monastrol and Colonic-Neoplasms

A series of conformationally flexible and restricted dimers of monastrol as well as related dihydropyrimidones have been synthesized by employing one-pot Biginelli multicomponent reaction. These dimers have been evaluated for cytotoxic potency against selected human cancer cell lines and some of the compounds have exhibited more cytotoxic potency than the parent monastrol. Further, the DNA binding ability by thermal denaturation studies and antimicrobial activities of these compounds are also discussed.

Topics: Anti-Infective Agents; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Colonic Neoplasms; Differential Thermal Analysis; Dimerization; DNA; Drug Screening Assays, Antitumor; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Inhibitory Concentration 50; Lung Neoplasms; Microbial Sensitivity Tests; Molecular Conformation; Pyrimidines; Pyrimidinones; Skin Neoplasms; Structure-Activity Relationship; Thiones

The kinesin-related protein HsEg5 plays essential roles in mitotic spindle dynamics. Although inhibition of HsEg5 has been suggested as an aid in cancer treatment, the effects of such inhibition on human cells have not been characterized. Here we studied the effects of monastrol, an allosteric HsEg5 inhibitor, on AGS and HT29 cell lines and compared them to those of taxol. While both cell lines were similarly sensitive to taxol, AGS cells were more sensitive to monastrol. The differences in sensitivity were determined by the degree of inhibitory effect on cell proliferation, reversibility of monastrol-induced G2/M arrest, intracellular phenotypes and induction of apoptosis. In both cell lines, monastrol-induced apoptosis was accompanied by mitochondrial membrane depolarization and poly-ADP-ribose polymerase 1 cleavage. In AGS, but not HT29 cells, monastrol-induced apoptosis involved a prominent cleavage of procaspases 8 and 3. While in AGS cells, monastrol induced the formation of symmetric microtubule asters only, in HT29 cells, asymmetric asters were also formed, which may be related to specific HsEg5 functions in HT29 cells.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Colonic Neoplasms; G2 Phase; HT29 Cells; Humans; Kinesins; Microtubules; Mitosis; Paclitaxel; Pyrimidines; Stomach Neoplasms; Thiones