New highly active taxoids from 9 beta-dihydrobaccatin-9,10-acetals

To synthesize new highly active taxoids, we designed and synthesized 9 beta-dihydro-9,10-acetal taxoids. In vitro study of these analogues clearly showed them to be more potent than docetaxel.     

New highly active taxoids from 9beta-dihydrobaccatin-9,10-acetals. Part 3

We synthesized novel water-soluble and orally active taxane analogues, 7-deoxy-9beta-dihydro-9,10-O-acetal taxanes. Cytotoxicities of the synthetic compounds were greater than those of paclitaxel and docetaxel, especially against resistant cancer cell lines expressing P-glycoprotein. In addition, some compounds showed potent antitumor effects against B16 melanoma BL6 in vivo by both iv and po administration.     

New highly active taxoids from 9beta-dihydrobaccatin-9,10-acetals. Part 4

It was shown that a new taxane analogue 3, which exhibited both in vitro antitumor activity and in vivo efficacy by both i.v. and p.o. administration, was prone to be metabolized by human liver microsomes. We identified a major metabolite, M-1, generated by human liver microsomes as 20a, a hydroxylated compound at the pyridine ring of 3. To improve the metabolic stability of 3, we designed and synthesized new taxane analogues based on the structure of M-1, and obtained some compounds that maintained excellent antitumor activity and were scarcely metabolized by human liver microsomes.     

New highly active taxoids from 9beta-dihydrobaccatin-9,10-acetals. Part 2

To investigate structure-activity relationships of the 9,10-acetal-9beta-dihydro taxoids, we modified the 7-hydroxyl groups of the 9,10-acetonide-3'-(4-pyridyl) analogue to deoxy, methoxy, alpha-F, and 7beta,8beta-methano group. As a result of this study, we found that the 7-deoxy analogue was the strongest among these analogues. In addition, we found that the 7-deoxy-3'-(4-pyridyl) and 7-deoxy-3'-(2-pyridyl) analogues showed stronger activity against cell lines expressing P-glycoprotein than the corresponding 3'-phenyl analogue.     

9,10-Anthraquinones and other biologically active compounds from the genus Rubia

The secondary metabolites isolated from Rubia species, their biological activities, and colouration properties have been reviewed. Over 150 chemical constituents belonging to different classes of bioactive compounds such as anthraquinones and their glycosides, naphthoquinones and glycosides, terpenes, bicyclic hexapeptides, iridoids, and carbohydrates are listed together with their source(s) and corresponding references.     

Synthesis of highly pure oxyphytosterols and (oxy)phytosterol esters. Part II. (Oxy)-sitosterol esters derived from oleic acid and from 9,10-dihydroxystearic acid [1

Several efficient synthetic routes giving readily access to (oxy)-sitosterol esters and (oxy)-cholesterol esters derived respectively from oleic acid and from 9,10-dihydroxystearic acid were developed for the first time. This approach allowed that sufficient amounts of the latter were available in order to carry out further biological studies.     

Design and synthesis of a highly selective EP4-receptor agonist. Part 2: 5-thia and 9beta-haloPG derivatives with improved stability.

Further chemical modification to identify more chemically stabilized EP4-receptor selective agonists was continued. As a result, a further two EP4-receptor selective agonists 5-thiaPGE(1) 2a, 10 and 9beta-chloroPGF(2) analogue 11 were discovered.     

omega-Hydroxylation of Z9-octadecenoic, Z9,10-epoxystearic and 9,10-dihydroxystearic acids by microsomal cytochrome P450 systems from Vicia sativa.

A microsomal fraction from etiolated Vicia sativa seedlings incubated aerobically with [1-14C]oleic acid (Z9-octadecenoic acid) or [1-14C]9,10-epoxystearic acid or [1-14C]9,10-dihydroxystearic acid catalyzed the NADPH-dependent formation of hydroxylated metabolites. The chemical structure of compounds formed from oleic, 9,10-epoxystearic or 9,10-dihydroxystearic acids was established by gas chromatography/mass spectra analysis to be 18-hydroxyoleic acid, 18-hydroxy-9,10-epoxystearic acid and 9,10,18-trihydroxystearic acid, respectively. The reactions required O2 and NADPH and were inhibited by carbon monoxide. As expected for monooxygenase reactions involving cytochrome P450, inhibition could be partially reversed by light and all three reactions were inhibited by antibodies raised against NADPH-cytochrome P450 reductase from Jerusalem artichoke. The omega-hydroxylation of the three substrates was enhanced in microsomes from clofibrate induced seedlings.     

