Synthesis and evaluation of alpha-hydroxymethylated conjugated nitroalkenes for their anticancer activity: inhibition of cell proliferation by targeting microtubules.
The Morita-Baylis-Hillman (MBH) type reaction 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 microM. 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.
Mohan
Renu
R
School of Biosciences and Bioengineering, Indian Institute of Technology, Bombay, Mumbai 400 076, India.
Rastogi
Namrata
N
Namboothiri
Irishi N N
IN
Mobin
Shaikh M
SM
Panda
Dulal
D
D000475:Alkenes / Q000138:chemical synthesis / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008745:Methylation; D008870:Microtubules / Q000187:drug effects*; D009574:Nitro Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D008941:Spindle Apparatus / Q000187:drug effects; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000473:pathology
D000475:Alkenes; D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D009574:Nitro Compounds; D014404:Tubulin