6h9b

1,1-Diheterocyclic Ethylenes Derived from Quinaldine and Carbazole as New Tubulin Polymerization Inhibitors: Synthesis, Metabolism, and Biological Evaluation1,1-Diheterocyclic Ethylenes Derived from Quinaldine and Carbazole as New Tubulin Polymerization Inhibitors: Synthesis, Metabolism, and Biological Evaluation

Structural highlights

6h9b is a 5 chain structure with sequence from Buffalo rat, Ovis ammon aries, Ovis aries and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , ,
Gene:	Stmn4 (Buffalo rat)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[STMN4_RAT] Exhibits microtubule-destabilizing activity.^[1] ^[2] ^[3]

Publication Abstract from PubMed

We report the synthesis, metabolism and biological evaluation of a series of 17 novel heterocyclic derivatives of isoCombretastatin-A4 and their structure-activity relationship. Among these derivatives, the most active compound 4f inhibited the growth of a panel of seven cancer cell lines with an IC50 in the low nanomolar range. In addition, 4f showed interesting activity against CA-4-resistant colon carcinoma cells and multidrug-resistant leukemia cells. It also induced G2/M cell cycle arrest. Structural data indicated binding of 4f to the colchicine site of tubulin, likely preventing the curved-to-straight tubulin structural changes that occur during microtubule assembly. Also, 4f disrupted the blood vessel-like assembly formed by human umbilical vein endothelial cells in vitro, suggesting its function as vascular disrupting agent. In vitro metabolism study of 4f showed its high human microsomal stability in comparison to isoCA-4. The physicochemical properties of 4f may be conducive to CNS permeability suggesting that this compound may be a possible candidate for the treatment of glioblastoma.

1,1-Diheterocyclic Ethylenes Derived from Quinaldine and Carbazole as New Tubulin Polymerization Inhibitors: Synthesis, Metabolism, and Biological Evaluation.,Naret T, Khelifi I, Provot O, Bignon J, Levaique H, Dubois J, Souce M, Kasselouri A, Deroussent A, Paci A, Varela PF, Gigant B, Alami M, Hamze A J Med Chem. 2018 Dec 10. doi: 10.1021/acs.jmedchem.8b01386. PMID:30525602^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Nakao C, Itoh TJ, Hotani H, Mori N. Modulation of the stathmin-like microtubule destabilizing activity of RB3, a neuron-specific member of the SCG10 family, by its N-terminal domain. J Biol Chem. 2004 May 28;279(22):23014-21. Epub 2004 Mar 22. PMID:15039434 doi:http://dx.doi.org/10.1074/jbc.M313693200
↑ Gavet O, El Messari S, Ozon S, Sobel A. Regulation and subcellular localization of the microtubule-destabilizing stathmin family phosphoproteins in cortical neurons. J Neurosci Res. 2002 Jun 1;68(5):535-50. PMID:12111843 doi:http://dx.doi.org/10.1002/jnr.10234
↑ Ravelli RB, Gigant B, Curmi PA, Jourdain I, Lachkar S, Sobel A, Knossow M. Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature. 2004 Mar 11;428(6979):198-202. PMID:15014504 doi:http://dx.doi.org/10.1038/nature02393
↑ Naret T, Khelifi I, Provot O, Bignon J, Levaique H, Dubois J, Souce M, Kasselouri A, Deroussent A, Paci A, Varela PF, Gigant B, Alami M, Hamze A. 1,1-Diheterocyclic Ethylenes Derived from Quinaldine and Carbazole as New Tubulin Polymerization Inhibitors: Synthesis, Metabolism, and Biological Evaluation. J Med Chem. 2018 Dec 10. doi: 10.1021/acs.jmedchem.8b01386. PMID:30525602 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b01386

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Nakao C, Itoh TJ, Hotani H, Mori N. Modulation of the stathmin-like microtubule destabilizing activity of RB3, a neuron-specific member of the SCG10 family, by its N-terminal domain. J Biol Chem. 2004 May 28;279(22):23014-21. Epub 2004 Mar 22. PMID:15039434 doi:http://dx.doi.org/10.1074/jbc.M313693200

[2] Gavet O, El Messari S, Ozon S, Sobel A. Regulation and subcellular localization of the microtubule-destabilizing stathmin family phosphoproteins in cortical neurons. J Neurosci Res. 2002 Jun 1;68(5):535-50. PMID:12111843 doi:http://dx.doi.org/10.1002/jnr.10234

[3] Ravelli RB, Gigant B, Curmi PA, Jourdain I, Lachkar S, Sobel A, Knossow M. Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature. 2004 Mar 11;428(6979):198-202. PMID:15014504 doi:http://dx.doi.org/10.1038/nature02393

[4] Naret T, Khelifi I, Provot O, Bignon J, Levaique H, Dubois J, Souce M, Kasselouri A, Deroussent A, Paci A, Varela PF, Gigant B, Alami M, Hamze A. 1,1-Diheterocyclic Ethylenes Derived from Quinaldine and Carbazole as New Tubulin Polymerization Inhibitors: Synthesis, Metabolism, and Biological Evaluation. J Med Chem. 2018 Dec 10. doi: 10.1021/acs.jmedchem.8b01386. PMID:30525602 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b01386

[1]

[2]

[3]

[4]