Formation of 9,10-epoxypalmitate and 9,10-dihydroxypalmitate from palmitoleic acid by a soluble system from Bacillus megaterium.

A soluble, cytochrome P-450-containing system from $\text{Bacillus}\text{megaterium}$ which catalyzes the monohydroxylation of long-chain saturated fatty acids has now been found to convert palmitoleic acid to 9,10-epoxypalmitate and 9,10-dihydroxypalmitate in addition to the expected isomeric mixture of monohydroxypalmitoleic acids.     

Purification of a highly active protease from aMicrosporum species

A method is described for obtaining a highly active proteolytic enzyme from aMicrosporum species. This protease was purified (200-fold) from a cell-free culture medium by concentration with Carbowax, ammonium sulfate fractionation, charcoal and Celite filtration, calcium phosphate gel treatment, and column chromatography. The pH and temperature optima are 6.8 and 35 C respectively. Requirement of one or more free sulfhydryl group(s) for enzyme activity was indicated by inhibition withp-chloromercuric benzoate. Ethylenediaminetetraacetic acid also caused inhibition of proteolytic activity, which suggests involvement of a metal ion. The enzyme appears to be most active in the reduced form;l-cysteine and 2,3 dimercapto-l-propanol doubled the rate of activity. It has an approximate molecular weight of 51,000 to 69,000. The enzyme was highly active on all proteins examined.     

Ouabain-insensitivity of highly active Na+, K+-dependent adenosinetriphosphatase from rat kidney.

Highly purified preparations of Na⁺+K⁺-dependent adenosinetriphosphatase were isolated from rat kidney by two different procedures. The I₅₀ values for ouabain inhibition of the rat kidney enzyme at various stages of purification were determined to be essentially the same for all fractions tested (0.7 to 1.0 × 10^?4M). These results suggest that the marked insensitivity of the rat enzyme to inhibition by cardiac glycosides is due to the primary structure of the enzyme, and not to some other component in the tissue.     

Metabolism investigation leading to novel drug design 2: orally active prostacyclin mimetics. Part 5

A metabolism study of FK788 (2) led to the discovery of new diphenylcarbamoyl derivatives as prostacyclin mimetics without the PG skeleton. We designed and evaluated PGI(2) mimetics based on blocking the main metabolic pathway of FK788. The new compound 7c was found to be equipotent to FK788 towards PGI(2) agonist activity and metabolically more stable than FK788.     

Comparative studies on highly metabolically active histone acetylation.

Histone acetate is hydrolyzed rapidly in logarithmically dividing hepatoma tissue culture cells (Jackson, V., Shires, A., Chalkley, R. and Granner, D.K. (1975) J. Biol. Chem. 250, 4856--4863). The phenomenon has been analyzed further in hepatoma tissue culture cells at various stages of the cell cycle, in stationary phase, and in the presence of actinomycin D. We also investigated the phenomenon in Tetrahymena pyriformis macronuclei, bovine thymocytes, and human foreskin fibroblasts. The data suggest that this highly metabolically active histone acetylation while altered in mitotic cells, is independent of the overall rate of cell division, and is only slightly sensitive to actinomycin D. Finally, we conclude that the same general phenomenon is found in both cancerous and normal cells and is apparently common to cells from various stages of the evolutionary scale.     

A highly active oxygen-evolving Photosystem II preparation from synechococcus lividus

A PS II preparation highly active in oxygen generation was prepared from the cyanophyte, Synechococcus lividus. This preparation was enriched in Hill reaction activity, manganese, cytochrome b-559, and possessed only trace amounts of cytochrome b-563. This non-phosphorylating, visually clear preparation appears to be a promising system for the detailed study of Photosystem II.