The most potent microtubule assembly inhibitor of newer diphenylpyridazinone derivatives examined was NSC 613241. Because NSC 613241 and (−)-rhazinilam also induce the formation of similar 2-filament ...spirals, these aberrant reactions were compared. Spiral formation with both compounds was enhanced by GTP and inhibited by GDP and by 15 other inhibitors of microtubule assembly. Similarly, microtubule assembly induced by paclitaxel or laulimalide is enhanced by GTP and inhibited by GDP and assembly inhibitors, but neither 3HNSC 613241 nor 3H(−)-rhazinilam bound to microtubules or inhibited the binding of 3Hpaclitaxel or 3Hpeloruside A to microtubules. Differences in the pitch of aberrant polymers were found: NSC 613241-induced and (−)-rhazinilam-induced spirals had average repeats of 85 and 79–80 nm, respectively. We found no binding of 3HNSC 613241 or 3H(−)-rhazinilam to αβ-tubulin dimer, but both compounds were incorporated into the polymers they induced in substoichiometric reactions, with as little as 0.1–0.2 mol compound/mol of tubulin, and no cross-inhibition by NSC 613241 or (−)-rhazinilam into spirals occurred. Under reaction conditions where neither compound induced spiral formation, both compounds together synergistically induced substantial spiral formation. We conclude that (−)-rhazinilam and NSC 613241 bind to different sites on tubulin that differ from binding sites for other antitubulin agents.
•(−)-Rhazinilam and NSC 613241 induce formation of spirals of different repeats.•(−)-Rhazinilam and NSC 613241 do not bind avidly to microtubules or tubulin dimer.•(−)-Rhazinilam and NSC 613241act substoichiometrically and synergistically.•(−)-Rhazinilam and NSC 613241 do not inhibit each other’s binding to spirals.•Spiral formation: enhanced by GTP; inhibited by assembly inhibitors and by GDP.
A series of 1,3thiazolo4,5-eisoindoles has been synthesized through a versatile and high yielding multistep sequence. Evaluation of the antiproliferative activity of the new compounds on the full NCI ...human tumor cell line panel highlighted several compounds that are able to inhibit tumor cell proliferation at micromolar-submicromolar concentrations. The most active derivative 11g was found to cause cell cycle arrest at the G2/M phase and induce apoptosis in HeLa cells, following the mitochondrial pathway, making it a lead compound for the discovery of new antimitotic drugs.
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•1,3Thiazolo4,5-eisoindoles were synthesized.•11i and 11g showed growth inhibitory activity at low micromolar concentrations.•11c showed 60% inhibition of colchicine binding to tubulin at 50 μM.•11g induced cell death by apoptosis through the mitochondrial pathway.
The synthesis and biological evaluation of a series of 12,13-aziridinyl epothilone B analogues is described. These compounds were accessed by a practical, general process that involved a ...12,13-olefinic methyl ketone as a starting material obtained by ozonolytic cleavage of epothilone B followed by tungsten-induced deoxygenation of the epoxide moiety. The attachment of the aziridine structural motif was achieved by application of the Ess–Kürti–Falck aziridination, while the heterocyclic side chains were introduced via stereoselective phosphonate-based olefinations. In order to ensure high (E) selectivities for the latter reaction for electron-rich heterocycles, it became necessary to develop and apply an unprecedented modification of the venerable Horner–Wadsworth–Emmons reaction, employing 2-fluoroethoxyphosphonates that may prove to be of general value in organic synthesis. These studies resulted in the discovery of some of the most potent epothilones reported to date. Equipped with functional groups to accommodate modern drug delivery technologies, some of these compounds exhibited picomolar potencies that qualify them as payloads for antibody drug conjugates (ADCs), while a number of them revealed impressive activities against drug resistant human cancer cells, making them desirable for potential medical applications.
A detailed account of the enantioselective total synthesis of (–)‐zampanolide, a macrolide marine natural product with high anticancer activity, is described. For the synthesis of the ...4‐methylenetetrahydropyran unit of (–)‐zampanolide, we initially 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 for the construction of a trisubstituted olefin, a ring‐closing metathesis to form a highly functionalized macrolactone, and a chiral phosphoric acid promoted formation of an N‐acyl aminal to furnish (–)‐zampanolide stereoselectively and in good yield. The synthetic (–)‐zampanolide had effects on cultured cells and on tubulin assembly consistent with the properties reported for the natural product.
An enantioselective synthesis of (–)‐zampanolide has been achieved. This rare marine natural product shows microtubule‐stabilizing properties. It also displays potent activity against taxol‐resistant cells. This synthesis will provide a convenient access to analogues for important structure–activity relationship studies and less complex anticancer agents related to zampanolide.
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. Compounds 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed 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.
We have devised a procedure for the synthesis of analogs of combretastatin A-4 (CA-4) containing sulfur and selenium atoms as spacer groups between the aromatic rings. CA-4 is well known for its ...potent activity as an inhibitor of tubulin polymerization, and its prodrugs combretastatin A-4 phosphate (CA-4P) and combretastatin A-1 phosphate (CA-1P) are being investigated as antitumor agents that cause tumor vascular collapse in addition to their activity as cytotoxic compounds. Here we report the preparation of two sulfur analogs and one selenium analog of CA-4. All synthesized compounds, as well as several synthetic intermediates, were evaluated for inhibition of tubulin polymerization and for cytotoxic activity in human cancer cells. Compounds 3 and 4 were active at nM concentration against MCF-7 breast cancer cells. As inhibitors of tubulin polymerization, both 3 and 4 were more active than CA-4 itself. In addition, 4 was the most active of these agents against 786, HT-29 and PC-3 cancer cells. Molecular modeling binding studies are also reported for compounds 1, 3, 4 and CA-4 to tubulin within the colchicine site.
Cell cycle experiments with our previously reported 4-biphenylaminoquinazoline (1–3) multityrosine kinase inhibitors revealed an activity profile resembling that of known tubulin polymerization ...inhibitors. Novel 4-biarylaminoquinazoline analogues of compound 2 were synthesized and evaluated as inhibitors of several tyrosine kinases and of tubulin. Although compounds 1–3 acted as dual inhibitors, the heterobiaryl analogues possessed only anti-tubulin properties and targeted the colchicine site. Furthermore, molecular modeling studies allowed the rationalization of the pharmacodynamic properties of the compounds.
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 ∼50% of inhibition on human HeLa and HCT116/chr3 cells at 0.5 μM, and these compounds inhibited the growth of HEK, M14, and U937 cells with IC50’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.
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 3H-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 3HHB 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.
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.
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