The Experts below are selected from a list of 726 Experts worldwide ranked by ideXlab platform
Timothy J. Mitchison - One of the best experts on this subject based on the ideXlab platform.
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small molecule and mutational analysis of allosteric eg5 inhibition by Monastrol
BMC Chemical Biology, 2006Co-Authors: Zoltan Maliga, Timothy J. MitchisonAbstract:A recent crystal structure of Monastrol in a ternary complex with the kinesin Eg5 motor domain highlights a novel, induced-fit drug binding site at atomic resolution. Mutational obliteration of the Monastrol binding site results in a Monastrol-resistant, but otherwise catalytically active Eg5 motor domain. However, considering the conformational changes at this site, it is unclear what specific interactions stabilize the interaction between Monastrol and the Eg5 motor domain. To study the molecular complementarity of the Monastrol-Eg5 interaction, we used a combination of synthetic chemistry and targeted mutations in Eg5 to measure the contribution of specific contacts to inhibition of Eg5 in vitro and in cultured cells. Structure-activity data on chemical derivatives, sequence analysis of Eg5 homologs from different species, and the effect of mutations near the drug binding site were consistent with the crystal structure. The mechanism of Monastrol revealed by our data rationalizes its specificity for Eg5 over other kinesins and highlights a potential mechanism of drug resistance for anti-cancer therapy targeting this site in Eg5.
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evidence that Monastrol is an allosteric inhibitor of the mitotic kinesin eg5
Chemistry & Biology, 2002Co-Authors: Zoltan Maliga, Tarun M. Kapoor, Timothy J. MitchisonAbstract:Monastrol, a cell-permeable inhibitor of the kinesin Eg5, has been used to probe the dynamic organization of the mitotic spindle. The mechanism by which Monastrol inhibits Eg5 function is unknown. We found that Monastrol inhibits both the basal and the microtubule-stimulated ATPase activity of the Eg5 motor domain. Unlike many ATPase inhibitors, Monastrol does not compete with ATP binding to Eg5. Monastrol appears to inhibit microtubule-stimulated ADP release from Eg5 but does not compete with microtubule binding, suggesting that Monastrol binds a novel allosteric site in the motor domain. Finally, we established that (S)-Monastrol, as compared to the (R)-enantiomer, is a more potent inhibitor of Eg5 activity in vitro and in vivo. Future structural studies should help in designing more potent Eg5 inhibitors for possible use as anticancer drugs and cell biological reagents.
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probing spindle assembly mechanisms with Monastrol a small molecule inhibitor of the mitotic kinesin eg5
Journal of Cell Biology, 2000Co-Authors: Tarun M. Kapoor, Thomas U. Mayer, Margaret Coughlin, Timothy J. MitchisonAbstract:Monastrol, a cell-permeable small molecule inhibitor of the mitotic kinesin, Eg5, arrests cells in mitosis with monoastral spindles. Here, we use Monastrol to probe mitotic mechanisms. We find that Monastrol does not inhibit progression through S and G2 phases of the cell cycle or centrosome duplication. The mitotic arrest due to Monastrol is also rapidly reversible. Chromosomes in Monastrol-treated cells frequently have both sister kinetochores attached to microtubules extending to the center of the monoaster (syntelic orientation). Mitotic arrest–deficient protein 2 (Mad2) localizes to a subset of kinetochores, suggesting the activation of the spindle assembly checkpoint in these cells. Mad2 localizes to some kinetochores that have attached microtubules in Monastrol-treated cells, indicating that kinetochore microtubule attachment alone may not satisfy the spindle assembly checkpoint. Monastrol also inhibits bipolar spindle formation in Xenopus egg extracts. However, it does not prevent the targeting of Eg5 to the monoastral spindles that form. Imaging bipolar spindles disassembling in the presence of Monastrol allowed direct observations of outward directed forces in the spindle, orthogonal to the pole-to-pole axis. Monastrol is thus a useful tool to study mitotic processes, detection and correction of chromosome malorientation, and contributions of Eg5 to spindle assembly and maintenance.
