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Giuseppe La Regina, Ruoli Bai,
Whilelmina Maria Rensen,
Erica Di Cesare,
Antonio Coluccia,
Francesco Piscitelli,
Valeria Famiglini,
Alessia Reggio,
Marianna Nalli,
Sveva Pelliccia, [......],
Andrea Brancale,
Giulio Dondio,
Stefania Vultaggio,
Mario Varasi,
Ciro Mercurio,
Claudia Martini,
Ernest Hamel,
Patrizia Lavia,
Ettore Novellino,
Romano Silvestri
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ABSTRACT: New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compound 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed an IC50 = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55 and 57 were notably more potent than vinorelbine, vinblastine and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes.
Journal of Medicinal Chemistry 12/2012; · 4.80 Impact Factor
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ABSTRACT: A detailed account of the enantioselective total synthesis of (-)-zampanolide, a macrolide marine natural product with high anti-cancer activity is described. For synthesis of the 4-methylene tetrahydropyran unit of (-)-zampanolide, initially, we relied upon an oxidative C-H activation of an alkenyl ether and intramolecular cyclization to provide the substituted tetrahydropyran ring. However, this strategy was unsuccessful. Subsequently, we found that a cinnamyl ether is critical for the successful oxidative intramolecular cyclization reaction. The synthesis also features a cross metathesis reaction to construct a tri-substituted olefin, a ring-closing metathesis to form a highly functionalized macrolactone and a chiral phosphoric acid promoted N-acyl aminal formation to furnish (-)-zampanolide stereoselectively and in good yield. The synthetic (-)-zampanolide had effects on cultured cells and on tubulin assembly consistent with properties reported for the natural product.
European Journal of Organic Chemistry 07/2012; 2012(22):4130-4139. · 3.33 Impact Factor
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ABSTRACT: We purified pseudolaric acid B (PAB) from the root and stem bark of Pseudolarix kaempferi (Lindl.) Gorden. Confirming previous findings, we found that the compound had high nanomolar IC₅₀ antiproliferative effects in several cultured cell lines, causing mitotic arrest and the disappearance of intracellular microtubules. PAB strongly inhibited tubulin assembly (IC₅₀, 1.1 μM) but weakly inhibited the binding of colchicine to tubulin, as demonstrated by fluorescence and with [³H]colchicine. Kinetic analysis demonstrated that the mechanism of inhibition was competitive, with an apparent K(i) of 12-15 μM. Indirect studies demonstrated that PAB bound rapidly to tubulin and dissociated more rapidly from tubulin than the colchicine analog 2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone, whose complex with tubulin is known to have a half-life of 17s at 37 °C. We modeled PAB into the colchicine site of tubulin, using the crystal structure 1SA0 that contains two αβ-tubulin heterodimers, both bound to a colchicinoid and to a stathmin fragment. The binding model of PAB revealed common pharmacophoric features between PAB and colchicinoids, not readily apparent from their chemical structures.
Biochemical pharmacology 05/2012; 84(4):444-50. · 4.25 Impact Factor
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ABSTRACT: Structure-activity relationship translation offers an expeditious means for discovery of new active series. This approach was applied to discover tetrahydroisoquinoline (THIQ)-based steroidomimetic microtubule disruptors. The two A-ring elements of a three-point steroidal pharmacophore were incorporated into a THIQ-based A,B-ring mimic to which an H-bond acceptor was attached as the third motif. Optimization of the representative 6c through conformational biasing delivered a 10-fold gain in activity and a new series of microtubule disruptors (e.g., 9c) with antiproliferative activity in the nanomolar range. The THIQ derivatives match, or surpass, the activities of the steroidal series and exhibit improved physicochemical properties.
