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The ethanolic extract of Elephantopus mollisyielded three novel cytotoxic antitumor germacranolides, molephantin, molephantinin, and phantomolin. The extract also yielded three inactive known triterpenes, β-amyrin acetate, lupeol acetate, and epifriedelanol, as well as stigmasterol. The structure and stereochemistry of the cytotoxic anti-tumor agents molephantin, molephantinin, and phantomolin were determined on the basis of chemical transformations and spectral evidence. Preliminary in vivotumor assays indicated that molephantinin and phantomolin were potent inhibitors of Ehrlich ascites carcinoma and Walker 256 carcinosarcoma. Molephantinin also showed significant antileukemic activity in the P-388 lymphocytic leukemia screen.

The antitumor sesquiterpene lactones microhelenins-A, B, and C, microlenin acetate, and plenolin were isolated from Helenium microcephalum. The structures and stereochemistry of these lactones were determined by physical methods as well as by chemical transformations and correlations. Microlenin acetate appears to be the first novel dimeric sesquiterpene lactone demonstrated to have significant antileukemic activity.

The structure and stereochemistry of the novel dimeric antitumor sesquiterpene lactone, microlenin, were determined on the basis of 1H-NMR, 13C-NMR, and mass spectral evidence.

Evidence is presented that a number of sesquiterpene lactones isolated from plants and synthesized pyrimidines containing the α-methylene-γ-lactone moiety are potent inhibitors of Walker 256 carcinosarcoma and Ehrlich ascites tumor growth and marginal inhibitors of P-388 lymphocytic leukemia and Lewis lung tumor growth. In vitroaerobic basal respiration and oxidative phosphorylation processes of Ehrlich ascites cells were inhibited by these agents as well as deoxyribonucleic acid polymerase and thymidylate synthetase enzymatic activities. These studies indicate that the α-methylene-γ-lactone moiety, the β-unsubstituted cyclopentenone ring, and the α-epoxycyclopentanone system are the essential moieties for inhibition of these biochemical parameters.

Evidence is presented that the antitumor agent eupahyssopin, a germacranolide, inhibits deoxyribonucleic acid, ribonucleic acid, protein, and cholesterol synthesis of Ehrlich ascites tumor cells in CF1male mice. Eupahyssopin appears to bind to nucleotide bases of deoxyribonucleic acid. The drug also inhibits deoxyribonucleic acid and messenger ribonucleic acid polymerase activities and, marginally, thymidylate synthetase activity. Template activity, as regulated by phosphorylation of histones and nonhistones, and cyclic 3ʹ,5ʹ-adenosine monophosphate levels also were affected by drug therapy. Lysosomal enzymes, e.g., deoxyribonuclease and ribonuclease, and cathepsin activities were inhibited by eupahyssopin administration. A number of sulfhydryl-bearing enzymes of the glycolytic and Krebs cycles were inhibited by drug treatment, as were enzymes required for glycogen synthesis and breakdown and for phosphatase hydrolysis. Eupahyssopin also inhibited both basal respiration and coupled oxidative phosphorylation processes of the tumor cell. It was proposed that eupahyssopin, which contains the O=CC=CH2as an α-methylene γ-lactone moiety within its allylic ester side chain, has the ability to undergo a rapid Michael-type addition with sulfhydryl groups of these enzymes and thus to inhibit their activities in a manner analogous to that described for other sesquiterpene antitumor agents containing the O=CC=CH2moiety.

□ Synthetic esters of the C-4 hydroxyl group of podophyllotoxin (I) were prepared. In addition, esters were synthesized using the diol system of tetrahydropyranyl podophyllol (XV), produced by reducing the lactone ring of tetrahydropyranyl podophyllotoxin with lithium aluminum hydride. Six compounds, the acrylate (IV), 3,3-dimethyl acrylate (V), phenoxyacetate (IX), and ethyl adipate (XI) of I as well as podophyllol (XIV) and tetrahydropyranyl podophyllol dimesylate (XVIII), showed significant activity when tested using the P-388 lymphocytic leukemia screen at 3 mg/kg/day. None of the esters showed higher activity than that shown by the parent molecule I when tested at the same dosage level.

A series of new bisbrusatolyl and brusatolyl esters and related compounds were synthesized and tested for in vivoantileukemic activity against a quassinoid sensitive strain of P-388 lymphocytic leukemia in BDF1mice. The bisbrusatolyl malonate, succinate, glutarate, adipate, and sebacate were as active or more active than brusatol. The C-3 esters of brusatol and bruceantin were also found to be as active or more active than brusatol or bruceantin in general. The free hydroxyl groups at C-ll and C-12 as well as the enone double bond in ring A of both bisbrusatolyl and brusatolyl esters are required for antileukemic activity. The presence of a double bond in the ester side chain contributes to the enhanced activity of these esters.