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Probing Spindle Assembly Mechanisms with Monastrol 987
1998Co-Authors: Tarun M. Kapoor, Margaret L. Coughlin, Thomas U. Mayer, Timothy J. MitchisonAbstract:Abstract. Monastrol, a cell-permeable small molecule inhibitor of the mitotic kinesin, Eg5, arrests cells in mitosis with monoastral spindles. Here, we use Monastrol to probe mitotic mechanisms. We find that Monastrol does not inhibit progression through S and G2 phases of the cell cycle or centrosome duplication. The mitotic arrest due to Monastrol is also rapidly reversible. Chromosomes in Monastrol-treated cells frequently have both sister kinetochores attached to microtubules extending to the center of the monoaster (syntelic orientation). Mitotic arrest–deficient protein 2 (Mad2) localizes to a subset of kinetochores, suggesting the activation of the spindle assembly checkpoint in these cells. Mad2 localizes to some kinetochores that have attached microtubules in Monastrol-treated cells, indicating that kinetochore microtubule attachment alone may not satisfy the spindle assembly checkpoint. Monastrol also inhibits bipolar spindle formation in Xenopus egg extracts. However, it does not prevent the targeting of Eg5 to the monoastral spindles that form. Imaging bipolar spindles disassembling in the presence of Monastrol allowed direct observations of outward directed forces in the spindle, orthogonal to the poleto-pole axis. Monastrol is thus a useful tool to study mitotic processes, detection and correction of chromosome malorientation, and contributions of Eg5 to spindle assembly and maintenance. Key words: kinetochor
Ahmed Kamal - One of the best experts on this subject based on the ideXlab platform.
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multicomponent access to novel proline cyclized cysteine tethered Monastrol conjugates as potential anticancer agents
Journal of Saudi Chemical Society, 2019Co-Authors: Shaheer M. Malik, Zaki S. Seddigi, Shaik Bajee, Shaik Azeeza, Syed Riyaz, Saleh A. Ahmed, Ismail I. Althagafi, Qazi Mohammad Sajid Jamal, Ahmed KamalAbstract:Abstract The versatility of multicomponent Biginelli’s reaction is exploited in the development of proline and cyclized cysteine tethered conjugates of Monastrol, a kinesin Eg5 inhibitor. Ten new conjugates are synthesized focusing on structural replacement of the ester moiety (C-5 position) of the Monastrol backbone with amino acid based amide moieties. On cytotoxic evaluation, conjugate 24 has shown promising in vitro cytotoxic activity against leukemia. Molecular docking studies revealed that the conjugates 19 and 24 exhibit better interaction at kinesin Eg5 receptor compared to Monastrol. Moreover, computational calculations and predictions of important molecular properties suggest that these new amino acid based conjugates could be further improved to provide potential anticancer agents.
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Multicomponent access to novel proline/cyclized cysteine tethered Monastrol conjugates as potential anticancer agents
Elsevier, 2019Co-Authors: Shaheer M. Malik, Zaki S. Seddigi, Shaik Bajee, Shaik Azeeza, Syed Riyaz, Saleh A. Ahmed, Ismail I. Althagafi, Qazi Sajid M. Jamal, Ahmed KamalAbstract:The versatility of multicomponent Biginelli’s reaction is exploited in the development of proline and cyclized cysteine tethered conjugates of Monastrol, a kinesin Eg5 inhibitor. Ten new conjugates are synthesized focusing on structural replacement of the ester moiety (C-5 position) of the Monastrol backbone with amino acid based amide moieties. On cytotoxic evaluation, conjugate 24 has shown promising in vitro cytotoxic activity against leukemia. Molecular docking studies revealed that the conjugates 19 and 24 exhibit better interaction at kinesin Eg5 receptor compared to Monastrol. Moreover, computational calculations and predictions of important molecular properties suggest that these new amino acid based conjugates could be further improved to provide potential anticancer agents. Keywords: Monastrol, Amino acids, Multicomponent Biginelli’s reaction, Anticancer agents, Docking studie
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synthesis and biological evaluation of conformationally flexible as well as restricted dimers of Monastrol and related dihydropyrimidones
ChemInform, 2011Co-Authors: Ahmed Kamal, Shaheer M. Malik, Shaik Bajee, Shaik Azeeza, Shaikh Faazil, Sistla Ramakrishna, V G M Naidu, M V P S VishnuwardhanAbstract:The one-pot Biginelli multi-component cyclocondensation reaction affords dimers of Monastrol and related dihydropyrimidones with flexible alkyl chain spacers of varying length and conformationally restricted spacers with unsaturation.
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synthesis and biological evaluation of conformationally flexible as well as restricted dimers of Monastrol and related dihydropyrimidones
European Journal of Medicinal Chemistry, 2011Co-Authors: Ahmed Kamal, Shaheer M. Malik, Shaik Bajee, Shaik Azeeza, Shaikh Faazil, Sistla Ramakrishna, V G M Naidu, M V P S VishnuwardhanAbstract: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.
