Abstract: (+)-Narciclasine (2), available in quantity from certain Amaryllidaceae species or by total synthesis, is employed in for a ten step synthetic conversion (3.6% overall yield) to natural (+)-pancratistatin (1a). The key procedures involve the epoxidation of natural (+)-narciclasine (2) to an epoxide (6), reduction of the epoxide (6) to diol (8), formation of cyclic sulfate (12) and its ring opening with cesium benzoate followed by saponification of the benzoate to afford (+)-pancratistatin (1a).

Abstract: A newly discovered antineoplastic compound denominated “phenstatin” is herein described as are synthetic methods for producing phenstatin and the active prodrug thereof. Phenstatin was converted to the sodium phosphate prodrug (3d) by a dibenzylphosphite phosphorylation and subsequent hydrogenolysis sequence 3b?3c?3d. Phenstatin (3b) was found to be a potent inhibitor of tubulin polymerization and the binding of colchicine to tubulin comparable to combretastatin A-4 (1b).

Abstract: The benzophenone derivative of combretastatin A-1, designated “hydroxyphenstatin”, was synthesized by compiling a protected bromobenzene and a benzaldehyde to form a benzhydrol which was subsequently oxidized to the ketone. Hydroxyphenstatin was converted to a sodium phosphate prodrug by dibenzyl phosphite phosphorylation and subsequent benzyl cleavage: Hydroxyphenstatin and the prodrugs thereof were found to be a potent inhibitor of tubulin polymerization and to demonstrate surprisingly effective antineoplastic activity against a series of human cancer cells and murine P388 lymphocytic leukemia cells.

Abstract: A new and efficient synthesis of the (+)-pancratistatin phosphate prodrug 2a has been accomplished. Selective protection (tetraacetate 4) of (+)-pancratistatin (1a) was followed by phosphorylation (to 5) with dibenzyl chlorophosphite (prepared in situ from dibenzyl phosphite). Cleavage of the acetate (with sodium methoxide) and benzyl (by hydrogenolysis) protecting groups followed by concomitant reaction with two equivalents of sodium methoxide afforded good yield of disodium (+)-pancratistatin phosphate (2a). Further increases in yields of the prodrug (2a) were realized by avoiding heat in the final purification steps. Fourteen (2b-o) additional metal and ammonium derived phosphate prodrugs were also synthesized.

Abstract: A new inhibitor of microtubule assembly (IC50 0.59 &mgr;M); with antineoplastic properties, denominated “dioxostatin”, has been synthesized and its effectiveness against human cancer and murine P388 lymphocytic leukemia cell lines demonstrated. Dioxostatin hs the following structure (I).

Abstract: (+)-Narciclasine (2), available in quantity from certain Amaryllidaceae species or by total synthesis, is employed as relay for a ten step synthetic conversion (3.6% overall yield) to natural (+)-pancratistatin (1a). The key procedures involve the epoxidation of natural (+)-narciclasine (2) to an epoxide (6), reduction of the epoxide (6) to diol (8), formation of cyclic sulfate (12) and its ring opening with cesium benzoate followed by saponification of the benzoate to afford (+)-pancratistatin (1a).

Abstract: A new and more efficient synthesis of combretastatin A-3 (2a) was completed (8.4% overall yield) starting front methyl gallate and isovanillin with aldehyde 5 and phosphonium salt 8 as key intermediates. Conversion of combretastatin A-3 (2a) to a series of diphosphate prodrugs (IOa-IOl) containing selected anions was achieved.

Abstract: A composition of matter, denominated herein as 12a-r, having the structural formula set forth below: wherein R is selected from the group consisting of: a) R=NHPh; b) R=NHCH2Ph; c) R=NH(CH2)2Ph; d) R=NH(CH2)2‘-4-F-Ph; e) R=NH(CH2)2-4-Cl-Ph; f) R=NH(CH2)2-3-Cl-Ph; g) R=NH(CH2)2-2-Cl-Ph; h) R=NH(CH2)2-4-Br-Ph; i) R=NH(CH2)2-4-NO2-Ph; j) R=NH(CH2)2-3,4-(CH3O)2Ph; k) R=NH(CH2)2-2-pyridine; l) R=NH(CH2)3Ph; m) R=L-Phe-OCH3; n) R=L-Met-OCH3; o) R=L-Pro-OCH3; p) R=NH-2-thiazolyl; q) R=NH-2-benzothiazolyl; r) R=NH-3-quinolyl; and methods of making these compounds 12a-r.

Abstract: The benzophenone derivative of combretastatin A-1, designated “hydroxyphenstatin”, was synthesized by compiling a protected bromobenzene and a benzaldehyde to form a benzhydrol which was subsequently oxidized to the ketone. Hydroxyphenstatin was converted to a sodium phosphate prodrug by dibenzyl phosphite phosphorylation and subsequent benzyl cleavage: Hydroxyphenstatin and the prodrugs thereof were found to be a potent inhibitor of tubulin polymerization and to demonstrate surprisingly effective anti neoplastic activity against a series of human cancer cells and murine P388 lymphocytic leukemia cells.

