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This approach enables an access to a range of substitution patterns at the 3-position of the benzothiophene ring.

Colchiceinamide on reaction with phosgene and thiophosgene in the presence of triethylamine afforded tetracyclic compounds:benzo[9,10]heptaleno[4,3-d]oxazolones , -oxazolethiones . Treatment of the resulting tetracyclic oxazolethione with sodium hydroxide afforded tetracyclic thiazolone . All three tetracyclic compounds had very high negative specific rotations, but none of them inhibited tubulin polymerization in vitro.

An array of cis-, trans-, and dihydrostilbenes and some N-arylbenzylamines were synthesized and evaluated for their cytotoxicity in the five cancer cell cultures A-549 lung carcinoma, MCF-7 breast carcinoma, HT-29 colon adenocarcinoma, SKMEL-5 melanoma, and MLM melanoma. Several cis-stilbenes, structurally similar to combretastatins, were highly cytotoxic in all five cell lines and these were also found to be active as inhibitors of tubulin polymerization. The most active compounds also inhibited the binding of colchicine to tubulin. The most potent of the new compounds, both as a tubulin polymerization inhibitor and as a cytotoxic agent, was (Z)-1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene (5a). This substance was almost as potent as combretastatin A-4 (1a), the most active of the combretastatins, as a tubulin polymerization inhibitor. Compound 5a was found to be approximately 140 times more cytotoxic against HT-29 colon adenocarcinoma cells and about 10 times more cytotoxic against MCF-7 breast carcinoma cells than combretastatin A-4. However, 5a was found to be about 20 times less cytotoxic against A-549 lung carcinoma cells, 30 times less cytotoxic against SKMEL-5 melanoma cells, and 7 times less cytotoxic against MLM melanoma cells than combretastatin A-4. The relative potencies 5a greater than 8a greater than 6a for the cis, dihydro, and trans compounds, respectively, as inhibitors of tubulin polymerization are in agreement with the relative potencies previously observed for combretastatin A-4 (1a), dihydrocombretastatin A-4 (1c), and trans-combretastatin A-4 (1b). The relative potencies 5a greater than 8a greater than 6a were also reflected in the results of the cytotoxicity assays. Structure-activity relationships of this group of compounds are also discussed.

Synthesis of isothiocyanato substituted thiocolchicines XI - XIV is described. Introduction of an isotope label is demonstrated with the deuterated isothiocyanate XII and the 14 C-labeled analog XIII . These isothiocyanates inhibit tubulin polymerization at low concentration. In addition, the 14 C-labeled XIII forms covalent bond(s) with tubulin. Unfortunately, the covalent reaction while rapid, is not inhibited by preincubation of tubulin with colchicine. The covalent interaction of XIII with tubulin thus appears to be nonspecific, limiting its use as a marker of the colchicine binding site on tubulin.

Trimethoxy-substituted dihydrodibenzocycloheptenes 4–7, required for a structure–activity study measuring the inhibition of tubulin polymerization in vitro, were synthesized by four different routes: (1) Synthesis of 4 was achieved from 2,3-dimethoxybenzaldehyde via biphenyl aldehyde 17, chain lengthening to propionic acid 20, acid-catalyzed cyclization toward ketone 21, and removal of the carbonyl group. (2) Compound 5 was obtained by eliminating the sterically most hindered methoxy group in 25 or 26 by metal reduction in alcohol. (3) Compound 6 was prepared from biphenyl aldehyde 34 obtained by Grignard reaction on oxazoline 32. (4) Compound 7 was obtained by reductive deoxygenation of the tetrazolyl ether derivative of N-acetylcolchinol 41. The key role of the aromatic oxygen atoms in colchicine and allo congeners as points of interaction with the colchicine binding site on tubulin was demonstrated by the lack of inhibitory activity of compounds 4–7. Optically active 5-acetamide 8a,b isomers of N-acety...

4-Deacetylpaclitaxel, prepared from baccatin III via two synthetic approaches and from paclitaxel via one synthetic approach, has minimal effects on tubulin polymerization and is not cytotoxic to human CA46 Burkitt lymphoma cells.

Total syntheses of the dibenzo[a,c]cycloheptylamines (±)-1 and (±)-2 have been developed; the spectroscopic properties of synthetic 2 match those reported for the alkaloid jerusalemine but compound 1 is different from the alkaloid salimine.

4-Deacetoxypaclitaxel ( 9 ) has been prepared in seven steps from paclitaxel (Taxol ® ). It is significantly less active than paclitaxel in tubulin-assembly and cytotoxicity bioassays.

The marine alkaloids lamellarin-Q 1, lamellarin-O 2 and lukianol-A 3 as well as their more highly oxygenated congeners 22 and 23 are synthesised using Stille, Suzuki or Negishi cross-coupling reactions as the key step.

Curacin D is a novel brine shrimp toxic metabolite isolated from a Virgin Islands collection of the marine cyanobacterium Lyngbya majuscula. Structure elucidation of curacin D was accomplished through multidimensional NMR, GC/MS, and comparisons with curacin A. Curacin D provides new insights into structure-activity relationships in this natural product class as well as some aspects of the likely biosynthetic pathway of the curacins.

A new type of inhibitor of tubulin polymerization was discovered based on the 3-aroyl-2-arylbenzo[b]thiophene molecular skeleton. The lead compound in this series, 2-(4′-methoxyphenyl)-3-(3′,4′,5′-trimethoxybenzoyl)-6-methoxybenzo[b]thiophene1, inhibited tubulin polymerization, caused an increase in the mitotic index of CA46 Burkitt lymphoma cells, and inhibited the growth of several human cancer cell lines.

