A dense ring of the trans-Neptunian object Quaoar outside its Roche limit.

Planetary rings are observed not only around giant planets, but also around small bodies such as the Centaur Chariklo and the dwarf planet Haumea. Up to now, all known dense rings were located close enough to their parent bodies, being inside the Roche limit, where tidal forces prevent material with reasonable densities from aggregating into a satellite. Here we report observations of an inhomogeneous ring around the trans-Neptunian body (50000) Quaoar.

Isolation and Structure of Cancer Cell Growth Inhibitory Tetracyclic Triterpenoids from the Zimbabwean Monadenium lugardae.

The Zimbabwean medicinal plant Monadenium lugardae was evaluated as a potential source of new anticancer constituents. Four new tetracyclic triterpene (1-4) were isolated, accompanied by four previously known triterpenes (5-8). Against a panel of human tumor cell lines, lugardstatins 1 (1) and 2 (2) had good cancer cell growth inhibitory activity.

The Cephalostatins. 23. Conversion of Hecogenin to a Steroidal 1,6-Dioxaspiro[5.5]nonane Analogue for Cephalostatin 11.

Cephalostatin 1 (1) has proved to be a remarkably potent cancer cell growth inhibitor. Since this steroidal alkaloid constituent of the marine worm Cephalodiscus gilchristi possesses a complex structure, providing preclinical supplies by total synthesis continues to be challenging. Therefore, syntheses of less complex structural modifications of this important pyrazine have also received substantial attention.

Antineoplastic agents. 590. X-ray crystal structure of dolastatin 16 and syntheses of the dolamethylleuine and dolaphenvaline units.

Three advances necessary to bring dolastatin 16 (1) into full-scale preclinical development as an anticancer drug have been accomplished. The X-ray crystal structure of dolastatin 16 has been solved, which allowed stereoselective syntheses of its two new amino acid units, dolamethylleuine (Dml) and dolaphenvaline (Dpv), to be completed. The X-ray crystal structures of synthetic Z-Dml and TFA-Dpv have also been completed.

Antineoplastic agents 582. Part 1: Isolation and structure of a cyclobutane-type sesquiterpene cancer cell growth inhibitor from Coprinus cinereus (Coprinaceae).

Bioassay-guided (murine P388 lymphocytic leukemia and human cancer cell lines) separation of an ethyl acetate extract prepared from the inky cap fungus Coprinus cinereus led to the isolation of three new sesquiterpenes, 7,7a-diepicoprinastatin 1 (1), 14-hydroxy-5-desoxy-2S,3S,9R-illudosin (2), and 4,5-dehydro-5-deoxyarmillol (3), together with the known armillol (4). The structure and relative configuration of 1 was determined by single-crystal X-ray diffraction experiments. The structures of compounds 2, 3, and 4 were each deduced by a combination of HRMS and 1D and 2D NMR techniques.

Antineoplastic agents. 565. Synthesis of combretastatin D-2 phosphate and dihydro-combretastatin D-2.

A modified synthetic route to combretastatin D-2 (5) was devised in order to further evaluate its biological activity, for its conversion to phosphate prodrugs (25-28), and as a route to obtaining dihydro-combretastatin D-2 (42). A parallel first total synthesis of dihydro-combretastatin D-2 was completed, proceeding from a saturated 3-phenylpropionic ester intermediate via the Ullmann biaryl ether reaction (39-41). In contrast to the cancer cell growth inhibitory activity exhibited by combretastatin D-2, relatively minor structural modifications (41, 42) caused elimination of those properties.

Antineoplastic agents. 573. isolation and structure of papilistatin from the papilionid butterfly Byasa polyeuctes termessa.

Bioassay-guided separation of an extract of the wings from a Taiwan butterfly, Byasa polyeuctes termessa, allowed isolation of a new cancer cell growth inhibitor designated papilistatin (1a). The structure was determined by analysis of 1D and 2D NMR spectra and by HRMS. Against a panel of six human and the murine P388 leukemia cancer cell lines, papilistatin exhibited cancer cell growth inhibition with GI(50)'s of 0.

Antineoplastic agents. 556. Isolation and structure of Coprinastatin 1 from Coprinus cinereus.

Cancer cell line bioassay-guided separation of an ethyl acetate extract prepared from a plant-associated fungus, Coprinus cinereus, led to the isolation of three new sesquiterpenes, coprinastatin 1 (1), coprinol (2), and the epimer (4a), of the known sesquiterpene triol (4b). The previously described sesquiterpene 3 and oxazolinone 5 were also isolated. The structure and relative configuration of coprinastatin 1 (1) were determined by HRMS and by 1D- and 2D-NMR spectroscopic analyses.

