Steroidal alpha-methylene delta-lactones as potential antitumor agents.

Four novel steroidal alpha-methylene delta-lactones have been synthesized and shown to be active against human nasopharyngeal carcinoma (KB) cells in culture. The syntheses involved the use of known alpha-methylenation procedures. In addition, the lactone 6 was directly methylenated by reaction with CH2O/KOH or Et2NH/CH2O/Et2NH.HCl. The formation of a cysteine adduct (15) with the alpha-methylene lactone 10 is reported.

3,17 beta-Dihydroxy-20,21-epoxy-19-norpregna-1,3,5(10)-trienes: synthesis, rearrangement, cytotoxicity, and estrogen-receptor binding.

Diastereoisomers of 3,17 beta-dihydroxy-20,21-epoxy-19-norpregna-1,3,5(10)-triene have been prepared as potential antitumor agents. Both isomers undergo the base-catalyzed Payne rearrangement. The isomers were cytotoxic to mammalian cells in culture and were able to displace [3H]estradiol from binding sites in rat uterine cytosols with 1/7 and 1/70 the potency of estradiol. The reasons for this difference are discussed.

The metabolism and biological activity of ABA analogues in normal and flacca mutant tomato plants.

The metabolism of deuterium-labelled analogues of ABA by normal and flacca mutant tomato plants was investigated. Comparison of the biological activity of ABA, ABA alcohol, ABA aldehyde and their 2-trans isomers was made in both mutant and non-mutant genotypes. While in normal plants ABA alcohol and ABA aldehyde were as effective as ABA in inducing stomatal closure, in the flacca mutants only ABA itself was biologically active. Both ABA alcohol and ABA aldehyde were converted to the inactive compound trans- ABA alcohol instead of ABA when fed to flacca plants. As trans-ABA aldehyde was also readily converted to trans-ABA alcohol by flacca plants, it was not possible to establish whether isomerization precedes reduction or vice versa in the synthesis of trans-ABA alcohol from ABA aldehyde.

Preparation of 16-formylestradiol and the 16-(alpha-methylenebutanolide) derivative.

Routes to the preparation of 16-formylestradiol are described. Estrone was converted to (E)-16-methoxymethylene estrone via the 16-hydroxymethylene estrone. Reduction of the methoxymethylene estrone with NaBH4 in the presence of CeCl3 gave 16-methoxymethylene estradiol. Deprotection by acid afforded the desired 16-formylestradiol. Attempts to prepare the 16-formylestradiol via the 16-butylthiomethylene derivative gave only 16-formylestra-1,3,5(10),16-tetraen-3-ol, and a route through the 16-dimethoxymethyl derivative gave a mixture of the 16-formyltetraen-3-ol and the 16-formylestradiol in low yield. The 16-formylestradiol was subsequently converted to the alpha-methylene lactone conjugate, 4-(3,17 beta-dihydroxyestra-1,3,5(10)trien-16-yl)-2-methylene-4-butanol ide by reaction with methyl alpha-(bromomethyl) acrylate and zinc.

Synthesis and cytotoxic activity of estrogen alpha-methylene-delta-lactones.

Several estrogen derivatives containing the alpha-methylene-delta-lactone group as part of the D-ring were prepared as anti-tumor agents. The compounds were highly toxic towards HeLa S3 cells grown in culture.

Preliminary investigations of some derivatives of oxamniquine.

Oxamniquine is a potent schistosomicide used clinically in the treatment of infections due to Schistosoma mansoni. Although relatively well tolerated, some central nervous system (CNS) effects characterised by convulsions have been reported in a small proportion of the population receiving this drug. Oxamniquine, the major metabolite and the secondary alcohol have been screened for convulsant activity by assessing their ability to potentiate catechol induced seizures in urethane anaesthetised mice. Significant (p < 0.05) potentiation was observed with subconvulsive doses (1.5 mg/kg) of strychnine. In contrast, oxamniquine and the secondary alcohol, each at 200 mg/kg ip, both produced significant (p < 0.05) depressions of seizures in this model whereas no effect was seen following 140 mg/kg ip of the acid derivative. These results indicate anticonvulsant rather than convulsant activity in oxamniquine and the alcohol derivative. The failure to observe any effect with the acid derivative may have been due to poorer CNS penetration.

Aspects of the effect of bile salts on Candida albicans.

Cholic acid, chenodeoxycholic acid, deoxycholic acid, glycocholic acid, glycodeoxycholic acid, hyodeoxycholic acid and lithocholic acid as their sodium salts, were fungistatic to the growth of Candida albicans. Of the compounds tested, cholic acid, deoxycholic acid and chenodeoxycholic acid were the most active. In combination with other antifungal agents only cholic acid exhibited synergism with amphotericin B, whilst the imidazole antifungal agents inhibited the action of the bile salts. The bile salt minimal inhibitory concentrations were close to the critical micelle concentrations. Even though the compounds are surface active they did not cause loss of intracellular K+ and were without effect on oxygen consumption. The bile salts, particularly cholic acid, produced morphological changes that gave rise to swollen cells.

Structure of (20R)-20,21-epoxy-19-norpregna-1,3,5(10)-triene-3,17 beta-diol.

C20H26O3, Mr = 314.4, orthorhombic, P2(1)2(1)2(1), a = 10.25 (1), b = 25.36 (2), c = 13.11 (1) A, V = 3410.14 A3, Z = 8, Dx = 1.225 g cm-3, lambda(Mo K alpha) = 0.71069 A, mu = 0.45 cm-1, F(000) = 1352, T = 293 K. The structure was solved by direct methods and refined to R = 0.051 for 2384 reflections with F/signa(F) greater than 5. Both the crystallographically independent molecules are in one 20R configuration and confirm predictions based on mechanistic and stereochemical arguments. In the crystal lattice the molecules form a two-dimensional network of hydrogen bonds approximately perpendicular to c.