Abstract: The present invention relates to the syntheses and structural elucidation of Combretastatin A1-Phosphate Prodrugs and Combretastatin B1-Phosphate Prodrugs and the utilization of those prodrugs in the treatment of neoplastic diseases. The prodrugs described herein have the structure: Combretastin A-1 Phosphate Prodrug (I) and Combretastin B-1 Phosphate Prodrug (II).

Abstract: The present invention relates to compounds of the formula ##STR1## and to pharmaceutically acceptable salts thereof, wherein R.sup.1 and R.sup.2 are as defined herein. The compounds are useful as anti-microbial agents, most specifically against gram positive bacteria. The invention further relates to pharmaceutical compositions and methods of treating bacterial infection using such compositions.

Abstract: Antifungals based on dolasatin 10 and four structural modifications thereof (herein “peptides”) and methods of treating a host afflicted with a fungi-induced infection are herein described. In broth macrodilution assays, these peptides were fungicidal for ATCC stains and clinical isolates of Cryptococcus neoformans. Specificity for C. neoformans was also demonstrated in the solid-phase disk diffusion assay, and fungicidal activity confirmed in killing kinetics experiments. Broth macrodilution minimum inhibitory and minimum fungicidal concentrations for the most potent modification ranged from 0.0975-1.56 &mgr;g/ml and 0.0975-6.24 &mgr;g/ml respectively. The minimum inhibitory concentrations were nearly identical in the presence of human serum, but increased with lowered pH. Suitable dosage forms for use of the novel antifungals are also described.

Abstract: Dolastatin 10, a linear pentapeptide, has shown potent antineoplastic activity profiles against various experimental cancer systems. The synthesis of structural modifications of dolastatin 10 having significant antineoplastic activity against human cancer cell lines has been accomplished; namely antineoplastic tetrapeptide w-amino alkyl amides related to dolastatin 10, which have been found to demonstrate effective antineoplastic activity against various human cancer cell lines. Members of this have demonstrated significant antineoplastic activity against human cancer cell lines. The human cancer cell lines against which the substances of the present invention have yielded the significant antineoplastic activity are: Ovarian OVCAR-3; Central Nervous System (“CNS”) SF295; Renal A498; Lung NCI460; Colon KM20L2 and Melanoma SK-MEL-3.

Abstract: The blue marine sponge Cribrochalina sp., collected in the Republic of Maldives was found to contain new cell growth inhibitors denominated cribrostatin 3, cribrostatin 4 and cribrostatin 5 which were found to be active against the NCI human melanoma panel and the P388 marine lymphocytic cell lines employed by the U.S. National Cancer Institute. Structural determination of all three substances were accomplished utilizing high yield NMR (400 MHz) and mass spectral studies. Cribrostatins 3-5 were also found to possess significant antibacterial and antifungal activity.

Abstract: Methoxy and ethoxy substituted 3-aroyl-2-arylbenzo[b]thiophenes and benzo[b]thiophene analogues are described for use in inhibiting tubulin polymerization. The compounds' use for treating tumor cells is also described. Additional aspects described here are certain diaryl ether benzo[b]thiophene derivatives. Also described are particular analogs derived from dihydronaphthalene which have proven particularly effective. Certain new benzofuran analogs are described, as well as certain sulfur oxide benzo[b]thiophene analogs. Important compounds described herein include the first nitrogen-containing derivatives of combretastatin. These include nitro, amino and azide combrdtastatin derivatives.

Abstract: The present invention provides compounds of the formula where R1-R5 are each, independently, a hydrogen atom or a normal or branched C1-C6-alkyl group; A is a methionyl, phenylalanyl or phenylglycyl residue; n is 0 or 1; R6 is a hydrogen atom; and R7 is a carbocylic group, an aromatic group, a C1-C4-alkyl group, a pyridylalkyl group or a heterocyclic group. In another embodiment, R6 is benzyl or —C(O)OR8, where R8 is a C1-C6-alkyl group, and R7 is a heteroaromatic group, such as a 2-thiazolyl group.

Abstract: Methoxy and ethoxy substituted 3-aroyl-2-arylbenzo[b]thiophenes and benzo[b]thiophene analogues are described for use in inhibiting tubulin polymerization. The compounds' use for treating tumor cells is also described.

Abstract: A human cancer cell line bioassay-directed investigation of the Western Pacific marine sponge agelas sp. led to isolation of a trace (7.42×10−6% yield) cancer cell growth inhibitor (lung NCI-H460 GI50 0.77 &mgr;g/ml to ovary OVCAR-3 GI50 2.8 &mgr;g/ml) designated agelagalastatin. Agelagalastatin is the first example of a natural product containing a digalactofuranosyl unit.

Abstract: Cytostatic linear and cyclo-depsipeptides, “Dolastatin 16”, “Dolastatin 18”, and “Dolastatin 17”, are disclosed which are obtained from Indian Ocean shelless mollusk Dolabella auricularia. Methods of using the substances to inhibit malignant cell growth associated with neoplastic diseases in animals and humans are also disclosed, as well as pharmaceutical preparations containing Dolastatin 16, Dolastatin 17, and Dolastatin 18.

Abstract: Methoxy and ethoxy substituted 3-aroyl-2-arylbenzo[b]thiophenes and benzo[b]thiophene analogues are described for use in inhibiting tubulin polymerization. The compounds' use for treating tumor cells is also described.