Abstract
The high mortality rate and lack of effective therapies make lung cancer an ideal target for novel therapeutic agents. The present study was designed to implement a novel chemical synthesis pathway and to determine the biological activities of synthetic makaluvamine analogs in human lung cancer. Seventeen compounds were synthesized and purified, and their chemical structures were elucidated on the basis of physicochemical constants and NMR spectra. Their in vitro activity was determined in human lung cancer cell lines. Based on initial screens, compound Ic was found to be the most potent, and was therefore used as a model for further studies in lung cancer cells. Ic induced both apoptosis and S-phase cell cycle arrest. Furthermore, it activated p53 and induced cleavage of PARP and caspases 8 and 9. Our preclinical data indicate that the makaluvamine analogs are potential therapeutic agents against lung cancer, providing a basis for further development of Ic (and perhaps other analogs) as a novel anti-cancer agent.
Keywords: Makaluvamine, marine alkaloid, lung cancer, apoptosis
Medicinal Chemistry
Title: Synthesis and In Vitro Anti-Lung Cancer Activity of Novel 1, 3, 4, 8- Tetrahydropyrrolo [4, 3, 2-de]quinolin-8(1H)-o ne Alkaloid Analogs
Volume: 5 Issue: 3
Author(s): Dwayaja H. Nadkarni, Feng Wang, Wei Wang, Elizabeth R. Rayburn, Scharri J. Ezell, Srinivasan Murugesan, Sadanandan E. Velu and Ruiwen Zhang
Affiliation:
Keywords: Makaluvamine, marine alkaloid, lung cancer, apoptosis
Abstract: The high mortality rate and lack of effective therapies make lung cancer an ideal target for novel therapeutic agents. The present study was designed to implement a novel chemical synthesis pathway and to determine the biological activities of synthetic makaluvamine analogs in human lung cancer. Seventeen compounds were synthesized and purified, and their chemical structures were elucidated on the basis of physicochemical constants and NMR spectra. Their in vitro activity was determined in human lung cancer cell lines. Based on initial screens, compound Ic was found to be the most potent, and was therefore used as a model for further studies in lung cancer cells. Ic induced both apoptosis and S-phase cell cycle arrest. Furthermore, it activated p53 and induced cleavage of PARP and caspases 8 and 9. Our preclinical data indicate that the makaluvamine analogs are potential therapeutic agents against lung cancer, providing a basis for further development of Ic (and perhaps other analogs) as a novel anti-cancer agent.
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Nadkarni H. Dwayaja, Wang Feng, Wang Wei, Rayburn R. Elizabeth, Ezell J. Scharri, Murugesan Srinivasan, Velu E. Sadanandan and Zhang Ruiwen, Synthesis and In Vitro Anti-Lung Cancer Activity of Novel 1, 3, 4, 8- Tetrahydropyrrolo [4, 3, 2-de]quinolin-8(1H)-o ne Alkaloid Analogs, Medicinal Chemistry 2009; 5 (3) . https://dx.doi.org/10.2174/157340609788185873
DOI https://dx.doi.org/10.2174/157340609788185873 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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