The aliphatic naphtha extract of the roots of Sphenosciadium capitellatum(A. Gray) has yielded isoimperatorin, phellopterin, imperatorin, oxypeucedanin, isopimpinellin, and a linear furanocoumarin, C17H16O5, which has been assigned the 5-γ,γ-dimethylallyloxy-8-methoxy psoralen structure on the basis of degradative and spectral studies. This linear furanocoumarin appears to be identical to cnidilin, recently isolated and characterized from Cnidium dubium(Schkuhr) Thell. The methanol extract yielded sucrose and the glycosidic coumarin, nodakenin, in excellent yield.

(±)-Norargemonine was synthesized in good yield by a multiple-step process. The procedure involved Bischler-Napieralski ring closure of N-4-benzyloxy-3-methoxy-phenethyl-2-(3,4-dimethoxyphenyl)acetamide, reduction of the ensuing 3,4-dihydro base to the tetrahydro form, and dehydrogenation of the latter to yield the isoquinoline which, however, had been debenzylated during dehydrogenation. Rebenzylation of the phenol, conversion to the methiodide, reduction to the corresponding N-methyl-1,2-dihydro base, and acid catalyzed cyclization accompanied by simultaneous debenzylation afforded (±)-norargemonine to complete the synthesis.

The ether extract of the root of Lomatium nuttallii(A. Gray) Macbr. has been examined and has provided a number of known coumarins. These are osthol, jatamansin, pteryxin, and lomatin. The ether extract also contained a new coumarin, provisionally named nuttallin, which has been identified as the senecioate ester of lomatin. The methanol extract yielded the glycosidic coumarin, columbianin.

(±)-Bisnorargemonine (I) was synthesized by two alternate but similar routes, differing only in the relative positions of the methoxy and benzyloxy groups on the aromatic rings of the 1-benzylisoquinoline-derived moieties. Both the standard Bischler-Napieralski procedure and the Pictet-Gams modification were employed in the construction of the needed isoquinoline intermediates. Conversion of the latter to the methiodide followed by partial reduction to the N-methyl-1,2-dihydro form and, finally, acid-catalyzed cyclization provided (±)-I, which was identical with natural (-)-I except for melting point and optical rotatory power.

Reaction of helenalin (I) with hydrogen chloride-chloroform and deactivated neutral alumina yielded three products: mexicanin A (II). 1-epiallohelenalin (IV), and a new oxide (V). These products were formed viaintermediates (VII, IX, and VIII, respectively) by the initial addition of hydrogen chloride to the exocyclic methylene grouping of the γ-lactone followed by elimination of hydrogen chloride upon treatment with neutral alumina. Exposure of II to hydrogen chloride-chloroform gave the same intermediates (VII, IX, and VIII) which, upon treatment with the neutral alumina, regenerated II, IV, and V, respectively. Thus, II was the common intermediate for IV and V in the reaction of I with hydrogen chloride-chloroform and neutral alumina. The conversion of IV to its intermediate [11,13-dihydro-l 3-chloro-l-epiallohelenalin (IX)] with hydrogen chloride-chloroform and the complete recovery of the starting material (IV) with neutral alumina were also observed. Treatment of I with concentrated hydrochloric acid afforded 2,3-di- hydro-2-chlorohelenalin (X). Compound X was also readily converted to I upon treatment with either neutral alumina or water. Further reaction of T with deactivated neutral alumina in chloroform led to the direct formation of II. The structures of these compounds were assigned on the basis of chemical as well as spectral evidence. The mode of formation of these compounds was also postulated.

A chloroform extract of the whole plant of Balduina angustifoliashowed significant in vitroinhibitory activity when tested against the growth of tissue culture cells derived from human epidermoid carcinoma of larynx (H.Ep.-2). The extract was examined and found to contain three known compounds. These included rotenone and helenalin, two cytotoxic constituents, and hispidulin, an inactive flavone. The chloroform extract also contained a new cytotoxic pseudoguaianolide sesquiterpene lactone, provisionally named angustibalin, which was identified as the acetate of helenalin. The relatively low content (0.024%) of helenalin in comparison with the previously reported high yield (0.53%) is noted. The isolation of rotenone also provided the first instance for its occurrence from the Compositae family.