ACS Medicinal Chemistry Letters 01/2012; 3(1):5-9. · 3.36 Impact Factor
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Giuseppe La Regina, Ruoli Bai,
Willeke Rensen,
Antonio Coluccia,
Francesco Piscitelli,
Valerio Gatti,
Alessio Bolognesi,
Antonio Lavecchia,
Ilaria Granata,
Amalia Porta, [......],
Angela Santoni,
Andrea Brancale,
Cristiano Ferlini,
Giulio Dondio,
Mario Varasi,
Ciro Mercurio,
Ernest Hamel,
Patrizia Lavia,
Ettore Novellino,
Romano Silvestri
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ABSTRACT: New arylthioindoles (ATIs) were obtained by replacing the 2-alkoxycarbonyl group with a bioisosteric 5-membered heterocycle nucleus. The new ATIs 5, 8, and 10 inhibited tubulin polymerization, reduced cell growth of a panel of human transformed cell lines, and showed higher metabolic stability than the reference ester 3. These compounds induced mitotic arrest and apoptosis at a similar level as combretastatin A-4 and vinblastine and triggered caspase-3 expression in a significant fraction of cells in both p53-proficient and p53-defective cell lines. Importantly, ATIs 5, 8, and 10 were more effective than vinorelbine, vinblastine, and paclitaxel as growth inhibitors of the P-glycoprotein-overexpressing cell line NCI/ADR-RES. Compound 5 was shown to have medium metabolic stability in both human and mouse liver microsomes, in contrast to the rapidly degraded reference ester 3, and a pharmacokinetic profile in the mouse characterized by a low systemic clearance and excellent oral bioavailability.
Journal of Medicinal Chemistry 11/2011; 54(24):8394-406. · 4.80 Impact Factor
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Demetrio Raffa,
Benedetta Maggio,
Fabiana Plescia,
Stella Cascioferro,
Salvatore Plescia,
Maria Valeria Raimondi,
Giuseppe Daidone,
Manlio Tolomeo,
Stefania Grimaudo,
Antonietta Di Cristina,
Rosaria Maria Pipitone, Ruoli Bai,
Ernest Hamel
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ABSTRACT: Several new 2-{[(2E)-3-phenylprop-2-enoyl]amino}benzamides 12a-s and 17t-v were synthesized by stirring in pyridine the (E)-3-(2-R1-3-R2-4-R3-phenyl)acrylic acid chlorides 11c-k and 11t-v with the appropriate anthranilamide derivatives 10a-c or the 5-iodoanthranilic acid 13. Some of the synthesized compounds were evaluated for their in vitro antiproliferative activity against the full NCI tumor cell line panel derived from nine clinically isolated cancer types (leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast). COMPARE analysis, effects on tubulin polymerization in cells and with purified tubulin, and effects on cell cycle distribution for 17t, the most active of the series, indicate that these new antiproliferative compounds act as antitubulin agents.
European journal of medicinal chemistry 07/2011; 46(7):2786-96. · 3.27 Impact Factor
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ABSTRACT: Compounds that modulate microtubule dynamics include highly effective anticancer drugs, leading to continuing efforts to identify new agents and improve the activity of established ones. Here, we demonstrate that [(3)H]-labeled halichondrin B (HB), a complex, sponge-derived natural product, is bound to and dissociated from tubulin rapidly at one binding site per αβ-heterodimer, with an apparent K(d) of 0.31 μM. We found no HB-induced aggregation of tubulin by high-performance liquid chromatography, even following column equilibration with HB. Binding of [(3)H]HB was competitively inhibited by a newly approved clinical agent, the truncated HB analogue eribulin (apparent K(i), 0.80 μM) and noncompetitively by dolastatin 10 and vincristine (apparent K(i)'s, 0.35 and 5.4 μM, respectively). Our earlier studies demonstrated that HB inhibits nucleotide exchange on β-tubulin, and this, together with the results presented here, indicated the HB site is located on β-tubulin. Using molecular dynamics simulations, we determined complementary conformations of HB and β-tubulin that delineated in atomic detail binding interactions of HB with only β-tubulin, with no involvement of the α-subunit in the binding interaction. Moreover, the HB model served as a template for an eribulin binding model that furthered our understanding of the properties of eribulin as a drug. Overall, these results established a mechanistic basis for the antimitotic activity of the halichondrin class of compounds.