Mario Sergio Mantovani - One of the best experts on this subject based on the ideXlab platform.
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comparison of the effects of Monastrol and oxoMonastrol on human hepatoma cell line hepg2 c3a
Anticancer Research, 2017Co-Authors: Lilian Areal Marques, Ângelo De Fátima, Simone Cristine Semprebon, Daniele Sartori, Lucia Regina Ribeiro, Mario Sergio MantovaniAbstract:Monastrol and its analog oxoMonastrol differ by replacement of the sulfur atom present in Monastrol to an oxygen atom in oxoMonastrol. Monastrol inhibits the mitotic kinesin family member 11 (EG5), which has been studied for its potential use in cancer therapy. The aim of this study was to investigate the effect of Monastrol and oxoMonastrol on HepG2/C3A cells. Our results showed that Monastrol induced DNA damage, reduced cell proliferation, and up-regulated the cytochrome P450 family 1 subfamily A member 1 (CYP1A1) mRNA levels. However, oxoMonastrol was cytotoxic only at the highest concentrations used, without reducing cell proliferation and viability. Moreover, no genotoxic damage or alteration of levels of mRNA were found. Our results suggest that Monastrol has greater antiproliferative activity compared to oxoMonastrol, and this effect is probably related to the DNA damage induced by Monastrol and its possible bioactivation demonstrated by the increase in CYP1A1 mRNA expression. Moreover, these effects appear to be related to the presence of the sulfur atom in its structure.
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Antiproliferative activity of Monastrol in human adenocarcinoma (MCF-7) and non-tumor (HB4a) breast cells
Naunyn-Schmiedeberg's Archives of Pharmacology, 2016Co-Authors: Lilian Areal Marques, Ângelo De Fátima, Simone Cristine Semprebon, Daniele Sartori, Lucia Regina Ribeiro, Andressa Megumi Niwa, Gláucia Fernanda Rocha D’epiro, Mario Sergio MantovaniAbstract:Monastrol is an allosteric inhibitor of the mitotic kinesin Eg5 that exhibits an antiproliferative effect against several cell lines. We investigated the antiproliferative effect of Monastrol on human breast adenocarcinoma cells (MCF-7) and mammary epithelial cells (HB4a, non-tumoral). Monastrol treatment decreased cell viability only in MCF-7 tumor cells. Real-time cell growth kinetic analysis showed a decrease in the proliferation of MCF-7 cells exposed to Monastrol, while in the HB4a cells, only a concentration of 100 μM was able to induce this effect. In a cell cycle analysis, exposure of MCF-7 cells to Monastrol led to an increased population of cells in both the G1 and G2/M phases. In HB4a cells, the proportion of cells in the G2/M phase was increased. Monastrol led to an increased mitotic index in both cell lines. Monastrol was not able to induce cell death by apoptosis in any of the cell lines studied. Gene expression analysis was performed to measure the mRNA levels of cell cycle genes, DNA damage indicator gene, and apoptotic related genes. Treatment with Monastrol induced in MCF-7 cells a 5-fold increase in the mRNA levels of the CDKN1A gene, an inhibitor of CDKs related with cell cycle arrest in response a stress stimulus, and a 2-fold decrease in CDKN1C mRNA levels in HB4a cells. These results provide evidence that Monastrol has a greater antiproliferative effect on MCF-7 tumor cells compared with non-tumor HB4a cells; however, no selective is observed.
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bio087 evaluation of cytotoxicity and apoptosis induction of oxo Monastrol in human hepatoma cell line c3a
Revista Eletrônica de Farmácia, 2012Co-Authors: Lilian Areal Marques, Ângelo De Fátima, Simone Cristine Semprebon, Glaucia Fernanda Rocha D Epiro, Leonardo Campo Zanellato, Mario Sergio MantovaniAbstract:Chemotherapeutic agents used for cancer treatment have as one of their principal aims mitosis arrest. Despite the great advances obtained in cancer treatment with these agents is necessary to obtain new substances having different targets of not microtubules in order to reduce side effects and thus optimize chemotherapy and quality of life those in need. With the understanding of cell cycle and its chemical mediators began the search for new targets for anti-mitotic not involving the microtubules, thereby preventing some side effects such as neurotoxicity. Kinesins stood out in this quest. Among the motor kinesins related to mitosis, the protein EG5 has been studied for their potential for cancer therapy because of its importance for cell division. This protein is overexpressed in tumor cells compared to non-tumor cells. Due to the specificity of Monastrol to act on targets that are specific to tumor cells, were developed some analogues of this compound in order to enhance its effect and understand its mechanism of action. One of these analogues is the Oxo-Monastrol, a precursor of Monastrol which the sulfur atom was replaced by an oxygen atom. It is believed that this analog, as well as Monastrol, inhibits EG5 motor activity by allosteric inhibition which prevents ATP, no movement of centrossomos toward the poles, the spindle pole is not formed, and then, the cell is arrested in G2-M phase of cell cycle and is programmed cell death (apoptosis).
