Biotinylated bleomycin A(5) was attached to streptavidin-derivatized microbubbles, and a solution containing the conjugate was passed over a monolayer of cultured MCF-7 cells. The bleomycin-derivatized microbubbles adhered to the MCF-7 cells, and the association could be monitored by the use of a microscope. Three other cancer cell lines gave similar results. The bleomycin-microbubble conjugate did not bind to a normal breast cell line (MCF-10A) or to the matched noncancer cell lines corresponding to the other cancer cell lines targeted by bleomycin. No binding to any tested cell line was observed when the microbubbles lacked conjugated bleomycin A(5) or when the microbubble contained a bleomycin A(5) analogue lacking the carbohydrate moiety.

The South African willow tree Combretum caffrum has yielded a number of potent cancer cell growth inhibitors. The present SAR studies of the antineoplastic agent combretastatin A-4 (1c) were focused mainly on the olefinic bridge to determine the effects on cancer cell growth and, potentially, to better define the combretastatin A-4 binding site on tubulin. The geometric trans-isomer 3a of combretastatin A-4 was converted to the (1S,2S)- and (1R,2R)-vicinal diols 4c and 4d, respectively, under Sharpless' asymmetric dihydroxylation conditions. Cancer cell line testing showed the (1S, 2S)-diol 4c to be more potent than its enantiomer 4d. Diol 4c weakly inhibited tubulin polymerization (IC50 = 22 microM, versus 1.2 microM for combretastatin A-4), while 4d was inactive (IC50 > 40 microM). Esterification of either stereoisomer at the diol and/or phenolic positions resulted in elimination of inhibitory activity.

Two new cyclodepsipeptides designated bacillistatins 1 (1) and 2 (2) have been isolated from cultures of a sample of Bacillus silvestris that was obtained from a Pacific Ocean (southern Chile) crab. Each 12-unit cyclodepsipeptide strongly inhibited growth of a human cancer cell line panel, with GI 50 s of 10 −4 -10 −5 μg/mL, and each compound was active against antibiotic-resistant Streptococcus pneumoniae. The structures were elucidated by a combination of X-ray diffraction and mass and 2D NMR spectroscopic analyses, together with chemical degradation.Marine microorganisms are rapidly becoming a very useful source of new cancer cell growth inhibitory substances that have unique structures. Illustrative are recent examples of antineoplastic substances from marine bacteria, 1a-h fungi, 2a-h cyanobacteria, 3a-e and dinoflagellates. 4a-d As part of our extended evaluation of terrestrial and marine microorganisms as sources of new anticancer drug candidates, we collected a marine crab on Chiloé Island, Chile, in 1998. A Bacillus species, subsequently identified as B. silvestris, was isolated from the crab, and extraction of the scaled up bacterial broth has led to the identification of two new cyclodepsipeptides with antibacterial and human cancer cell line inhibitory activity. Bioactive cyclodepsipeptides have been isolated previously from other Bacillus species, including B. cereus ,5a, d B. polymyxa ,5c and B. natto. 5b Members of the genus Bacillus are common in both terrestrial and marine sediments. Bacillus silvestris was first described in 1999, when it was isolated from a sample of forest soil in Germany, 6a and more recently it was identified in water samples taken from the southern Baltic Sea, a brackish environment. 6b Results and DiscussionThe Bacillus silvestris culture was scaled up and extracted as described in the Experimental Section to give a dark-brown gum (3.14 g; P388 lymphocytic leukemia: ED 50 0.0066 μg/mL), which was shown by HPLC analysis to comprise a mixture with at least six closely spaced peaks. Subsequent high-resolution LC-MS showed the mixture to be more complex than was apparent from the HPLC analysis (Table 1).Attempts at separation by way of gel permeation and partition chromatography using Sephadex LH-20 and silica gel Lobar C 8 columns were unsuccessful. Separation using an Ito multi-layer † Dedicated to Dr. David G. I. Kingston of Virginia Polytechnic Institute and State University for his pioneering work on bioactive natural products. ‡ Dedicated also to Diane Middlebrook Djerassi (1939Djerassi ( -2007 Table 1 shows that 1 and 2 have molecular weights a little higher than that of the antibiotic valinomycin (3).By X-ray crystallographic analysis of 1 (Figure 1), its structure was shown to be a 36-membered cyclodepsipeptide that incorporates R-valine (R-Val), S-lactic acid, (S-Lac), S-valine (S-Val), and 2R-hydroxy-3S-methyl-valeric acid (2R-Hy-3S-Me-v) and that closely resembles 3, which consists of three repeating sequences of R-Val, S-Lac, S-Val, and 2R-hydroxyisova...