Journal of Chemical Information and Modeling 05/2011; 51(6):1393-404. · 4.68 Impact Factor
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ABSTRACT: Synthesis and biological evaluation of jasplakinolide analogs are described. The synthesis of analogs utilized a diastereoselective syn-aldol reaction and an orthoester Claisen rearrangement as key steps. All synthetic analogs were evaluated for their ability to disrupt the actin cytoskeleton. Compounds 2, 3, and 4 essentially displayed similar activity to jasplakinolide.
Bioorganic & medicinal chemistry letters 09/2010; 20(17):5104-7. · 2.65 Impact Factor
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Giuseppe La Regina,
Taradas Sarkar, Ruoli Bai,
Michael C Edler,
Roberto Saletti,
Antonio Coluccia,
Francesco Piscitelli,
Lara Minelli,
Valerio Gatti,
Carmela Mazzoccoli, [......],
Claudio Falcone,
Anna Ivana Scovassi,
Vincenzo Giansanti,
Pietro Campiglia,
Amalia Porta,
Bruno Maresca,
Ernest Hamel,
Andrea Brancale,
Ettore Novellino,
Romano Silvestri
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ABSTRACT: New arylthioindoles along with the corresponding ketone and methylene compounds were potent tubulin assembly inhibitors. As growth inhibitors of MCF-7 cells, sulfur derivatives were superior or sometimes equivalent to the ketones, while methylene derivatives were substantially less effective. Esters 24, 27-29, 36, 39, and 41 showed approximately 50% of inhibition on human HeLa and HCT116/chr3 cells at 0.5 microM, and these compounds inhibited the growth of HEK, M14, and U937 cells with IC(50)'s in the 78-220 nM range. While murine macrophage J744.1 cell growth was significantly less affected (20% at higher concentrations), four other nontransformed cell lines remained sensitive to these esters. The effect of drug treatment on cell morphology was examined by time-lapse microscopy. In a protocol set up to evaluate toxicity on the Saccharomyces cerevisiae BY4741 wild type strain, compounds 24 and 54 strongly reduced cell growth, and 29, 36, and 39 also showed significant inhibition.
Journal of Medicinal Chemistry 08/2009; 52(23):7512-27. · 4.80 Impact Factor
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ABSTRACT: (-)-Rhazinilam was spontaneously generated from a natural product during isolation. In cultured cells, it causes microtubule bundle formation, like those caused by paclitaxel. With tubulin, (-)-rhazinilam causes formation of an aberrant spiral polymer. Using glutamate and GTP, we developed an assay for spiral formation and applied it to 17 new (+/-)-rhazinilam analogs with either a modified side chain or a different size D ring. There was reasonable correlation between spiral formation and inhibition of human MCF-7 breast carcinoma cell growth. Only one side chain analog was as active as (+/-)-rhazinilam. During these studies, we observed that omitting GTP from the reaction mixture caused a major change in the morphology of the (-)-rhazinilam-induced polymer, with half the observed polymer being microtubule-like and half being spirals. This mixed polymer slowly disassembled at 0 degrees C, but there was no apparent difference in the lability of the microtubules versus the spirals.
Archives of Biochemistry and Biophysics 07/2009; 487(2):98-104. · 2.93 Impact Factor
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ABSTRACT: A bicycle built for tubulin: The total synthesis of (+)-chamaecypanone C has been achieved by using a tandem retro-Diels-Alder/Diels-Alder cascade reaction (see scheme). Initial biological studies demonstrate that (+)-chamaecypanone C is an inhibitor of tubulin assembly and binds at the colchicine site.
