Synthesis and biological evaluation of 4-aza-2,3-dihydropyridophenanthrolines as tubulin polymerization inhibitors
A series of novel 4-aza-2,3-dihydropyridophenanthrolines 12(a-t) were synthesized by a one-step three component condensation of 1,10-phenanthroline amine, tetronic acid and various aromatic aldehydes. These were evaluated for their antiproliferative activity against three human cancer cell lines (MI...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2014-08, Vol.24 (15), p.3356-3360 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Kamal, Ahmed Srinivasa Reddy, T Polepalli, Sowjanya Paidakula, Suresh Srinivasulu, Vunnam Ganga Reddy, V Jain, Nishant Shankaraiah, Nagula |
| description | A series of novel 4-aza-2,3-dihydropyridophenanthrolines 12(a-t) were synthesized by a one-step three component condensation of 1,10-phenanthroline amine, tetronic acid and various aromatic aldehydes. These were evaluated for their antiproliferative activity against three human cancer cell lines (MIAPACA, MCF-7 and HeLa) using SRB assay. Majority of the tested compounds exhibited significant anticancer activity on these cell lines and interestingly compounds 12h and 12i were more potent than etoposide and podophyllotoxin against all three tested cancer cell lines with GI50 values in the range of 0.01-0.5 μM. Furthermore, these compounds showed significant inhibition of tubulin polymerization which is comparable to that of podophyllotoxin and disrupted microtubule network by accumulating tubulin in the soluble fraction. The flow cytometry analysis confirmed that the synthesized compounds led to cell cycle arrest at the G2/M phase. Moreover, the structure activity relationship studies in this series are also discussed. |
| doi_str_mv | 10.1016/j.bmcl.2014.05.096 |
| format | Article |
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These were evaluated for their antiproliferative activity against three human cancer cell lines (MIAPACA, MCF-7 and HeLa) using SRB assay. Majority of the tested compounds exhibited significant anticancer activity on these cell lines and interestingly compounds 12h and 12i were more potent than etoposide and podophyllotoxin against all three tested cancer cell lines with GI50 values in the range of 0.01-0.5 μM. Furthermore, these compounds showed significant inhibition of tubulin polymerization which is comparable to that of podophyllotoxin and disrupted microtubule network by accumulating tubulin in the soluble fraction. The flow cytometry analysis confirmed that the synthesized compounds led to cell cycle arrest at the G2/M phase. Moreover, the structure activity relationship studies in this series are also discussed.</description><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Cell Cycle Checkpoints - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Screening Assays, Antitumor</subject><subject>HeLa Cells</subject><subject>Heterocyclic Compounds, 4 or More Rings - chemical synthesis</subject><subject>Heterocyclic Compounds, 4 or More Rings - chemistry</subject><subject>Heterocyclic Compounds, 4 or More Rings - pharmacology</subject><subject>Humans</subject><subject>MCF-7 Cells</subject><subject>Molecular Structure</subject><subject>Phenanthrolines - chemical synthesis</subject><subject>Phenanthrolines - chemistry</subject><subject>Phenanthrolines - pharmacology</subject><subject>Polymerization - drug effects</subject><subject>Structure-Activity Relationship</subject><subject>Tubulin - metabolism</subject><subject>Tubulin Modulators - chemical synthesis</subject><subject>Tubulin Modulators - chemistry</subject><subject>Tubulin Modulators - pharmacology</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkctKxDAUhoMoOl5ewIV06cLWk0trshTxBoILFdyFNE2cDGlTk1aoT2-HGV27OpzD_39w-BA6xVBgwNXlqqhb7QsCmBVQFiCqHbTArGI5ZVDuosV8gZwL9n6ADlNawRwExvbRAWGipJzgBYovUzcsTXIpU12T1S748OG08pn5Un5UgwtdFmzGcvWtcnJB88YtpyaGfoquCf3SdGoGxOBdZ2ZGyoaxHucl64OfWhPd94bhuqWr3RBiOkZ7VvlkTrbzCL3d3b7ePORPz_ePN9dPuWZQDbkFaitKVWm5IVY0HCipCWdGa6EFF1Y3tZm_FYSXXFBBbEMVrQwF4DUXih6h8w23j-FzNGmQrUvaeK86E8YkcVniigiA6h9Rxq4YvmLrKNlEdQwpRWNlH12r4iQxyLUWuZJrLXKtRUIpZwlz6WzLH-vWNH-VXw_0B5Ahi_g</recordid><startdate>20140801</startdate><enddate>20140801</enddate><creator>Kamal, Ahmed</creator><creator>Srinivasa Reddy, T</creator><creator>Polepalli, Sowjanya</creator><creator>Paidakula, Suresh</creator><creator>Srinivasulu, Vunnam</creator><creator>Ganga Reddy, V</creator><creator>Jain, Nishant</creator><creator>Shankaraiah, Nagula</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20140801</creationdate><title>Synthesis and biological evaluation of 4-aza-2,3-dihydropyridophenanthrolines as tubulin polymerization inhibitors</title><author>Kamal, Ahmed ; 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These were evaluated for their antiproliferative activity against three human cancer cell lines (MIAPACA, MCF-7 and HeLa) using SRB assay. Majority of the tested compounds exhibited significant anticancer activity on these cell lines and interestingly compounds 12h and 12i were more potent than etoposide and podophyllotoxin against all three tested cancer cell lines with GI50 values in the range of 0.01-0.5 μM. Furthermore, these compounds showed significant inhibition of tubulin polymerization which is comparable to that of podophyllotoxin and disrupted microtubule network by accumulating tubulin in the soluble fraction. The flow cytometry analysis confirmed that the synthesized compounds led to cell cycle arrest at the G2/M phase. Moreover, the structure activity relationship studies in this series are also discussed.</abstract><cop>England</cop><pmid>24953821</pmid><doi>10.1016/j.bmcl.2014.05.096</doi><tpages>5</tpages></addata></record> |
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| subjects | Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Cell Cycle Checkpoints - drug effects Cell Line, Tumor Cell Proliferation - drug effects Dose-Response Relationship, Drug Drug Screening Assays, Antitumor HeLa Cells Heterocyclic Compounds, 4 or More Rings - chemical synthesis Heterocyclic Compounds, 4 or More Rings - chemistry Heterocyclic Compounds, 4 or More Rings - pharmacology Humans MCF-7 Cells Molecular Structure Phenanthrolines - chemical synthesis Phenanthrolines - chemistry Phenanthrolines - pharmacology Polymerization - drug effects Structure-Activity Relationship Tubulin - metabolism Tubulin Modulators - chemical synthesis Tubulin Modulators - chemistry Tubulin Modulators - pharmacology |
| title | Synthesis and biological evaluation of 4-aza-2,3-dihydropyridophenanthrolines as tubulin polymerization inhibitors |
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