The principal antineoplastic constituent of the South African tree Combretum caffrum has been isolated and designated combretastatin A-1. The structure of this new cis-stilbene was unequivocally established by X-ray crystal structure determination and total synthesis. A Wittig reaction sequence in THF comprised the synthetic key step (92.5% yield) and provided a very favorable 9:1 ratio of the cis:trans [1c:2c, geometrical isomers]. Selective hydrogenation of combretastatin A-1 afforded combretastatin B-1, a companion cell growth inhibitory constituent of C. caffrum. Combretastatin A-1 provided 26-29% life extension at 2.75-11 mg/kg dose levels with ED50 0.99 microgram/ml against the murine P-388 lymphocytic leukemia in vivo and in vitro systems. Both combretastatin A-1 and combretastatin B-1 are potent inhibitors of microtubule assembly in vitro and among the most potent inhibitors of the binding of colchicine to tubulin yet described. The structural simplicity and ready synthesis of combretastatin A-1 and combretastatin B-1 suggest that these new biosynthetic products will become useful in a variety of biological endeavors.

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. Can. J. Chem. 66, 406 (1988). Cotnbretum caffrtrm, a tree in the family Combretaceae, has been found to contain three 9.10-dihydrophenanthrenes (6,7-dihydroxy-2,3,4-trirnethoxy; 7-hydroxy-2.3,4,6-tetramethoxy; and 2.7-dihydroxy-3,4,6-trimethoxy) that inhibit (ED50 2.2, 2.8, and 2.6 pg/mL) growthof the murine lymphocytic leukemiacell line. Onephenanthrene (7-hydroxy-2.3,4,6-tetramethoxy) was also isolated with similar (ED50 2.0 pg/mL) activity. Structures for each of these substances, including a dihydrophenanthrene (2-hydroxy-3,4,6,7-tetramethoxy-9,10-dihydrophenanthrene), were determined by detailed high resolution nuclear magnetic resonance and mass spectral studies and (or) X-ray crystal structure analysis. GEORGE R. PETTIT, SHEO BUX SINGH, MARGARET L. NIVEN et JEAN M. SCHMIDT. Can. J. Chcm. 66,406 (1988).On a trouvC que le Combretum caffrlrm, un arbre de la famille des Combretaceae, contient trois dihydro-9,10 phenanthrenes (les dihydro-6,7 trimCthoxy-2,3,4, hydroxy-7 tetramCthoxy-2,3,4,6 et dihydroxy-2,7 trimCthoxy-3,4,6) qui inhibcnt (ED5" 2,2, 2,8 et 2,6 pg/mL) la croissance des cellules de la IeucCmie lymphocytairc de la rnurine. On a aussi isole I'hydroxy-7 tetramCthoxy-2,3,4,6 phknanthrenc qui possede une activite semblable (ED5o 2,0 pg/mL). Pour dCterminer les structures de chacunes de ces substances, y compris celle de l'hydroxy-2 tCtrarnCthoxy-3.4,6,7 dihydro-9,10 phenanthrene, on a fait appel la rtsonance magnetique nuclCaire a haute resolution, 6 des Ctudes par spectrometric de masse ainsi que par des analyses de diffraction des rayons-X.[Traduit par la revue]In 1979 we began, in collaboration with the U.S. National Cancer Institute (NCI), a detailed investigation of the South African tree Combretum caffi-um (Combretaceae) in respect to antineoplastic constituents. Two years later we isolated and determined the structure of combretastatin (I), a new substance that caused pronounced astrocyte reversal in the NCI astrocytoma bioassay (2-4). In 1985 the principal antineoplastic constituent of Cotnbretum caffi-urn was found and designated combretastatin A-1 (5). The cis stilbene 2 proved to have in vivo activity against the murine P388 lymphocytic leukemia (6) and, most importantly, was found to be the most potent inhibitor of tubulin polymerization so far known, leading to complete inhibition at 1.5 p,M concentrations. Some of the fractions accompanying combretastatin A-1 were found to inhibit growth of the PS cell line, and investigation of those leads forms the basis of this report.As previously described (5), the stem-wood of Combreturn caffrum was extracted with methylene chloride -methanol, and the methylene chloride fraction, prepared by dilution of the extract with water, was dissolved in 9:l methanol-water and extracted with hexane. Next, the methanol-water solution was diluted to 3:2 with water and extracted with methylene chloride. The resulting methylene chloride fraction was employed for the original isolation of combretastatin A-1 (5) and as starting point forthe present study of PS ce...

Further investigation of a CH2Cl2 fraction prepared from the South African tree Combretum caffrum for substances inhibitory to the murine P-388 lymphocytic leukemia (PS system) cell line has led to the isolation of two new bibenzyls, designated combretastatins B-3 and B-4, accompanied by the previously known bibenzyls 7, 8, and 9. The structure of each substance was ascertained by results of mass and nmr spectral analyses and confirmed by crystal structure determination (for 7) or synthesis. Combretastatins B-3 and B-4 gave PS ED50 values of 0.4 and 1.7 micrograms/ml, respectively, and bibenzyls 7, 8, and 9 were comparably cell growth inhibitory against the PS cell line with ED50 results of 1.7, 2.5, and 0.25 ug/ml, respectively. All the bibenzyls caused leukemia cells to accumulate in mitosis at cytotoxic drug concentrations; however, a wide range of in vitro activity against the protein tubulin (the major component of the mitotic spindle) was observed.

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Studies in Werner Clathrates. Part 4.' Structures of Tetrakis(4-ethy1pyridine)diisothiocyanatonickel(i1) and its Clathrates with p-, m-, and o-Xylene, Carbon Disulphide, and Carbon Tetrachloride t

iodine cell Fig. 2. Diagram of the experimental setup: MCP, multichannel plates; TR. transient recorder; PC, dedicated computer H P QS/20; PD, photodiode; INT, integrator: SMS, control of the stepping motor for frequency-doubling crystal. the detected ZEKE signal on the laser wavelength gives information on the rovihronic states of the ionized molecule.