Jun Ping Xu

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.

Isolation and structure of the exceptional Pterobranchia human cancer inhibitors cephalostatins 16 and 171

Abstract The Southeast African marine worm Cephalodiscus gilchristi has been found to contain two new and exceedingly potent human cancer cell growth inhibitors Cephalostatins 16 (3) and 17 (4).

Synthesis of the Marine Sponge Cycloheptapeptide Phakellistatin 51

Phakellistatin 5 (1), a constituent of The Federated States of Micronesia (Chuuk) marine sponge Phakellia costada, was synthesized by solution-phase and solid-phase techniques. Because the linear peptide bearing (R)-Asn resisted cyclization, the synthesis of this peptide was repeated using the PAL resin attachment proceeding from N-Fmoc-D-Asp-alpha-OCH(2)CH=CH(2). After addition of the final unit (Ala), the allyl ester was removed under neutral conditions with Pd(o) [P(C(6)H(5))(3)](4). Removal of the final Fmoc-protecting group and cyclization with PyAOP provided (R)-Asn-phakellistatin 5 (2) in 28% overall yield. The same synthetic route from (S)-Asp led to natural phakellistatin 5 (1) in 15% overall recovery. The solution-phase and solid-phase synthetic products derived from (S)-Asp were found to be chemically but not biologically identical with natural phakellistatin 5 (1). This important fact suggested that a trace, albeit highly cancer-cell growth inhibitory, constituent accompanied the natural product or that there is a subtle conformational difference between the synthetic and natural cyclic peptides.

Isolation and structure of the human cancer cell growth inhibitory cyclic decapeptides phakellistatins 7, 8 and 91,2

Abstract Phakellistatins 7–9 respresent the first cancer cell growth inhibitory (P388 ED50 3.0, 2.9 and 4.1 μg/mL respectively) cyclic decapeptides. Each was isolated from the Federated States of Micronesia (Chuuk) marine sponge Phakellia costata. The Federated States of Micronesia (Chuuk) marine sponge Phakellia costata has been found to contain (10−5 and 10−6% yields) three cancer cell line active (P388 ED50 3.0, 2.9 and 4.1 μg/mL respectively) cyclic decapeptides named phakellistatins 7 (1), 8 (2) and 9 (3). Phakellistatins 7–9 represent the first cancer cell growth inhibitory cyclic decapeptides isolated from a marine sponge.

ISOLATION AND STRUCTURE OF THE SYMMETRICAL DISTEROIDAL ALKALOIDS CEPHALOSTATIN 12 AND CEPHALOSTATIN 13

Abstract Re-examination of a Western Indian Ocean worm Cephalodiscus gilchristi has led to discovery of cephalostatins 12 and 13. Cephalostatin 12 ( 2 ) proved to be the first example of a symmetrical disteroidal alkaloid. Both new cephalostatins significantly inhibited growth of animal and human cancer cell lines.

Antineoplastic agents 315. Isolation and structure of the marine sponge cancer cell growth inhibitor phakellistatin 5

Abstract The Federated State of Micronesia (Chuuk) marine sponge Phakellia costada has been found to contain (9.6 x 10 −6 % yield) a new human cancer cell growth inhibitor designated phakellistatin 5 (3). Structural elucidation was accomplished employing high resolution FAB tandem MS/MS and high field (500 MHz) 2D-NMR techniques. Extension of the NMR experiments over the temperature range −25 to 25°C allowed the principal solution conformation of phakellistatin 5 to be assigned (Figure 2). The absolute configuration was found to correspond to S-amino acid units except for R-Asn.

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 370. Isolation and structure of dolastatin 18

Abstract Bioassay-guided separation of cancer cell growth inhibitory fractions derived from the sea hare Dolabella auricularia obtained in Papua New Guinea led to isolation (1.51 × 10 −7 % yield) of the new thiazole-containing peptide, dolastatin 18 (4). Structural determination was completed by employmentment of results from high-field (500 MHz) 2-D NMR experiments and tandem MS/MS mass spectral sequence analyses. Dolastatin 18 (4) was found to inhibit a selection of cancer cell lines among which GI 50 0.39 μg/mL was found for the nonsmall cell lung cancer NCI-H460.

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. Regrettably, the synthetic dolastatin 16 (1), while otherwise identical (by X-ray crystal structure and spectral analyses) with the natural product, did not reproduce the powerful (nanomolar) cancer cell growth inhibition displayed by the natural isolate. Presumably this result can be attributed to conformation(s) of the synthetic dolastatin 16 (1) or to a chemically undetected component isolated with the natural product.

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.