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Synthesis and evaluation of alpha-hydroxymethylated conjugated nitroalkenes for their anticancer activity: inhibition of cell proliferation by targeting microtubules

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Title Synthesis and evaluation of alpha-hydroxymethylated conjugated nitroalkenes for their anticancer activity: inhibition of cell proliferation by targeting microtubules
 
Creator MOHAN, RENU
RASTOGI, NAMRATA
NAMBOOTHIRI, IRISHI NN
SHAIKH, MOBIN M
PANDA, DULAL
 
Subject conjugated nitroalkenes
microtubules
hela cell proliferation
depolymerization
 
Description The Morita–Baylis–Hillman (MBH) type eaction of a variety of aromatic and heteroaromatic conjugated nitroalkenes with formaldehyde in the presence of stoichiometric amounts of imidazole and catalytic amounts (10 mol %) of anthranilic acid at room temperature provided the corresponding hydroxymethylated derivatives in moderate to good yield. The parent nitroalkenes and their MBH adducts were subsequently screened for their anticancer activity. Some of the MBH adducts were found to inhibit cervical cancer (HeLa) cell proliferation at low micromolar concentrations with half-maximal inhibitory concentrations in the range of 1–2 lM. The antiproliferative activity of 3-((E)-2-nitrovinyl)furan and three potent MBH adducts, namely, hydroxymethylated derivatives of 3-((E)-2-nitrovinyl)thiophene, 1-methoxy-4-((E)-2-nitrovinyl)benzene, and 1,2-dimethoxy-4-((E)-2-nitrovinyl)benzene was correlated well with their antimicrotubule activity. At their effective concentration range, the tested compounds perturbed the organization of mitotic spindle microtubules and chromosomes. In the presence of hydroxymethylated nitroalkenes, abnormal bipolar or multipolar mitotic spindles were apparent. Interphase microtubules were found to be significantly depolymerized at relatively higher concentrations of the tested compounds. These compounds inhibited tubulin assembly into microtubules in vitro by binding to tubulin at a site distinct from the vinblastine and colchicine binding sites. The compounds reduced the intrinsic tryptophan fluorescence of tubulin and the fluorescence of tubulin-1-anilinonaphthalene-8-sulfonic acid (ANS) complex indicating that they induced conformational changes in the tubulin. The results suggest that hydroxymethylated nitroalkenes exert their antiproliferative activity at least in part by depolymerizing cellular microtubules through tubulin binding and indicate that hydroxymethylated nitroalkenes are promising lead compounds for cancer therapy.
Copyright to Elsevier Publisher
 
Publisher Elsevier
 
Date 2007-12-20T09:48:40Z
2011-11-25T12:20:13Z
2011-12-26T13:05:09Z
2011-12-27T05:51:15Z
2007-12-20T09:48:40Z
2011-11-25T12:20:13Z
2011-12-26T13:05:09Z
2011-12-27T05:51:15Z
2006
 
Type Article
 
Identifier Bioorganic Medical and Chemistry 14 (23) 8073–85
09680896
http://dx.doi.org/10.1016/j.bmc.2006.07.035
http://hdl.handle.net/10054/62
http://dspace.library.iitb.ac.in/xmlui/handle/10054/62
 
Language en