Angewandte Chemie International Edition 02/2009; 48(8):1494-7. · 13.45 Impact Factor
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ABSTRACT: Tasidotin, an oncolytic drug in phase II clinical trials, is a peptide analog of the antimitotic depsipeptide dolastatin 15. In tasidotin, the carboxyl-terminal ester group of dolastatin 15 has been replaced by a carboxy-terminal tert-butyl amide. As expected from studies with cemadotin, [(3)H]tasidotin, with the radiolabel in the second proline residue, was hydrolyzed intracellularly, with formation of N,N-dimethylvalyl-valyl-N-methylvalyl-prolyl-proline (P5), a pentapeptide also present in dolastatin 15 and cemadotin. P5 was more active as an inhibitor of tubulin polymerization and less active as a cytotoxic agent than tasidotin, cemadotin, and dolastatin 15. [(3)H]P5 was not the end product of tasidotin metabolism. Large amounts of [(3)H]proline were formed in every cell line studied, with proline ultimately becoming the major radiolabeled product. The putative second product of the hydrolysis of P5, N,N-dimethylvalyl-valyl-N-methylvalyl-proline (P4), had little activity as either an antitubulin or cytotoxic agent. In seven suspension cell lines, the cytotoxicity of tasidotin correlated with total cell uptake of the compound and was probably affected negatively by the extent of degradation of P5 to proline and, presumably, P4. The intracellular enzyme prolyl oligopeptidase probably degrades tasidotin to P5. When CCRF-CEM human leukemia cells were treated with N-benzyloxycarbonylprolylprolinal (BCPP), an inhibitor of prolyl oligopeptidase, there was a 30-fold increase in the IC(50) of tasidotin and a marked increase in intracellular [(3)H]tasidotin. BCPP also caused a 4-fold increase in the IC(50) of P5, so the enzyme probably does not convert P5 to P4. Inhibiting degradation of P5 should have led to a decrease in the IC(50) obtained for P5 in the presence of BCPP.
Molecular pharmacology 11/2008; 75(1):218-26. · 4.53 Impact Factor
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ABSTRACT: Current microtubule inhibitory agents used in the clinic to treat cancer have severe side effects, and development of resistance is frequent. We have evaluated the antitumor effect of a novel 30-compound library of phenoxy pyridine and phenyl sulfanyl pyridine derivatives. MTT assays revealed that, of all 30 compounds tested, compounds 2 and 3 showed the largest decrease in proliferation (low muM range) against Panc1 and HS766T human pancreatic cancer cells. Flow cytometry experiments with MCF7 breast cancer cells showed a G2/M arrest comparable to that of colcemid. Immunofluorescence staining demonstrated complete disappearance of intracellular microtubules. Tubulin assembly assays, however, showed a dose-dependent decrease in tubulin assembly with compound 3 that seemed limited to about 50% of the control reaction. With compound 2 treatment, there was only a delay in the onset of assembly, with no effect on the extent of the reaction. Taken together, our results show that these novel microtubule inhibitors have promising anticancer activity and can be potentially used to overcome paclitaxel resistance in the clinical setting.
Journal of Medicinal Chemistry 10/2008; 51(19):5953-7. · 4.80 Impact Factor
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ABSTRACT: The natural product cyclostreptin reacts covalently and stoichiometrically with microtubules, at either of two amino acid residues of beta-tubulin, Thr-218 or Asn-226, but much less extensively and only at Thr-218 in unpolymerized tubulin. It was found that 8-acetylcyclostreptin (8AcCS) induces tubulin assembly in a manner almost identical with that of cyclostreptin. We therefore synthesized [ (14)C-acetyl]8AcCS and studied the kinetics of its interaction with glutaraldehyde-stabilized microtubules and with unassembled tubulin. With the microtubules, we found that 8AcCS bound rapidly, with a minimal (unmeasurable with the radiolabeled analogue) lag prior to the occurrence of the covalent reaction. Apparent reaction rate constants for the overall reaction ranged from 6.2 x 10 (2) M (-1) s (-1) at 0 degrees C to 5.6 x 10 (3) M (-1) s (-1) at 20 degrees C. The rate constants obtained at 0 and 10 degrees C indicate an activation energy for the reaction of about 27 kcal/mol, while those obtained at 10 and 20 degrees C indicate an activation energy of about 7.7 kcal/mol. With the unpolymerized tubulin, we did find a minimal covalent reaction occurred without apparent microtubule assembly, but a substantial reaction only occurred following assembly. In conclusion, the radiolabeled 8AcCS shows that an extensive covalent interaction of ligand with tubulin requires microtubule assembly and that the covalent reaction occurs rapidly after the initial binding interaction.