Antineoplastic agents. 570. Isolation and structure elucidation of bacillistatins 1 and 2 from a marine Bacillus silvestris.

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) microg/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.

Antineoplastic agents. 558. Ampelocissus sp. cancer cell growth inhibitory constituents.

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.

Antineoplastic agents. 550. Synthesis of 10b(s)-epipancratistatin from (+)-narciclasine.

By means of a five-step reaction sequence, narciclasine (2a), isolated from Narcissus sp., was converted to 10b(S)-epipancratistatin (3a) in 5.7% overall yield.

Isolation and structural modification of 7-deoxynarciclasine and 7-deoxy-trans-dihydronarciclasine.

As an extension of structure-activity relationship studies of pancratistatin (1), various techniques were first evaluated for separating the mixtures of 7-deoxynarciclasine (2b) and 7-deoxy-trans-dihydronarciclasine (3a) isolated from Hymenocallis littoralis. An efficient solution for that otherwise difficult separation then allowed the lactam carbonyl group of protected (4c and 5c) alcohols 2b and 3a to be reduced employing lithium aluminum hydride. Cleavage (TBAF followed by H2SO4) of the silyl ester/acetonide protected 6a gave amine 8.

Antineoplastic agents. 553. The Texas grasshopper Brachystola magna.

Bioassay (P388 lymphocytic leukemia cell line and human cancer cell lines) guided separation of an extract prepared from the previously chemically uninvestigated Texas grasshopper Brachystola magna led to isolation of the cancer cell growth inhibitory pancratistatin (1), narciclasine (2), and ungeremine (3). Pancratistatin (1) was first isolated from the bulbs of Hymenocallis littoralis), and the original crystal structure was deduced by X-ray analysis of a monomethyl ether derivative. In the present study pancratistatin (1) was isolated from an extract of B.

Antineoplastic agents 540. The Indian Gynandropsis gynandra (Capparidaceae).

The CH3OH-CH2Cl2 extract of an Indian collection (entire plant) of Gynandropsis gynandra (L.) Briq. was separated based on bioassay results employing cancer cell lines.

Antineoplastic agents. 445. Synthesis and evaluation of structural modifications of (Z)- and (E)-combretastatin A-41.

A series of cis- and trans-stilbenes related to combretastatin A-4 (1a), with a variety of substituents at the 3'-position of the aryl B-ring, were synthesized and evaluated for inhibitory activity employing six human cancer cell lines (NCI-H460 lung carcinoma, BXPC-3 pancreas, SK-N-SH neuroblastoma, SW1736 thyroid, DU-145 prostate, and FADU pharynx-squamous sarcoma) as well as the P-388 murine lymphocyte leukemia cell line. Several of the cis-stilbene derivatives were significantly inhibitory against all cell lines used, with potencies comparable to that of the parent 1a. All were potent inhibitors of tubulin polymerization.

Antineoplastic agents 470. Absolute configuration of the marine sponge bromopyrrole agelastatin A.

Two bromopyrrole marine alkaloids were isolated from the Mexican sponge, Agelas sp.: hymenidin (1) and agelastatin A (2). The structures were elucidated by analysis of their spectroscopic data and found to correspond to those in the literature.

Antineoplastic agents. 529. Isolation and structure of nootkastatins 1 and 2 from the Alaskan yellow cedar Chamaecyparis nootkatensis.

The yellow cedar tree, Chamaecyparis nootkatensis, collected in southeast Alaska was evaluated as a potential source of new anticancer agents. Two new diterpene anticancer constituents termed nootkastatins 1 (4) and 2 (5) were isolated along with three previously known diterpene cancer cell growth inhibitors where two were reported as synthetic modifications of totarol and not previously found in nature. All five diterpene structures were established by HRMS and 1D and 2D NMR spectroscopic analyses combined with three X-ray crystal structure determinations (2, 3, and 5).

Isolation and structure of gustastatin from the Brazilian nut tree Gustavia hexapetala.

A bioassay-guided investigation of Gustavia hexapetala led to the isolation of a new cancer cell growth inhibitor designated gustastatin (1) and four previously known cancer cell growth inhibitors that included betulinic acid (2). The structures were assigned on the basis of analyses of HRMS combined with 1D and 2D NMR data. The structure of portentol (5) was confirmed by an X-ray crystal structure determination.

Synthesis and X-ray crystal structure of the dolabellaauricularia peptide dolastatin 18.