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The phenanthridone core of pancratistatin lacking all aromatic oxygenation was prepared by cyclotrimerization of acetylene-containing scaffolds 30 and 41, reflecting the natural and the C-1 epi configuration, respectively, of the amino inositol moiety. The cobalt-catalyzed formation of the aromatic core led to bisTMS derivatives 39 and 48, as well as bisacetyl derivative 51. The effectiveness of cyclotrimerization of the natural or trans series was compared with that of the cis series. In addition, the yields of cyclotrimerization were compared for propargylic amines and propargylic amides. Eleven derivatives, including the fully hydroxylated phenantridone 39, were tested against seven cancer cell lines. Three of the compounds displayed activities only an order of magnitude less than those of 7deoxypancratistatin. Full experimental and spectral details are provided for all key compounds and future projections for the preparation of unnatural analogs of Amaryllidaceae constituents are advanced, along with some new insight into the minimum pharmacophore of pancratistatin.Résumé : Faisant appel à une cyclotrimérisation des dérivés acétyléniques 30 et 41 qui reflètent respectivement les configurations naturelle et C-1-épi, on a préparé la phénanthridone, le squelette fondamental de la pancratistatine ne comportant pas d'oxygène aromatique. La formation catalysée par le cobalt du noyau fondamental à conduit aux dérivés bisTMS 39 et 48 ainsi qu'au dérivé bisacétylé 51. On a comparé l'efficacité de la cyclotrimérisation de la série nature ou trans avec celle de la série cis. De plus, on a comparé les rendements des cyclotrimérisations avec des amines et des amides propargyliques. Onze dérivés, y compris la phénantridone totalement hydroxylé (39) ont été évalués contre sept souches de cancer. Trois de ces composés présentent des activités qui ne sont qu'un ordre de grandeur inférieures à celle de la 7-désoxypancratistatine. On rapporte l'ensemble des détails expérimentaux et spectraux relatifs à tous les intermédiaires clés. Les projections relatives à la préparation d'analogues non naturels des constituants de l'Amaryllidaceae sont avancées et l'on possède déjà de nombreuses pistes nouvelles concernant la nature du pharmacophore minimal de la pancratistatine.

A series of substituted quinoline-5,8-diones were synthesized and evaluated as inhibitors of the chaperone protein Hsp90 using two assays: competition for binding to C-terminal ATP-binding site and competition for binding to N-terminal ATP-binding site. In addition, the ability of the compounds to induce the heat shock response was determined using a reporter fibroblast cell line. Of all the compounds assayed, only 6-aziridinyl-2-biphenylquinoline-5,8-dione induced a heat shock response and did so without interacting at the ATP binding sites of Hsp90. COMPARE analysis was carried out on quinoline-5,8-diones active in the National Cancer Institute's 60-cell line screen with the goal of discovering quinoline-5,8-dione structures that interact with other cellular targets (molecular targets) important for cancer chemotherapy. COMPARE analysis led to the discovery of a combretastatin-like quinoline-5,8-dione structure that, in fact, inhibited angiogenesis.

An investigation of the Phillippine Ampelocissus sp. roots for cancer cell growth inhibitory components led to the isolation of a new acetogenin characterized as 22-epicalamistrin (1) employing primarily 2D NMR and high-resolution mass spectral analysis. Two other antineoplastic constituents proved to be the known acetogenin uvaribonin (2) and chalcone 3. Constituents 1-3 were all found to show significant cancer cell growth inhibitory activity against a panel of human cancer cell lines.