Antineoplastic Agents. 607. Emetine Auristatins.

The remarkable biological activity of the dolastatin 10 structural modifications quinstatins and isoquinstatins prompted further investigation into drug hybrids containing biologically active isoquinoline moieties. In this study, the isoquinoline alkaloid emetine was selected as one of the structural domains of a hybrid molecule. That was accomplished by covalently bonding the Dov-Val-Dil-Dap peptide sequence of dolastatin 10 peptide at the N-2' secondary amine of emetine.

Antineoplastic Agents. 606. The Betulastatins.

The medicinal potential of the plant pentacyclic triterpene betulin has generated long-term interest focused on various SAR research avenues. The present approach was based on producing further analogues (chimeras) arising from a studied modification of betulin bonded to the Dov-Val-Dil-Dap unit of the powerful anticancer drug dolastatin 10, which provided betulastatins 1 (7b), 2 (11b), 3 (16b), and 4 (18b). Betulastatin 1, 2, and 4 exhibited modest levels of cancer cell growth inhibition against six cancer cell lines.

Antineoplastic Agents. 605. Isoquinstatins.

In order to further explore quinoline-type structural modification of the powerful anticancer drug dolastatin 10, an Indian Ocean sea hare constituent and parent molecule of the very successful antibody drug conjugate (ADC) Adcetris, our recent quinstatin study has been extended by replacing the quinoline ring with an isoquinoline. The resulting isoquinstatins (4-6) were modified to N-terminal desmethylisoquinstatins (7-9) and, in turn, bonded to appropriate linker units to give linker-desmethylisoquinstatin conjugates 11-13 in preparation for eventual monoclonal antibody attachment. Comparison of the new isoquinstatins with their quinstatin counterparts against six human cancer cell lines indicated the isoquinstatins to have GI values that were comparable to or somewhat higher than those of the isomeric quinstatins.

Antineoplastic Agents. 604. The Path of Quinstatin Derivatives to Antibody Drug Conjugates.

To further evaluate the exceptional cancer cell growth inhibition by the quinstatins, of which one of the series, quinstatin 8, approaches the exceptional cytotoxic activity of the parent dolastatin 10 (1), four of the quinstatins have been converted to desmethyl derivatives. Three of the four (4, 5, and 8 [7b-d]) were next bonded to the linker (8) employed in the synthesis of the very successful and structurally related anticancer drug Adcetris (3). Owing to these structural modifications, a next step could be taken by bonding to a monoclonal antibody, thereby producing an antibody drug conjugate (ADC) related to Adcetris structurally but with the possibility of a wider spectrum of activity and utility.

Antineoplastic Agents. 603. Quinstatins: Exceptional Cancer Cell Growth Inhibitors.

Discovery of the exceptionally powerful anticancer drug dolastatin 10 (1), contained in the sea hare Dolabella auricularia, opened a new frontier needed for improving human cancer treatment. Subsequently, major advances have been achieved based on results of structurally modifying this unusual natural peptide while maintaining the remarkable anticancer activity necessary for preparation of successful monoclonal antibody drug conjugates (ADC). Among the first several hundred SAR products based on dolastatin 10 our group synthesized and termed auristatins was auristatin E (2a).

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.

Antineoplastic Agents. 585. Isolation of Bridelia ferruginea Anticancer Podophyllotoxins and Synthesis of 4-Aza-podophyllotoxin Structural Modifications.

Cytotoxic constituents of the terrestrial plant Bridelia ferruginea were isolated using bioactivity-guided fractionation, which revealed the presence of the previously known deoxypodophyllotoxin (1), isopicrodeoxypodophyllotoxin (2), β-peltatin (3), β-peltatin-5-O-β-D-glucopyranoside (3a), and the indole neoechinulin (4). As an extension of previous podophyllotoxin research, SAR studies were undertaken focused on 4-aza-podophyllotoxin structural modifications. A number of such derivatives were synthesized following modifications to the A and E rings.

The Cephalostatins. 24. Isolation, Structure, and Cancer Cell Growth Inhibition of Cephalostatin 20.

For the purpose of advancing knowledge of the structural variations available in the natural cephalostatins contained in the marine worm Cephalodiscus gilchristi, the isolation and structure of the 20th member (1) has been accomplished (10(-7) % yield). In turn cephalostatin 20 (1) proved to be enough for an initial SAR study comprising six important human cancer cell lines. A parallel objective was aimed at the possible discovery of a natural cephalostatin with a more accessible structure for total synthesis and/or synthetic modifications, but with powerful cancer cell growth inhibition.

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. 599. Total synthesis of dolastatin 16.

The first 23-step total synthesis of the cyclodepsipeptide dolastatin 16 (1) has been achieved. Synthesis of the dolaphenvaline and dolamethylleuine amino acid units using simplified methods improved the overall efficiency. The formation of the 25-membered macrocycle employing lactonization with 2-methyl-6-nitrobenzoic anhydride completed a key step in the synthesis.

Antineoplastic agents. 600. From the South Pacific Ocean to the silstatins.

The recent advances in the development of antibody and other drug conjugates for targeted cancer treatment have further increased the need for powerful cancer cell growth inhibitors. Toward that objective we have extended our earlier discovery of the remarkable anticancer bacillistatins 1 and 2 from Bacillus silvestris to SAR and other structural modifications such as availability of a free hydroxy group for antibody-drug conjugate (ADC) and other prodrug linkage. That direction has resulted in seven structural modifications designated silstatins 1-8 (7a, 8a, 8b, 14a, 15a, 15b, 18a, and 18b), where the exceptional cancer cell growth inhibition of some of them are in the range GI50 10(-3)-10(-4) μM/mL.

