Originally purified as a major lipid component of a strain of the cyanobacterium Lyngbya majuscula isolated in Curaçao, curacin A is a potent inhibitor of cell growth and mitosis, binding rapidly and tightly at the colchicine site of tubulin. Because its molecular structure differs so greatly from that of colchicine and other colchicine site inhibitors, we prepared a series of curacin A analogs to determine the important structural features of the molecule. These modifications include reduction and E-to-Z transitions of the olefinic bonds in the 14-carbon side chain of the molecule; disruption of and configurational changes in the cyclopropyl moiety; disruption, oxidation, and configurational reversal in the thiazoline moiety; configurational reversal and substituent modifications at C13; and demethylation at C10. Inhibitory effects on tubulin assembly, the binding of colchicine to tubulin, and the growth of MCF-7 human breast carcinoma cells were examined. The most important portions of curacin A required for its interaction with tubulin seem to be the thiazoline ring and the side chain at least through C4, the portion of the side chain including the C9-C10 olefinic bond, and the C10 methyl group. Only two modifications totally eliminated the tubulin-drug interaction. The inactive compounds were a segment containing most of the side chain, including its two substituents, and analogs in which the methyl group at the C13 oxygen atom was replaced by a benzoate residue. Antiproliferative activity comparable with that observed with curacin A was only reproduced in compounds that were potent inhibitors of the binding of colchicine to tubulin. Molecular modeling and quantitative structure-activity relationship studies demonstrated that most active analogs overlapped extensively with curacin A but failed to provide an explanation for the apparent structural analogy between curacin A and colchicine.

No abstract

No abstract

No abstract

The intraand intermolecular condensation of alcohols with bis-sulfone methylenes, i.e., dehydrative alkylation, using DEAD and PhgP proceeds stereospecifically at room temperature under essentially neutral conditions affording good to excellent yields of alkylation/ annulation products.The classic Mitsunobu condensation2 of an alcohol with a carboxylic acid, mediated by dialkyl azodicarboxylate/ triphenylphosphine, involves the in situ generation of a highly reactive alkoxyphosphonium intermediate3 which undergoes nucleophilic displacement under mild, nearly neutral conditions with virtually complete inversion of configuration at the electrophilic site (eq 1). Numerous PPh3 ro2cn=nco2r HX OPPh3 V ' y (eq 1) X = RC02", RCOS", RN", ArO'JsO; R3S¡0" I", Br", Cl", F, CNT modifications4 of this protocol have extended its utility to other types of nucleophiles, inter alia, thiolacetate, halides, silanols, tosylate, phthalimide, and heterocycles. Our recent observation5 that DEAD/PhsP complex converts 7-nitroalkanols to -nitrocyclopropanes in good to excellent yields represents a rare example of participation by a carbon-centered nucleophile.6 However, all efforts to exploit the latter dehydrative alkylation of nitro paraffins to form larger rings or for intermolecular condensations failed and, thus, prompted us to evaluate other functionalities.7 Herein, we report that bis-sulfones are particularly effective for a wide variety of dehydrative alkylations/annulations8 as summarized in Table I. Cyclizations affording both small-(entries 1 and 2) and medium-sized rings (entry 3) were achieved with equal ease. Likewise, intermolecular alkylative dehydrations proceeded smoothly (entry 4) and, when applied to diols in the presence of excess reagent, provided