Interaction of the cyanobacterial thiazoline-containing lipid curacin A with bovine brain tubulin

Ludueña, Richard F.; Prasad, Veena; Roach, Mary Carmen; Banerjee, Mohua; Yoo, Hye Dong; Gerwick, William H.

doi:10.1002/(sici)1098-2299(199703)40:3<223::aid-ddr2>3.0.co;2-m

Cited by 6 publications

(2 citation statements)

References 27 publications

(29 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[1,3] The parent compound, apratoxin A, induces G1-phase cell cycle arrest and apoptosis through interaction with STAT3 and FGFR signaling. [3] Metabolites such as the curacins, [4] the dolastatins and their analogues (e.g. symplostatins, gallinamide A, malevamide D, belamide A), [5] and the cryptophycins [6] have been shown to interfere with the normal function of microtubules.…”

Section: Introductionmentioning

confidence: 99%

The Carmaphycins: New Proteasome Inhibitors Exhibiting an α,β‐Epoxyketone Warhead from a Marine Cyanobacterium

et al. 2012

Self Cite

View full text Add to dashboard Cite

Two new peptidic proteasome inhibitors were isolated as trace components from a Curaçao collection of Symploca sp. marine cyanobacteria. Carmaphycin A (1) and carmaphycin B (2) feature a leucine-derived α, β -epoxyketone warhead directly connected to either methionine sulfoxide or methionine sulfone. Their structures were elucidated on the basis of extensive NMR/MS analyses and confirmed by total synthesis, which in turn provided more material for further biological evaluations. Pure carmaphycins A and B were found to inhibit the β5 subunit (chymotrypsin-like activity) of the S. cerevisiae 20S proteasome in the low nanomolar range. Additionally, they exhibited strong cytotoxicity to lung and colon cancer cell lines, as well as exquisite antiproliferative effects in the NCI60 cell line panel. These assay results as well as initial structural biology studies suggest a distinctive binding mode for these new inhibitors.

show abstract

Section: Introductionmentioning

confidence: 99%

The Carmaphycins: New Proteasome Inhibitors Exhibiting an α,β‐Epoxyketone Warhead from a Marine Cyanobacterium

et al. 2012

Self Cite

View full text Add to dashboard Cite

show abstract

“…Initial studies demonstrated that curacin A stimulated the uncoupled GTPase reaction typical of colchicine site agents, and indirect observations were consistent with curacin A binding rapidly and dissociating slowly from tubulin (Blokhin et al, 1995). Further, curacin A inhibits formation of the Cys239-Cys354 cross-link in ␤-tubulin (Ludueñ a et al, 1997). Moreover, under reaction conditions where tubulin can polymerize, high concentrations of curacin A induced formation of complex abnormal tubulin polymers resembling twisted cables of fine spiral filaments (Hamel et al, 1995).…”

mentioning

confidence: 99%

Structure-Activity Analysis of the Interaction of Curacin A, the Potent Colchicine Site Antimitotic Agent, with Tubulin and Effects of Analogs on the Growth of MCF-7 Breast Cancer Cells

Lai²,

et al. 1998

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Effect of diethylstilbestrol on the polymerization and alkylation of tubulin

1999

Self Cite

View full text Add to dashboard Cite

Interaction of the cyanobacterial thiazoline-containing lipid curacin A with bovine brain tubulin

Cited by 6 publications

References 27 publications

The Carmaphycins: New Proteasome Inhibitors Exhibiting an α,β‐Epoxyketone Warhead from a Marine Cyanobacterium

The Carmaphycins: New Proteasome Inhibitors Exhibiting an α,β‐Epoxyketone Warhead from a Marine Cyanobacterium

Structure-Activity Analysis of the Interaction of Curacin A, the Potent Colchicine Site Antimitotic Agent, with Tubulin and Effects of Analogs on the Growth of MCF-7 Breast Cancer Cells

Effect of diethylstilbestrol on the polymerization and alkylation of tubulin

Contact Info

Product

Resources

About