain of Leptosphaeria sp. originally separated from the marine alga Sargassum tortile. Their absolute stereostructures have been elucidated on thebasis of spectroscopic analyses of their acetate derivatives (6-10) using various ID and 2D NMR techniques and some chemical transformations. The NMR and NOE spectral analyses of 6-10 revealed that they exist in a single conformer of B type in CDCl 3 . Among these metabolites, leptosins O (1) and P (2) exhibited significant cytotoxicity against cultured P388 cells.

Synthesis and chiroptical properties of bridged 2,2′-diaminobiphenyl derivatives

The relationship between c.d. spectra and the conformation of chiral 2,2′-diaminobiphenyls was investigated as a function of the torsion angle between the benzene ring planes. The molecular structures of (S)-(+)-4,5,6,7,11,12,13,14-octahydro[1]benzazocino[7,6,5-efg][1]benzazocine (22), (S)-(–)-2,2′-diamino-6,6′-dimethylbiphenyl (25), and (S)-(–)-(6R,7R)-5,6,7,8-tetrahydro-1,6,7,12-tetramethyldibenzo[e,g][1,4]diazocine (27) were determined by X-ray analysis. The shape of the c.d. spectrum of (22)(trans-conformation) is similar to those of (25) and (27)(cis-conformation). The experimental results and theoretical consideration by the exciton approximation and the π-SCF-MO approximation indicated that the shape of the c.d. spectrum is the same at least for torsion angles of 0–120°. On the other hand, the shape of the c.d. spectrum of the protonated species was inverted with a critical torsion angle of ca. 90°.

Penostatins F–I, novel cytotoxic metabolites from a Penicillium species separated from an Enteromorpha marine alga

Penostatins F–I have been isolated from a strain of Penicillium sp. originally separated from the marine alga Enteromorpha intestinalis, and their stereostructures have been established on the basis of spectral analyses. All the compounds exhibit significant cytotoxicity against cultured P388 cells.

Synthesis and pharmacological properties of ureidomethylcarbamoylphenylketone derivatives. A new potent and subtype-selective nonpeptide CCK-B/gastrin receptor antagonist, S-0509.

A novel series of CCK-B/gastrin receptor antagonists-ureidomethylcarbamoylphenylketone derivatives-were designed, synthesized, and evaluated for activity. Structure-activity relationship studies revealed the importance of a carboxylic acid at substituent R2 and tert-butoxycarbonyl group at R1 in structure A. Compound 7a (S-0509) showed remarkable affinity for the CCK-B/gastrin receptor and a subtype selectivity profile in vitro. Administration (id) of 7a led to excellent inhibition of gastric acid secretion induced by pentagastrin in anesthetized rats with an ED50 value of 0.014 mg/kg. Furthermore, 7a proved to have poor blood-brain permeability by its small effect on enhancement of morphine analgesia. Thus, S-0509 has an increase in selectivity for the peripheral effects of gastrin antagonism from the central effects of CCK-B antagonism.

Design, synthesis, and pharmacological evaluation of dual histamine H2 and gastrin receptor antagonists

Abstract The joint type of hybrid molecules composed of two pharmacophore moieties taken from histamine H2 and gastrin receptor antagonists have been designed and synthesized to exhibit dual histamine H2 and gastrin receptor antagonistic activities. Here we report the importance of spacers as well as binding sites of both pharmacophores for the dual activity.

Potent and subtype-selective CCK-B/gastrin receptor antagonists: 2,4-dioxo-1,5-benzodiazepines with a plane of symmetry

A series of CCK-B/gastrin receptor antagonists, 2,4-dioxo-1,5-benzodiazepine derivatives with a plane of symmetry, were designed, synthesized, and evaluated for antagonistic activity. Structure-activity relationship studies revealed that carbonylmethyl groups at both N-1 and N-5 positions and hydrophilic groups, such as the carboxyl group on the benzene ring attached to the ureido group at the C-3 position, brought about potent affinity and subtype selectivity for CCK-B/gastrin receptors. Several compounds showed excellent in vivo inhibition of gastric acid secretion induced by pentagastrin in anesthetized rats.

Synthesis and pharmacological evaluation of highly potent dual histamine H2 and gastrin receptor antagonists

Abstract The chemical modification of the dual histamine H2 and gastrin receptor antagonists described in our preceding paper, particularly the modification of spacers as well as the alteration of their connecting bonds at the gastrin receptor antagonist site (GA) from the amide bond to the carbamate bond, significantly improved not only their dual activity but also the GA versus CCK-A receptor selectivity.

Synthesis and structure-activity relationships of dual histamine H2 and gastrin receptor antagonists with modified benzodiazepine skeletons

Three different types of dual histamine H2 and gastrin receptor antagonists, e.g. those bearing a benzazepine, benzoxazepine, or benzothiazepine skeleton instead of the benzodiazepine one as a gastrin receptor antagonistic moiety were synthesized to reduce high hydrophobicity of parent compounds and evaluated for the dual activities. These skeletal modifications significantly potentiated the binding affinity of dual antagonists with histamine H2 receptor but markedly diminished their binding affinity with the gastrin receptor and the gastrin versus CCK-A receptor selectivity. We evaluated in vivo gastric acid antisecretory activities for some representative compounds by the rat pylorus ligation method for 10 mg kg(-1) dose by oral route. However, they exerted only low inhibitory activities for oral dose with % inhibition values ranging between 32 and 53%.