Setsuo Saito

Spirostanols obtained by cyclization of pseudosaponin derivatives and comparison of anti-platelet agglutination activities of spirostanol glycosides.

Naturally occurring saponins 3 and 4 have a normal type F ring and alpha-arranged CH(3)-21 group. Treatments of pseudosaponin peracetates 18 and 19 derived from 3 and 4, respectively, with alcoholic KOH, followed by acidification with acetic acid, gave spirostanols 20 and 22 having iso type F rings as major products. Structural analyses of sapogenins and saponins derived from pseudo derivatives 11, 12, 18 and 19 were performed by comparisons of their 1H-NMR spectral data and the X-ray analytical data of 3-O-p-bromobenzoyl sarsasapogenin 7, 3-O-acetyl diosgenin 13 and saponin 20. The mechanisms of ring-closure reaction of the side chain at C-22 of pseudosapogenins and pseudosaponins were deduced using stereomodels of the spirostanols derived from 11 under various reaction conditions. Inhibitory activities of saponin diglycosides 3, 4, 20, 21 and 25 on human platelet agglutinations induced by ADP and ristocetin were compared.

α-Trifluoromethylated acyloins induce apoptosis in human oral tumor cell lines

Cytotoxic activity of newly synthesized trifluoromethyl ketones and related compounds was studied using two human oral tumor cell lines (HSG and HSC-2). Among them, α-trifluoromethylacyloins (1 and 2) were found to induce apoptotic cell death, as judged by the terminal deoxynucleotidyl transferase (TdT) dUTP nick end-labeling (TUNEL) method which detects DNA nick or fragments. Furthermore, the cytoplasm of 1 or 2 treated HSG cells was stained by M30 monoclonal antibody, which detects the product resulting from the cleavage of cytokeratin 18 by activated caspase.

Chemistry and biological activity of new 3-benzazepines.

This review summarizes our experiments investigating structure-activity relationships of 3-benzazepines. Three 7, 8-dihydroxy-3-benzazepines [7-9] were cytotoxic to human promyelotic leukaemia HL-60 cells. Compound [9] showed the highest cytotoxicity and the activity was twice as high as that of dopamine (DA, [11]). Three active compounds [7-9] produced radicals, whereas other less potent benzazepines [1-6, 10] did not produce radicals. Furthermore, cytotoxic 3-benzazepines [7-9] also enhanced the decay of ascorbic acid in rat brain homogenate. Two 7,8-dimethoxy-3-benzazepines [5, 10] were able to form a complex with the replicative form of plasmid DNA. The multidrug resistance (MDR) P-glycoprotein (Pgp) efflux pump of mouse lymphoma cells was inhibited by three compounds [5, 8, 10]. Compound [8] has the highest activity in MDR reversal and is two times more potent than verapamil. Three cytotoxic 3-benzazepines [7-9] showed inhibitory effects against reverse transcriptase (RT) of Moloney leukemia.

Preparations of heterospirostanols and their pharmacological activities

(3beta,20S,22S,25R)-22-Thiospirosol-5-en-3-ol (9) and (3beta,20S,22S,25R)-22-seleno-spirosol-5-en-3-ol (11) were prepared from diosgenin (3) via 26-iodopseudodiosgenin (6) as a key intermediate. Diosgenone (15), solasodinone (16), (20S,22S,25R)-22-thio-spirosol-4-en-3-one (17), (20S,22S,25R)-22-selenospirosol-4-en-3-one (18) and (20R,22S,25R)-spirosol-4-en-3-one (19) were prepared by Oppenauer oxidation of 3, solasodine 4, 9, 11 and (3beta,20R,22R,25R)-spirosol-5-en-3-ol 14, respectively. Oxidations of 15 and 16 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) provided corresponding dienone products, (20S,22S,25R)-spirosol-1,4-dien-3-one (20) and (20S,22S,25R)-22-thiospirosol-1,4-dien-3-one (21), respectively, while oxidation of 19 (C-20 diastereoisomer of 15) gave no dienone product but 21-exo vinyl product 22. 26-Thioacetylpseudodiosgenone (24) and 26-cyanoselenopseudodiosgenone (25) were prepared by treatment of 26-iodopseudodiosgenose (23), which was obtained by Oppenauer oxidation of 6, with potassium thioacetate and potassium selenocyanate, respectively. Compounds 15 and 19 exhibited more than 80% inhibitions in INF-gamma productions at 10.0 microM. Compounds 4 and 25 showed cytotoxic activities (IC(50) = 6 and 5 microM, respectively) against cancerous HCT 116 cell lines. Compounds 12 and 25 had antiurease activities (IC(50) = 12.4 and 11.4 microM, respectively), in which only the latter showed an inhibition zone (mean zone diameter = 12.2 mm) formed by Bacillus subtilis 168 trp.