Tarun M. Kapoor - One of the best experts on this subject based on the ideXlab platform.
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JCB Article Minus-end capture of preformed kinetochore fibers contributes to spindle morphogenesis
2013Co-Authors: Alexey Khodjakov, Lily Copenagle, Michael B. Gordon, Duane A. Compton, Tarun M. KapoorAbstract:Near-simultaneous three-dimensional fluorescence/ differential interference contrast microscopy was used to follow the behavior of microtubules and chromosomes in living �-tubulin/GFP-expressing cells after inhibition of the mitotic kinesin Eg5 with Monastrol. Kinetochore fibers (K-fibers) were frequently observed forming in association with chromosomes both during Monastrol treatment and after Monastrol removal. Surprisingly, these K-fibers were oriented away from, and not directly connected to, centrosomes and incorporated into the spindle by th
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Monastrol inhibition of the mitotic kinesin eg5
Journal of Biological Chemistry, 2005Co-Authors: Jared C Cochran, Tarun M. Kapoor, Joseph E Gatial, Susan P GilbertAbstract:Monastrol is a small, cell-permeable molecule that arrests cells in mitosis by specifically inhibiting Eg5, a member of the Kinesin-5 family. We have used steady-state and presteady-state kinetics as well as equilibrium binding approaches to define the mechanistic basis of S-Monastrol inhibition of monomeric human Eg5/KSP. In the absence of microtubules (Mts), the basal ATPase activity is inhibited through slowed product release. In the presence of microtubules, the ATPase activity is also reduced with weakened binding of Eg5 to microtubules during steady-state ATP turnover. Monastrol-treated Eg5 also shows a decreased relative affinity for microtubules under equilibrium conditions. The Mt·Eg5 presteady-state kinetics of ATP binding and the subsequent ATP-dependent isomerization are unaffected during the first ATP turnover. However, Monastrol appears to stabilize a conformation that allows for reversals at the ATP hydrolysis step. Monastrol promotes a dramatic decrease in the observed rate of Eg5 association with microtubules, and ADP release is slowed without trapping the Mt·Eg5·ADP intermediate. We propose that S-Monastrol binding to Eg5 induces a stable conformational change in the motor domain that favors ATP re-synthesis after ATP hydrolysis. The aberrant interactions with the microtubule and the reversals at the ATP hydrolysis step alter the ability of Eg5 to generate force, thereby yielding a nonproductive Mt·Eg5 complex that cannot establish or maintain the bipolar spindle.
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evidence that Monastrol is an allosteric inhibitor of the mitotic kinesin eg5
Chemistry & Biology, 2002Co-Authors: Zoltan Maliga, Tarun M. Kapoor, Timothy J. MitchisonAbstract:Monastrol, a cell-permeable inhibitor of the kinesin Eg5, has been used to probe the dynamic organization of the mitotic spindle. The mechanism by which Monastrol inhibits Eg5 function is unknown. We found that Monastrol inhibits both the basal and the microtubule-stimulated ATPase activity of the Eg5 motor domain. Unlike many ATPase inhibitors, Monastrol does not compete with ATP binding to Eg5. Monastrol appears to inhibit microtubule-stimulated ADP release from Eg5 but does not compete with microtubule binding, suggesting that Monastrol binds a novel allosteric site in the motor domain. Finally, we established that (S)-Monastrol, as compared to the (R)-enantiomer, is a more potent inhibitor of Eg5 activity in vitro and in vivo. Future structural studies should help in designing more potent Eg5 inhibitors for possible use as anticancer drugs and cell biological reagents.