Journal of Natural Products 04/2008; 71(3):370-4. · 3.13 Impact Factor
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ABSTRACT: The complex marine natural product halichondrin B was compared with NSC 707389 (E7389), a structurally simplified, synthetic macrocyclic ketone analog, which has been selected for clinical trials in human patients. NSC 707389 was invariably more potent than halichondrin B in its interactions with tubulin. Both compounds inhibited tubulin assembly, inhibited nucleotide exchange on beta-tubulin, and were noncompetitive inhibitors of the binding of radiolabeled vinblastine and dolastatin 10 to tubulin. Neither compound seemed to induce an aberrant tubulin assembly reaction, as occurs with vinblastine (tight spirals) or dolastatin 10 (aggregated rings and spirals). We modeled the two compounds into a shared binding site on tubulin consistent with their biochemical properties. Of the two tubulin structures available, we selected for modeling the complex of a stathmin fragment with two tubulin heterodimers with two bound colchicinoid molecules and a single bound vinblastine between the two heterodimers (Nature (Lond) 435:519-522, 2005). Halichondrin B and NSC 707389 fit snugly between the two heterodimers adjacent to the exchangeable site nucleotide. Fitting the compounds into this site, which was also close to the vinblastine site, resulted in enough movement of amino acid residues at the vinblastine site to cause the latter compound to bind less well to tubulin. The model suggests that halichondrin B and NSC 707389 most likely form highly unstable, small aberrant tubulin polymers rather than the massive stable structures observed with vinca alkaloids and antimitotic peptides.
Molecular Pharmacology 01/2007; 70(6):1866-75. · 4.88 Impact Factor
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ABSTRACT: Synthetic investigations of ustiloxin natural products are described. The first total synthesis of ustiloxin F was completed in 15 steps via ethynyl aziridine ring-opening by a phenol derivative. The results of biological tests of synthetic ustiloxins D and F, and two analogs, O-Me-ustiloxin D and 6-Ile-ustiloxin, demonstrated that the free hydroxyl group ortho to the ether linkage is critical for activity and variations at the Val/Ala site produce changes in the biological activity suggesting the need for further perturbations at this site to more extensively study the tubulin binding.
Bioorganic & Medicinal Chemistry Letters 10/2006; 16(18):4804-7. · 2.55 Impact Factor
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ABSTRACT: Bistramide A (1) is a marine natural product with broad, potent antiproliferative effects. Bistramide A has been reported to selectively activate protein kinase C (PKC) delta, leading to the view that PKCdelta is the principal mediator of antiproliferative activity of this natural product. Contrary to this observation, we established that bistramide A binds PKCdelta with low affinity, does not activate this kinase in vitro and does not translocate GFP-PKCdelta. Furthermore, we identified actin as the cellular receptor of bistramide A. We report that bistramide A disrupts the actin cytoskeleton, inhibits actin polymerization, depolymerizes filamentous F-actin in vitro and binds directly to monomeric G-actin in a 1:1 ratio with a Kd of 7 nM. We also constructed a fully synthetic9 bistramide A-based affinity matrix and isolated actin as a specific bistramide A-binding protein. This activity provides a molecular explanation for the potent antiproliferative effects of bistramide A, identifying it as a new biochemical tool for studies of the actin cytoskeleton and as a potential lead for development of a new class of antitumor agents.
Nature Chemical Biology 01/2006; 1(7):383-8. · 14.69 Impact Factor
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ABSTRACT: Tubulin with bound [5-3H]dolastatin 10 was exposed to ultraviolet light, and 8-10% of the bound drug cross-linked to the protein, most of it specifically. The primary cross-link was to the peptide spanning amino acid residues 2-31 of beta-tubulin, but the specific amino acid could not be identified. Indirect studies indicated that cross-link formation occurred between cysteine 12 and the thiazole moiety of dolastatin 10. An equipotent analog of dolastatin 10, lacking the thiazole ring, did not form an ultraviolet light-induced cross-link to beta-tubulin. Preillumination of tubulin with ultraviolet light, known to induce cross-link formation between cysteine 12 and exchangeable site nucleotide, inhibited the binding of [5-3H]dolastatin 10 and cross-link formation more potently than it inhibited the binding of colchicine or vinblastine to tubulin. Conversely, binding of dolastatin 10 to tubulin inhibited formation of the cross-link between cysteine 12 and the exchangeable site nucleotide. Dithiothreitol inhibited formation of the beta-tubulin/dolastatin 10 cross-link but not the beta-tubulin/exchangeable site nucleotide cross-link. Modeling studies revealed a highly favored binding site for dolastatin 10 at the + end of beta-tubulin in proximity to the exchangeable site GDP. Computational docking of an energy-minimized dolastatin 10 conformation at this site placed the thiazole ring of dolastatin 10 8-9 A from the sulfur atom of cysteine 12. Dolastatin 15 and cryptophycin 1 could also be docked into positions that overlapped more extensively with the docked dolastatin 10 than with each other. This result was consistent with the observed binding properties of these peptides.