A previously synthesized unit of dolastatin 10 (1), dolaphenine (Doe, 3), was converted in four steps to tripeptide 10. Subsequent condensation with carboxylic acid 11 (four steps from Meldrum's acid) provided a practical synthesis of the cancer cell growth inhibitor dolastatin 18 (2, Dhex-(S)-Leu-(R)-N-Me-Phe-Doe). The synthesis of dolastatin 18 (2) confirmed the R stereochemistry of the N-Me-Phe unit as originally assigned and unusual among amino acid components of the sea hare Dolabella auricularia.

Antineoplastic agents 491. Synthetic conversion of aaptamine to isoaaptamine, 9-demethylaaptamine, and 4-methylaaptamine.

Aaptamine (1) was used as starting material for synthetic transformation to isoaaptamine (2), 9-demethylaaptamine (5), and 4-methylaaptamine (6). A general method for the selective O-demethylation of such 1H-benzo[de][1,6]-naphthyridine (1) marine sponge constituents at position C-9 has been developed. Selective O-demethylation of aaptamine (1) and 1-methylaaptamine (11) with 48% hydrobromic acid led to 9-demethylaaptamine (5) and isoaaptamine (2), respectively.

Antineoplastic agents. 380. Isolation and X-ray crystal structure determination of isoaaptamine from the Republic of Singapore Hymeniacidon sp. and conversion to the phosphate prodrug hystatin 1.

By use of bioassay (murine P388 lymphocytic leukemia cell line) guided isolation procedures, extracts of the Republic of Singapore marine sponge Hymeniacidon sp. were found to contain demethyloxyaaptamine (1) and aaptamine (3) as prominent cancer cell growth inhibitory constituents accompanied by the trace, albeit more active, component isoaaptamine (4). The isolation, X-ray structure elucidation, and antineoplastic and antimicrobial activities of isoaaptamine (4) have been summarized.

Antineoplastic agents. 511. Direct phosphorylation of phenpanstatin and pancratistatin.

Selective phosphorylation of phenpanstatin (3a) with tetrabutylammonium dihydrogen phosphate and dicyclohexylcarbodiimide in pyridine followed by cation-exchange chromatographic procedures was found to provide an efficient route to a new series (3b-3d) of promising 3,4-O-cyclic phosphate prodrugs designated phenpanstatin phosphates. Application of analogous reaction conditions to pancratistatin (1a) led to a mixture of monophosphate derivatives where sodium pancratistatin 4-O-phosphate (4a) was isolated and the structure confirmed by X-ray crystallography. Modification of the reaction conditions allowed direct phosphorylation of pancratistatin followed by cation-exchange chromatography to afford sodium pancratistatin 3,4-O-cyclic phosphate (5a), which was selected for preclinical development.

Antineoplastic agents. 499. Synthesis of hystatin 2 and related 1H-benzo[de][1,6]-naphthyridinium salts from aaptamine.

The marine sponge constituent aaptamine (1) has been converted to the cancer cell growth inhibitor and antibiotic designated hystatin 2 (8a). Herein, we also report results of an initial SAR evaluation of new benzyl derivatives of aaptamine (1). Single benzylation was found to occur at nitrogen N-4 and led to the formation of the 4-benzylaaptamine derivatives 7a-c, whereas double benzylation gave the quaternary 1H-benzo[de][1,6]-naphthyridinium salts 8a-c.

Antineoplastic agents. 522. Hernandia peltata (Malaysia) and Hernandia nymphaeifolia (Republic of Maldives).

Bioassay (P388 lymphocytic leukemia cell line and human tumor cell lines)-guided separation of the extracts prepared from the tropical and coastal trees Hernandia peltata (Malaysia) and Hernandianymphaeifolia (Republic of Maldives) led to the isolation of a new lignan designated as hernanol (1) and 12 previously known lignans: (-)-deoxypodophyllotoxin (2), deoxypicropodophyllin (3), (+)-epiaschantin (4), (+)-epieudesmin (5), praderin (6), 5'-methoxyyatein (7), podorhizol (8), deoxypodorhizone (9), bursehernin (10), kusunokinol (11), clusin (12), and (-)-maculatin (13). The oxidative cyclization (with VOF(3)) of lignans 8, 9, and 10 resulted in a new and unusual benzopyran (14), isostegane (15), and a new dibenzocyclooctadiene lactone (16), respectively. The structure and relative stereochemistry of hernanol (1) and lignans 3, 7, 8, 9, 10, 11, and 12 were determined by 1D and 2DNMR and HRMS analyses.