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probing spindle assembly mechanisms with Monastrol a small molecule inhibitor of the mitotic kinesin eg5
Journal of Cell Biology, 2000Co-Authors: Tarun M. Kapoor, Thomas U. Mayer, Margaret Coughlin, Timothy J. MitchisonAbstract:Monastrol, a cell-permeable small molecule inhibitor of the mitotic kinesin, Eg5, arrests cells in mitosis with monoastral spindles. Here, we use Monastrol to probe mitotic mechanisms. We find that Monastrol does not inhibit progression through S and G2 phases of the cell cycle or centrosome duplication. The mitotic arrest due to Monastrol is also rapidly reversible. Chromosomes in Monastrol-treated cells frequently have both sister kinetochores attached to microtubules extending to the center of the monoaster (syntelic orientation). Mitotic arrest–deficient protein 2 (Mad2) localizes to a subset of kinetochores, suggesting the activation of the spindle assembly checkpoint in these cells. Mad2 localizes to some kinetochores that have attached microtubules in Monastrol-treated cells, indicating that kinetochore microtubule attachment alone may not satisfy the spindle assembly checkpoint. Monastrol also inhibits bipolar spindle formation in Xenopus egg extracts. However, it does not prevent the targeting of Eg5 to the monoastral spindles that form. Imaging bipolar spindles disassembling in the presence of Monastrol allowed direct observations of outward directed forces in the spindle, orthogonal to the pole-to-pole axis. Monastrol is thus a useful tool to study mitotic processes, detection and correction of chromosome malorientation, and contributions of Eg5 to spindle assembly and maintenance.
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Probing Spindle Assembly Mechanisms with Monastrol 987
1998Co-Authors: Tarun M. Kapoor, Margaret L. Coughlin, Thomas U. Mayer, Timothy J. MitchisonAbstract:Abstract. Monastrol, a cell-permeable small molecule inhibitor of the mitotic kinesin, Eg5, arrests cells in mitosis with monoastral spindles. Here, we use Monastrol to probe mitotic mechanisms. We find that Monastrol does not inhibit progression through S and G2 phases of the cell cycle or centrosome duplication. The mitotic arrest due to Monastrol is also rapidly reversible. Chromosomes in Monastrol-treated cells frequently have both sister kinetochores attached to microtubules extending to the center of the monoaster (syntelic orientation). Mitotic arrest–deficient protein 2 (Mad2) localizes to a subset of kinetochores, suggesting the activation of the spindle assembly checkpoint in these cells. Mad2 localizes to some kinetochores that have attached microtubules in Monastrol-treated cells, indicating that kinetochore microtubule attachment alone may not satisfy the spindle assembly checkpoint. Monastrol also inhibits bipolar spindle formation in Xenopus egg extracts. However, it does not prevent the targeting of Eg5 to the monoastral spindles that form. Imaging bipolar spindles disassembling in the presence of Monastrol allowed direct observations of outward directed forces in the spindle, orthogonal to the poleto-pole axis. Monastrol is thus a useful tool to study mitotic processes, detection and correction of chromosome malorientation, and contributions of Eg5 to spindle assembly and maintenance. Key words: kinetochor
Ângelo De Fátima - One of the best experts on this subject based on the ideXlab platform.
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comparison of the effects of Monastrol and oxoMonastrol on human hepatoma cell line hepg2 c3a
Anticancer Research, 2017Co-Authors: Lilian Areal Marques, Ângelo De Fátima, Simone Cristine Semprebon, Daniele Sartori, Lucia Regina Ribeiro, Mario Sergio MantovaniAbstract:Monastrol and its analog oxoMonastrol differ by replacement of the sulfur atom present in Monastrol to an oxygen atom in oxoMonastrol. Monastrol inhibits the mitotic kinesin family member 11 (EG5), which has been studied for its potential use in cancer therapy. The aim of this study was to investigate the effect of Monastrol and oxoMonastrol on HepG2/C3A cells. Our results showed that Monastrol induced DNA damage, reduced cell proliferation, and up-regulated the cytochrome P450 family 1 subfamily A member 1 (CYP1A1) mRNA levels. However, oxoMonastrol was cytotoxic only at the highest concentrations used, without reducing cell proliferation and viability. Moreover, no genotoxic damage or alteration of levels of mRNA were found. Our results suggest that Monastrol has greater antiproliferative activity compared to oxoMonastrol, and this effect is probably related to the DNA damage induced by Monastrol and its possible bioactivation demonstrated by the increase in CYP1A1 mRNA expression. Moreover, these effects appear to be related to the presence of the sulfur atom in its structure.
