The bulbs of Pancratium littorale collected in Hawaii were found to contain a new phenanthridone biosynthetic product designated pancratistatin (4a) that proved to be effective (38-106% life extension at 0.75-12.5 mg/kg dose levels) against the murine P-388 lymphocytic leukemia. Pancratistatin also markedly inhibited (ED50, 0.01 microgram/ml) growth of the P-388 in vitro cell line and in vivo murine M-5076 ovary sarcoma (53-84% life extension at 0.38-3.0 mg/kg). An X-ray crystal structure determination of pancratistatin monomethyl ether (4c) and a detailed high resolution (400 MHz) nmr study of pancratistatin and its pentaacetate (4b) completed assignment of structure 4a. Companion antineoplastic constituents of P. littorale were found to be narciclasine (2c) and its 7-deoxy derivative (2a). The structure of 7-deoxynarciclasine (2c) was also confirmed by an X-ray crystallographic analysis.

The history of certain Amaryllidaceous plants used in the primitive treatment of cancer can be traced to the fourth century B.C.2 In the genus Zephyranthes, Z. parulla Killip appears in a history of Peru (by Padre Cobo) dated 1653, for treating tumors, and Z. rosea

fancratium iittorale Jacq. collected in Hawaii has been found to produce a new phenanthridone, pancratistatin, that significantly inhibits growth of the murine P388 lymphocytic leukaemia; an X-ray crystal structure determination of pancratistatin monomethyl ether (Ic) was employed to assign structure ( l a ) to pancratistatin.Because of early2 interest in certain medicinal and/or poisonous plant species of the relatively large Amaryllidaceae family? about 10% have been investigated for alkaloid constituents, and over 70 such basic metabolites have been isolated.4 Some 30 Amaryllidaceae species have found use in primitive treatment of cancer.' Most significantly, in the U.S. National Cancer Institute's (N. C. I .) exploratory plant evaluation programme some Amaryllidaceae species have yielded extracts with confirmed levels of anticancer activity. We now report that roots of the Hawaiian Parzcratiurn liftorale Jacq.t contain a new anticancer (3$--106% life extension at 0.75-12.5 mg dose levels using the murine P388 lymphocytic leukaemia, PS system, and 53-84% life extension at 0.38-3.0 mgikg against the murine M5076 ovary sarcoma) biosynthetic product herein named pancratistatin (la).The bulb section (45 kg) of P. littorale was extracted with methylene chloride-methanol-water and pancratistatin was concentrated (separation was guided primarily by bioassay using the PS in vivo system) in a butyl alcohol extract of the aqueous phase. Purification of half of the crude product employing selective solubility properties and gel permeation chromatography (Sephadex LH-20) afforded 6.5 g (0.028% t The more usual range is tropical Africa to Asia; also known as Hjwwnocallis littoralis (Jacq .) Salisb. OR^ OR 0 yield) of pancratistatin (la) that separated from dimethylformamide-methanol-ether as a colourless solid, m.p. 322-324 "C, electron impact mass spectrum m l z 325 ( M f . C14H15NOX); [cwID'4 + 48" ( c 1.0, Me,SO); A , , ,(log E) 209 (sh), 219 (sh), 233 (4.32), 278 (3.91), and 308 (br. sh) nm; i.r. (

Amaryllis belladonna bulbs were examined for constituents inhibitory against the murine P-388 lymphocytic leukemia (PS system). Two in vitro active alkaloids, acetylcaranine (2; 9PS ED50 0.23 microgram/ml) and ambelline (3; 9PS ED50 1.6 micrograms/ml), were isolated accompanied by undulatine. However, the non-chiral anhydrolycorinium chloride (5) was found to be the principal antineoplastic (3 PS, 64-69% life extension at dose levels 10 to 20 mg/kg in vivo, ED50 1.4 micrograms/ml in vitro) component. Quaternary chloride 5 has not been located previously among plant or animal biosynthetic products.

10 aryl propylene oxides and 6 aryl butylene oxides were synthesized. Dose-mutagenicity relationships were studied for these compounds and for 1,2-epoxybutane, using both the preincubation and plate incorporation Ames tests with Salmonella typhimurium strains TA100 and TA1535. Structure-mutagenicity relationships were further examined by concurrent testing at single doses with the plate incorporation assay in strain TA100. In both series of compounds, mutagenicity showed very correlation to chemical reactivity, molar volume and partition values. However, all compounds were mutagenic in at least one system with the propylene oxides being more mutagenic than the corresponding butylene oxide derivatives. The naphthyl derivatives in each series were the most mutagenic.