Synthesis and tubulin-binding properties of new allocolchicinoids

Boyer, François‐Didier; Dubois, Joëlle; Thoret, Sylviane; Dau, Marie‐Elise Tran Huu; Hanna, Issam

doi:10.1016/j.bioorg.2010.03.003

Cited by 25 publications

(15 citation statements)

References 51 publications

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“…The OD 340 was measured every minute for one hour and the resulting graph is shown in Figure 5A. Our results indicate that NSC 51046 induced slight tubulin inhibition at the lower dose, which corresponds to previous studies [31], [32]; however, we observed that a higher dose of NSC 51046 caused rapid tubulin polymerization, which was unexpected. As expected, colchicine inhibited tubulin polymerization.…”

Section: Resultssupporting

confidence: 88%

“…It is well established that compounds that target DNA replicative machinery affect not only the fast dividing cancer cells, but also fast dividing non-cancerous cells in the body, leading to therapy associated side effects with common chemotherapy. NSC 51046 is known to inhibit tubulin polymerization at low doses [31], [32], which we also observed; surprisingly, it was observed the NSC 51046 induced rapid tubulin polymerization at a higher dose. NSC 51046 was also observed to be non-selective, further illustrating that tubulin is not an optimal target for cancer targeting drugs.…”

Section: Discussionsupporting

confidence: 79%

“…Structurally, our working hypothesis centers around the effect of the rearranged methoxy groups on the biaryl dihedral angle. It is well established that the presence of the seven membered B ring is key for activity in the allocolchicines [32]. This imposes dihedral angles for the biaryls in the 49–53 o range [35], [36], which appear to be near optimal for tubulin binding.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Novel Analogue of Colchicine Induces Selective Pro-Death Autophagy and Necrosis in Human Cancer Cells

et al. 2014

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Colchicine, a natural product of Colchicum autumnae currently used for gout treatment, is a tubulin targeting compound which inhibits microtubule formation by targeting fast dividing cells. This tubulin-targeting property has lead researchers to investigate the potential of colchicine and analogs as possible cancer therapies. One major study conducted on an analogue of allocolchicine, ZD 6126, was halted in phase 2 clinical trials due to severe cardio-toxicity associated with treatment. This study involves the development and testing of novel allocolchicine analogues that hold non-toxic anti-cancer properties. Currently we have synthesized and evaluated the anti-cancer activities of two analogues; N-acetyl-O-methylcolchinol (NSC 51046 or NCME), which is structurally similar to ZD 6126, and (S)-3,8,9,10-tetramethoxyallocolchicine (Green 1), which is a novel derivative of allocolchicine that is isomeric in the A ring. NSC 51046 was found to be non-selective as it induced apoptosis in both BxPC-3 and PANC-1 pancreatic cancer cells and in normal human fibroblasts. Interestingly, we found that Green 1 was able to modestly induce pro-death autophagy in these pancreatic cancer cells and E6-1 leukemia cells but not in normal human fibroblasts. Unlike colchicine and NSC 51046, Green 1 does not appear to affect tubulin polymerization indicating that it has a different molecular target. Green 1 also caused increased reactive oxygen species (ROS) production in mitochondria isolated from pancreatic cancer cells. Furthermore, in vivo studies revealed that Green 1 was well tolerated in mice. Our findings suggest that a small change in the structure of colchicine has apparently changed the mechanism of action and lead to improved selectivity. This may lead to better selective treatments in cancer therapy.

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Section: Resultssupporting

confidence: 88%

Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

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Novel Analogue of Colchicine Induces Selective Pro-Death Autophagy and Necrosis in Human Cancer Cells

et al. 2014

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“…[7] The discovery and development of molecules that affect tubulin polymerization, which is the origin of microtubules, is of immense importance. [8][9][10] Molecules like colchicine (1) and combretastatin A-4 (CA-4; 2) (Figure 1) bind to tubulin thereby inhibiting its polymerization into microtubules. Due to its structural simplicity, ease of synthesis, and potent antitumor activity, this class of molecules is widely studied to find potent anticancer agents.…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Imidazo[2,1‐b]thiazole–Chalcone Conjugates: Microtubule‐Destabilizing Agents

et al. 2014

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A series of chalcone conjugates featuring the imidazo[2,1-b]thiazole scaffold was designed, synthesized, and evaluated for their cytotoxic activity against five human cancer cell lines (MCF-7, A549, HeLa, DU-145 and HT-29). These new hybrid molecules have shown promising cytotoxic activity with IC50 values ranging from 0.64 to 30.9 μM. Among them, (E)-3-(6-(4-fluorophenyl)-2,3-bis(4-methoxyphenyl)imidazo[2,1-b]thiazol-5-yl)-1-(pyridin-2-yl)prop-2-en-1-one (11 x) showed potent antiproliferative activity with IC50 values ranging from 0.64 to 1.44 μM in all tested cell lines. To investigate the mechanism of action, the detailed biological aspects of this promising conjugate (11 x) were carried out on the A549 lung cancer cell line. The tubulin polymerization assay and immunofluoresence analysis results suggest that this conjugate effectively inhibits microtubule assembly in A549 cells. Flow cytometric analysis revealed that this conjugate induces cell-cycle arrest in the G2/M phase and leads to apoptotic cell death. This was further confirmed by Hoechst staining, activation of caspase-3, DNA fragmentation analysis, and Annexin V-FITC assay. Moreover, molecular docking studies indicated that this conjugate (11 x) interacts and binds efficiently with the tubulin protein.

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“…(2) 19 and its analogues [9][10][11][20][21][22][23][24][25][26][27] were identified as promising candidates for further development. Recently, our group reported on the synthesis and biological evaluation of a series of heterocyclic allocolchicine congeners (for instance 3 and 4; Figure 1), in which ring C of the parent compound 2 is replaced by an indole 28,29 or a benzofurane 30 pharmacophore.…”

Section: An Alkaloid Isolated From Plants Of the Genusmentioning

confidence: 99%

Synthesis of indole-derived allocolchicine congeners exhibiting pronounced anti-proliferative and apoptosis-inducing properties

et al. 2015

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Basing on the natural antimitotic agent allocolchicine as a lead structure, a series of novel indole-based allocolchicine congeners was synthesized and assessed in vitro for cytostatic properties. Several compounds exhibited potent antiproliferative and apoptosis-inducing activity towards lymphoma cells along with low unspecific cytotoxicity. The observed activity is supposed to result from the inhibition of microtubule assembly, as indicated by the tubulin polymerisation assay.

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Synthesis and tubulin-binding properties of new allocolchicinoids

Cited by 25 publications

References 51 publications

Novel Analogue of Colchicine Induces Selective Pro-Death Autophagy and Necrosis in Human Cancer Cells

Novel Analogue of Colchicine Induces Selective Pro-Death Autophagy and Necrosis in Human Cancer Cells

Design and Synthesis of Imidazo[2,1‐b]thiazole–Chalcone Conjugates: Microtubule‐Destabilizing Agents

Synthesis of indole-derived allocolchicine congeners exhibiting pronounced anti-proliferative and apoptosis-inducing properties

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