Synthesis and in vitro anti-lung cancer activity of novel 1, 3, 4, 8-tetrahydropyrrolo [4, 3, 2-de]quinolin-8(1H)-one alkaloid analogs.
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.
1Department of Chemistry, Division of Clinical Pharmacology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Dwayaja H
DH
Nadkarni
Feng
F
Wang
Wei
W
Wang
Elizabeth R
ER
Rayburn
Scharri J
SJ
Ezell
Srinivasan
S
Murugesan
Sadanandan E
SE
Velu
Ruiwen
R
Zhang
D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015363:Quinolones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
D000470:Alkaloids; D000970:Antineoplastic Agents; D015363:Quinolones