New macrocyclic trichothecenes from Baccharis megapotamica.

The isolation and structural elucidation of biologically active baccharinoids B1 [11a], B2 [12a], B3 [5a], and B7 [6a] are reported with crystal structure determinations of baccharinoid B7 and of the triacetate of baccharinoid B2. All four compounds are isomeric with 11a/12a and 5a/6a being epimeric at C13'.

Psorospermin, a new antileukemic xanthone from Psorospermum febrifugum.

An ethanolic extract of Psorospermum febrifugum was fractionated with antileukemic activity in vivo in the P388 lymphocytic leukemia in mice and in vitro in the KB cell culture system used as a guide. The new antileukemic xanthone psorospermin 1 was isolated, and its structure was elucidated. The chlorohydrin of O-methylpsorospermin 2 was also isolated after treatment of the fraction containing psorospermin chlorohydrin 6 with diazomethane. Psorospermin 1 was demonstrated to have significant antitumor activity in the P388 in vivo system as well as cytotoxicity against the KB in vitro system.

Structure-activity relationships among in vivo active germacranolides.

Nine structurally related germacranolides from Eupatorium semiserratum and Eriophyllum confertiflorum were assayed in two standard tumor systems (PS and KB) to determine the structural features required for in vivo antileukemic activity. The moieties necessary for in vivo activity were found to be an alpha,beta-unsaturated ester side chain adjacent to the gamma-lactone and either a primary or secondary allylic alcohol or both.

Structural requirements for antileukemic activity among the naturally occurring and semisynthetic maytansinoids.

In an effort to determine the structural requirements for the significant antileukemic, cytotoxic, antitubulin, and antimitotic activity exhibited by the novel ansa macrolide, maytansine (1), four new C-3 ester and six new C-9 ether homologues were synthesized. The biological activities of these compounds were assayed and compared to the activities of previously reported, naturally occurring maytansinoids. From the data, it is apparent that presence of the C-3 ester is necessary for significant activity, and variations in the ester group are not accompanied by marked changes in activity. However, elimination of the ester group, as in maytansinol (7), maysine (8), normaysine (9), and maysenine (10), results in a significant decrease in biological activity. Blockage of the C-9 carbinolamide via etherification markedly reduces antileukemic and cytotoxic activity and slightly reduces antitubulin activity but has relatively little effect on antimitotic activity against sea urchin eggs. Thus, a free carbinolamide at C-9 is advantageous for optimal activity.

Antimitotic and antitubulin activity of the tumor inhibitor steganacin.

Steganacin, a newly isolated tumor inhibitor, completely inhibits cleavage in sea urchin eggs at 3 X 10(-7) M by preventing the formation of the mitotic apparatus. Steganacin inhibits the polymerization of tubulin in vitro and also causes a slow depolymerization of preformed microtubules. Optical ultracentrifuge studies of steganacin-treated tubulin show a small reduction in 20 S and 30 S peaks at 0 degree. In electron microscope studies the ring structure of tubulin is seen at 0 degree but disappears if the temperature of tubulin incubated with steganacin is raised to 37 degrees. Steganacin inhibits the binding of colchicine to tubulin and thus resembles podophyllotoxin, which also competitively inhibits colchicine binding. Steganacin had a trimethoxybenzene ring and probably interacts with that portion of the colchicine-binding site that recognizes the trimethoxybenzene ring of colchicine.

Structural requirements for biological activity among antileukemic glaucarubolone ester quassinoids.

A C-15 ester substituent is required for significant antileukemic activity among the glaucarubolone ester quassinoids, and variations in the ester group are not accompanied by particularly marked changes in antileukemic activity. Unsaturation at the 3,4 position is advantageous for optimal activity, and hydrogenation of this double bond results in marked diminution in both cytotoxicity toward KB cells in tissue culture and inhibitory activity against the P-388 lymphocytic leukemia in mice.

Novel plant-derived tumor inhibitors and their mechanisms of action.

The activity-directed isolation of new tumor inhibitors of plant origin has yielded many novel compounds with significant growth-inhibitory properties. A large proportion of the new compounds contain highly electrophilic functionalities and chemical and biochemical studies are yielding a growing body of evidence to support the view that these compounds may act by selective alkylation of growth-regulatory biologic macromolecules. The selectivity may result from many factors, among which are transport of the tumor inhibitor into the cell and the chemical nature and steric environment of the specific nucleophile to be alkylated. Model studies support the hypothesis that the inhibition of tumor growth by the new agents may be attributable to selective alkylation of key enzymes which control cell division.

Tumor inhibitors. 114. Aloe emodin: antileukemic principle isolated from Rhamnus frangula L.

A systematic fractionation of an ethanol-water (1:1) extract of the seeds of Rhamnus frangula L., guided by assays for tumore-inhibitory activity, led to the isolation of aloe emodin (1). This compound was found to show significant antileukemic activity against the P-388 lymphocytic leukemia in mice. A note-worthy vehicle-dependence of the testing results is reported. In the light of this vehicle-dependence, the re-examination of other anthraquinone derivatives is recommended.