Journal of Biological Chemistry 08/2004; 279(29):30731-40. · 4.77 Impact Factor
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ABSTRACT: Previous work has shown that laulimalide, a sponge-derived natural product, resembles paclitaxel in enhancing tubulin assembly and in its effects on cellular microtubules. The two compounds, however, seem to have distinct binding sites on tubulin polymer. Nearly equimolar amounts of tubulin, laulimalide, and paclitaxel are recovered from microtubules formed with both drugs. In the present study, we searched for differences between laulimalide and paclitaxel in their interactions with tubulin polymer. Laulimalide was compared with paclitaxel and epothilone A, a natural product that competes with paclitaxel in binding to microtubules, for assembly properties at different temperatures and for effects of GTP and microtubule-associated proteins on assembly. Although minor differences were observed among the three drugs, their overall effects were highly similar, except that aberrant assembly products were observed more frequently with paclitaxel and that the polymers formed with laulimalide and epothilone A were more stable at 0 degrees C. The most dramatic difference observed between laulimalide and epothilone A was that only laulimalide was able to enhance assembly synergistically with paclitaxel, as would be predicted if the two drugs bound at different sites in polymer. Because stoichiometric amounts of laulimalide and paclitaxel can cause extensive tubulin assembly, maximum synergy was observed at lower temperatures under reaction conditions in which each drug alone is relatively inactive. Laulimalide-induced assembly, like paclitaxel-induced assembly, was inhibited by drugs that inhibit tubulin assembly by binding at either the colchicine- or vinblastine-binding site. When radiolabeled GTP is present in a reaction mixture with either laulimalide or paclitaxel, nucleotide hydrolysis occurs with incorporation of radiolabeled GDP into polymer.
Molecular Pharmacology 08/2004; 66(1):113-21. · 4.88 Impact Factor
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ABSTRACT: In order to study the influence of 3-substitution on the cytotoxic activity of 2-styrylquinazolinones, new 6-chloro-2-styryl-3-(heteroaryl)-4(3H)-quinazolinones were synthesized by refluxing equimolar amounts of 6-chloro-2-methyl-3-(heteroaryl)-4(3H)-quinazolinones and benzaldehyde in glacial acetic acid. At 1 microg ml(-1) concentration, almost all 2-styrylquinazolinones showed some cytotoxic activity against the L1210 and K562 leukemia cell lines. However, only 6-chloro-2-styryl-3-(pyrimidin-2yl)-4(3H)-quinazolinone inhibited the growth of these cells by over 50%. This last compound was also the only member of the series that inhibited tubulin polymerization, with an IC(50) value of 5.8 versus 3.2 microM for colchicine. It was also examined for effects on the growth of human MCF7 breast carcinoma cells and Burkitt lymphoma CA46 cells, which had IC(50) values of 0.34 and 1.0 microM, respectively. At 10 microM 6-chloro-2-styryl-3-(pyrimidin-2yl)-4(3H)-quinazolinone induced G2/M arrest (66%) in Burkitt cells, with a mitotic index of 20%. At 3.4 microM, it caused disruption of the cellular microtubule system of the MCF7 cells. Both these cellular effects are consistent with its mechanism of action resulting from its inhibitory effect on tubulin assembly.
European Journal of Medicinal Chemistry 05/2004; 39(4):299-304. · 3.35 Impact Factor