[structure: see text]. Flexible, convergent access to 2,3-disubstituted benzo[b]thiophenes has been developed. The most concise approach involves sequential coupling of o-bromoiodobenzenes with benzylmercaptan and zinc acetylides to give benzyl o-ethynylphenyl sulfides which react with iodine to give 3-iodobenzo[b]thiophenes in a 5-endo-dig iodocyclization. These iodides can be further elaborated using palladium-mediated coupling and/or metalation techniques. This method has been applied to the synthesis of some novel tubulin binding agents.

A number of analogues of combretastatin A-4 (1), containing a thiophene ring interposed between the two phenyl groups, have been prepared. The synthesis of these compounds employed a combination of palladium-mediated coupling and iodocyclization techniques. The thiophene compounds 11, 14, 18, and 19 also represent non-benzofused analogues of some recently described tubulin binding benzo[b]thiophenes 3-5. The most active thiophene compounds identified in this study were 11, 14, and 18. Overall they are less active than 1 but exhibit comparable activity to the most active of the benzo[b]thiophenes 3-5. A structure-activity relationship of these compounds is considered.

Benzo[b]furan and indole analogues of some recently identified benzo[b]thiophene inhibitors of tubulin polymerization have been prepared, and their biological activity has been assessed. Several very potent analogues were identified.

The synthesis of a simplified analogue of the potent, cytotoxic tubulin-depolymerizing agent spongistatin 1, based on the AB spiroketal framework, is presented. The new structural analogue is an extension of a recently described spongistatin congener reported to disrupt microtubules in breast cancer cells in vitro and to alter the microtubule assembly reaction. Cytotoxicity data on the new structural analogue, as well as the parent congener, are reported. We found no significant cytotoxic or antitubulin activity with either compound.

Peloruside B (2), a natural congener of peloruside A (1), was isolated in sub-milligram quantities from the New Zealand marine sponge Mycale hentscheli. Peloruside B promotes microtubule polymerization and arrests cells in the G(2)/M phase of mitosis similar to paclitaxel, and its bioactivity was comparable to that of peloruside A. NMR-directed isolation, structure elucidation, structure confirmation by total synthesis, and bioactivity of peloruside B are described in this article. The synthesis features Sharpless dihydroxylation, Brown's asymmetric allylboration reaction, reductive aldol coupling, Yamaguchi macrolactonization, and selective methylation.

A hybrid structure was synthesized in which one portion is characteristic of a cryptophycin and a second sector bears the signature of an epothilone. The hybrid, in contrast to parent cryptophycin and epothilone systems, showed no effect on the tubulin assembly reaction.

The title compound 3, an analogue of the naturally-derived spindle toxin rhazinilam (1), has been synthesised, characterised crystallographically and subjected to a preliminary biological evaluation.

A series of stilbenes has been prepared and tested for cytotoxicity in the five human cancer cell lines A-549 non-small cell lung, MCF-7 breast, HT-29 colon, SKMEL-5 melanoma, and MLM melanoma. The cis stilbenes 6a-f proved to be cytotoxic in all five cell lines, with potencies comparable to that of combretastatin A-4. These cytotoxic compounds were all potent inhibitors of tubulin polymerization. The corresponding trans stilbenes 7b-f were inactive as tubulin polymerization inhibitors and were significantly less cytotoxic in the five cancer cell lines. In the dihydro series, 8b, 8c, and 8f were inactive as tubulin polymerization inhibitors, while 8a, 8d, and 8e were less active than the corresponding cis compounds 6a, 6d, and 6e. The lack of tubulin polymerization inhibitory activity and cytotoxicity displayed by the phenanthrene 23b, which was synthesized as a conformationally rigid analogue of the lead compound 1, indicates that the activity of the stilbenes is not due to a totally planar conformation. Similarly, inactivity of the conformationally restricted analogue 26 suggests that the biologically active conformation of 1a resembles that of the cis alkene 1. Additional inactive compounds prepared include the benzylisoquinoline series 28-32 as well as the protoberberines 38 and 39. Shortening the two-carbon bridge of 1a to a one-carbon bridge in the diphenylmethane 20 resulted in a decrease in cytotoxicity and tubulin polymerization inhibitory activity. Although the corresponding benzophenone 18 was as active as 1a as a tubulin polymerization inhibitor, it was less cytotoxic than 1a, and the benzhydrol 19 was essentially inactive. With the exception of the amide 15c, which displayed low antitubulin activity, all of the phenylcinnamic acid derivatives 14a-c and 15a-f were inactive in the tubulin polymerization inhibition assay. The acid 14b and the ester 15a were cytotoxic in several of the cancer cell cultures in spite of their inactivity as tubulin polymerization inhibitors.

A novel series of 2-styrylquinazolin-4(3H-ones which inhibited tubulin polymerization and the growth of L1210 murine leukemia cells was discovered. Extensive structure-activity relationship studies suggest that the entire quinazolinone structure was required, but activity was further enhanced by halide or small hydrophobic substituents at position 6. These analogues did not substantially interfere with the binding of radiolabeled colchicine, vinblastine, or GTP to tubulin and weakly stimulated GTP hydrolysis uncoupled from polymerization. Several analogues have shown in vivo tumor growth inhibitory activity in the L1210 leukemia model, with the lead compound 5o exhibiting good antitumor activity against murine solid tumors as well as human tumor xenografts.

The 2'-monosubstituted and 2',5'-disubstituted title compounds (III) and (IV) as well as the dicarboxylic acid (V) are prepared as models for colchicine (VI); however, only (III) shows appreciable activities in the tubulin binding assay or as inhibitor of tubulin polymerization.