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Antiproliferative activity of Monastrol in human adenocarcinoma (MCF-7) and non-tumor (HB4a) breast cells
Naunyn-Schmiedeberg's Archives of Pharmacology, 2016Co-Authors: Lilian Areal Marques, Ângelo De Fátima, Simone Cristine Semprebon, Daniele Sartori, Lucia Regina Ribeiro, Andressa Megumi Niwa, Gláucia Fernanda Rocha D’epiro, Mario Sergio MantovaniAbstract:Monastrol is an allosteric inhibitor of the mitotic kinesin Eg5 that exhibits an antiproliferative effect against several cell lines. We investigated the antiproliferative effect of Monastrol on human breast adenocarcinoma cells (MCF-7) and mammary epithelial cells (HB4a, non-tumoral). Monastrol treatment decreased cell viability only in MCF-7 tumor cells. Real-time cell growth kinetic analysis showed a decrease in the proliferation of MCF-7 cells exposed to Monastrol, while in the HB4a cells, only a concentration of 100 μM was able to induce this effect. In a cell cycle analysis, exposure of MCF-7 cells to Monastrol led to an increased population of cells in both the G1 and G2/M phases. In HB4a cells, the proportion of cells in the G2/M phase was increased. Monastrol led to an increased mitotic index in both cell lines. Monastrol was not able to induce cell death by apoptosis in any of the cell lines studied. Gene expression analysis was performed to measure the mRNA levels of cell cycle genes, DNA damage indicator gene, and apoptotic related genes. Treatment with Monastrol induced in MCF-7 cells a 5-fold increase in the mRNA levels of the CDKN1A gene, an inhibitor of CDKs related with cell cycle arrest in response a stress stimulus, and a 2-fold decrease in CDKN1C mRNA levels in HB4a cells. These results provide evidence that Monastrol has a greater antiproliferative effect on MCF-7 tumor cells compared with non-tumor HB4a cells; however, no selective is observed.
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bio087 evaluation of cytotoxicity and apoptosis induction of oxo Monastrol in human hepatoma cell line c3a
Revista Eletrônica de Farmácia, 2012Co-Authors: Lilian Areal Marques, Ângelo De Fátima, Simone Cristine Semprebon, Glaucia Fernanda Rocha D Epiro, Leonardo Campo Zanellato, Mario Sergio MantovaniAbstract:Chemotherapeutic agents used for cancer treatment have as one of their principal aims mitosis arrest. Despite the great advances obtained in cancer treatment with these agents is necessary to obtain new substances having different targets of not microtubules in order to reduce side effects and thus optimize chemotherapy and quality of life those in need. With the understanding of cell cycle and its chemical mediators began the search for new targets for anti-mitotic not involving the microtubules, thereby preventing some side effects such as neurotoxicity. Kinesins stood out in this quest. Among the motor kinesins related to mitosis, the protein EG5 has been studied for their potential for cancer therapy because of its importance for cell division. This protein is overexpressed in tumor cells compared to non-tumor cells. Due to the specificity of Monastrol to act on targets that are specific to tumor cells, were developed some analogues of this compound in order to enhance its effect and understand its mechanism of action. One of these analogues is the Oxo-Monastrol, a precursor of Monastrol which the sulfur atom was replaced by an oxygen atom. It is believed that this analog, as well as Monastrol, inhibits EG5 motor activity by allosteric inhibition which prevents ATP, no movement of centrossomos toward the poles, the spindle pole is not formed, and then, the cell is arrested in G2-M phase of cell cycle and is programmed cell death (apoptosis).
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Synthesis and differential antiproliferative activity of Biginelli compounds against cancer cell lines: Monastrol, oxo-Monastrol and oxygenated analogues.
Bioorganic chemistry, 2006Co-Authors: Dennis Russowsky, Rômulo Faria Santos Canto, Sérgio Augusto Antunes Sanches, Marcelo G. Montes D’oca, Ângelo De Fátima, Ronaldo A. Pilli, Luciana K. Kohn, Márcia Aparecida Antônio, João Ernesto De CarvalhoAbstract:Abstract The synthesis and differential antiproliferative activity of Monastrol ( 1a ), oxo-Monastrol ( 1b ) and eight oxygenated derivatives 3a , b – 6a , b on seven human cancer cell lines are described. For all evaluated cell lines, Monastrol ( 1a ) was shown to be more active than its oxo-analogue, except for HT-29 cell line, suggesting the importance of the sulfur atom for the antiproliferative activity. Monastrol ( 1a ) and the thio-derivatives 3a , 4a and 6a displayed relevant antiproliferative properties with 3,4-methylenedioxy derivative 6a being approximately more than 30 times more potent than Monastrol ( 1a ) against colon cancer (HT-29) cell line.