Heterocyclization of 4-trifluoroacetyl-2,3-dihydropyrroles with hydrazines and amidines: A new access to trifluoromethylated pyrazoles and pyrimidines bearing a β-aminoethyl side chain

Abstract Trifluoromethyl-substituted heterocycles have been prepared by condensation of the new 4-trifluoroacetyl-2,3-dihydropyrroles with hydrazines or amidines as a bifunctional N-nucleophile with opening of the dihydropyrrole ring.

In vitro susceptibility of Helicobacter pylori to trifluoromethyl ketones

Heteroaromatic trifluoromethyl ketones (TFMKs) showed strong inhibitory activity against Helicobacter pylori. The MIC50 observed for 2-trifluoroacetonylbenzoxazole (1) is 20-fold more active than metronidazole and is only twice as high as that of clarithromycin. The inhibitory mode of TFMKs on Hp growth was not related to inhibition of urease.

Synthetic studies on the relationship between anti-HIV activities and micelle forming abilities of various alkylated glycyrrhetinate diglycoside sodium sulfates and related compounds

Summary Sodium sulfates 11–14, 29–32, 35 and 37 of various alkyl glycyrrhizin and related compounds were synthesized. In vitro anti-HIV activities of the sulfates were compared to the activities of glycyrrhizin 1 in the inhibition of replications of HTLV-III and GUN-4. The activities of the sulfates were increased 11.1, 15.2, 9.1 and 5.0 times for 11-14 , 100.0, 125.5, 83.3 and 11.6 times for 29-32 , and 11.6 and 50.0 times for 35 and 37. From the relationship between CMC values and anti-HIV activities of the sulfates, it appeared that the sulfates exhibiting more potent antiviral activities had higher micelle forming abilities. Sodium sulfates having a triterpenoid or steroid ring in the molecule showed more potent activities than those of thioglycosides which had no such ring. From the investigation of syncytium formation, we suggest that the active sulfates inhibited HIV-1 infection early in the replication cycle of the virus.

Synthesis and biological activity of N-acylphenothiazines

Previous studies have demonstrated the relationship between radical intensity and cytotoxic activity in water-soluble compounds. This relationship was investigated in lipophilic compounds. Several N-acylphenothiazines showed higher cytotoxic activity against human leukemic and squamous carcinoma cell lines than phenothiazine, the parent compound. Electron spin resonance (ESR) spectroscopy showed that these active compounds produced much lower amounts of radicals than phenothiazine. Several compounds failed to inhibit the cytopathic effects of human immunodeficiency virus (HIV) infection in MT-4 cells. It suggested that the radical-mediated-mechanisms has not involved in the induction of cytotoxic activity by lipophilic compounds, such as N-acylphenothiazines.

Synthesis of glycyrrhetic acid diglycosides and their cytoprotective activities against CCl4--induced hepatic injury in vitro

Summary Glycyrrhetic acid diglycosides 2 and 46 ,, with respectively β- d --glucuronopyranosyl-(1→3)-β- d --glucopyranose, -(1→6)-α- d --glucopyranose, -(1→6)-β- d --glucopyranose, -(1→6)-β- d --galactopyranose, and β- d --galacturonopyranosyl-(→2)-β- d --glucopyranose as sugar components at the O --3 positions on the aglycons, were synthesized. In vitro cytoprotective activities, against CCl 4 --induced hepatic injury, of the synthetic diglycosides, methyl β- d --glucuronopyranosyl-(1→4)-α- d --glucopyranosyl- d --glycyrrhetinate 3 a and methyl esters 5 a and 3 ( (the precursors of 6 a and 4 r respectively) were compared with those of glycyrrhizin 1 and β- d --glucuronopyranosyl-(1→2)-β- d --glucopyranosyl-glycyrrhetic acid 2 .. Of the glycosides 4 , and, and 5 ,, with β- d --glucuronopyranosyl-glucopyranose as the sugar component, 6 a and 4 w were as cytoprotective as 1 and 2 ,, whereas 5 s showed no remarkable activity. From stereomodels of the glycosides these differences in activity were inferred to be due to the stereochemistries of the terminal β- d --glucuronopyranoses in the molecules. Glycoside 6 ,, in which the terminal β- d --glucuronopyranose of 2 was replaced by β- d --galacturonopyranose, was as potent as 2 .. Further, it was confirmed that a free COOH group on the E ring of aglycon was essential for the activity.

Transdermal delivery of the potent analgesic dihydroetorphine: kinetic analysis of skin permeation and analgesic effect in the hairless rat.

Dihydroetorphine is an extraordinarily strong opioid analgesic. To assess its effectiveness after topical application in hairless rats we have examined the kinetic analysis of skin permeation through excised skin and the in‐vitro reservoir effect of skin, and have investigated the predictability of plasma concentration and analgesic effect following in‐vivo transdermal application.