Isolation and structures of axistatins 1-3 from the Republic of Palau marine sponge Agelas axifera Hentschel .

An investigation begun in 1979 directed at the Republic of Palau marine sponge Agelas axifera Hentschel for cancer cell growth inhibitory constituents subsequently led to the isolation of three new pyrimidine diterpenes designated axistatins 1 (1), 2 (2), and 3 (3), together with the previously reported formamides 4, 5, and agelasine F (6). The structures were elucidated by analysis of 2D-NMR spectra and by HRMS. All of the isolated compounds were found to be moderate inhibitors of cancer cell growth.

Antineoplastic agents. 587. Isolation and structure of 3-epipancratistatin from Narcissus cv. Ice Follies.

Bioassay-guided (cancer cell line) separation of an extract prepared from Narcissus cv. Ice Follies (from The Netherlands) led to the isolation of a new Amaryllidaceae isocarbostiryl, 3-epipancratistatin (1b), as well as narciclasine (2). This Narcissus cultivar was found to be a good source of narciclasine.

Antineoplastic agents. 548. Synthesis of iodo- and diiodocombstatin phosphate prodrugs.

Toward the objective of designing a structurally modified analogue of the combretastatin A-4 phosphate prodrug (1b) with the potential for increased specificity toward thyroid carcinoma, synthesis of a series of iodocombstatin phosphate (11a-h) and diiodocombstatin phosphate prodrugs (12a-h) has been accomplished. The diiodo series was obtained via 8a and 9c from condensation of 4 and 6, and the iodo sequence involved a parallel pathway. Both series of iodocombstatins were found to display significant to powerful inhibition of the growth of a panel of human cancer cell lines and of the murine P388 lymphocytic leukemia cell line.

Synthesis and evaluation of verticipyrone analogues as mitochondrial complex I inhibitors.

Verticipyrone has recently been isolated from the culture broth of Verticillium sp. and shown to inhibit NADH fumarate reductase, as well as NADH oxidoreductase (complex I) of the mitochondrial electron transport chain. In order to assess the structural elements in verticipyrone essential for complex I inhibitor, 15 structural analogues were prepared and analyzed for their effects on mitochondrial NADH oxidoreductase and NADH oxidase activities.

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.

E-Combretastatin and E-resveratrol structural modifications: antimicrobial and cancer cell growth inhibitory beta-E-nitrostyrenes.

As part of a broad-based SAR investigation of E-resveratrol (strong sirtuin activator and antineoplastic) and the anticancer vascular-targeting combretastatin-type stilbenes, a series of twenty-three beta-E-nitrostyrenes was synthesized in order to evaluate potential antineoplastic, antitubulin, and antimicrobial activities. The beta-E-nitrostyrenes evaluated ranged from monosubstituted phenols to trimethoxy and 3-methoxy-4,5-methylenedioxy derivatives. Two of the beta-nitrostyrenes were synthesized as water-soluble sodium phosphate derivatives (4t, 4v).

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. 571. Total synthesis of bacillistatin 2.

The first total synthesis of bacillistain 2 (2) has been achieved in 24 steps and 22.9% overall yield, providing a quite efficient route with maximal convergence. Notable features of this approach include two successful applications of the Mitsunobu reaction during respective assemblies of key intermediates 22 and 27, successful employment of 2-methyl-6-nitrobenzoic anhydride (MNBA) in the formation by lactonization of a macrocyclic (36-membered) ring, and very flexible access to structural modifications of the bacillistatin-type cyclodepsipeptides.

Carbohydrate dependent targeting of cancer cells by bleomycin-microbubble conjugates.

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.

Synthesis and characterization of Deltalac-acetogenins that potently inhibit mitochondrial complex I.

Four Deltalac-acetogenins have been prepared and characterized as inhibitors of the mitochondrial respiratory chain, to define the effects of unsaturation within the alkyl substituents. In keeping with earlier reports, the presence of acetylenic functionalities within the alkyl substituents slightly diminished their potency of inhibition of NADH oxidase activity, which measures the overall transfer of electrons from NADH to oxygen through mitochondrial complexes I, III, and IV. In contrast, both of the acetylenic Deltalac-acetogenins were far more active in a NADH-ubiquinone Q(1) oxidoreductase assay that measures complex I function per se.

Antineoplastic agents. 536. New sources of naturally occurring cancer cell growth inhibitors from marine organisms, terrestrial plants, and microorganisms(1a,).

Bioassay-guided fractionation of extracts of various plants, marine organisms, and microorganisms has led to the discovery of new natural sources of a number of known compounds that have significant biological activity. The isolation of interesting and valuable cancer cell growth inhibitors including majusculamide C ( 1), axinastatin 5 ( 5), bengazoles A ( 6), B ( 7), and E ( 8), manzamine A ( 10), jaspamide ( 11), and neoechinulin A ( 19) has been summarized.

Combretastatin dinitrogen-substituted stilbene analogues as tubulin-binding and vascular-disrupting agents.

Several stilbenoid compounds having structural similarity to the combretastatin group of natural products and characterized by the incorporation of two nitrogen-bearing groups (amine, nitro, serinamide) have been prepared by chemical synthesis and evaluated in terms of biochemical and biological activity. The 2',3'-diamino B-ring analogue 17 demonstrated remarkable cytotoxicity against selected human cancer cell lines in vitro (average GI 50 = 13.9 nM) and also showed good activity in regard to inhibition of tubulin assembly (IC 50 = 2.

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.