Preliminary data based on cell line studies suggest that the compounds might be effective against breast and colon cancer,” say Srijita Paul Chowdhuri (left) and Biswajit Kundu.
Twenty-five quinoline derivatives synthesised by IICB researchers and tested in the lab by IACS team show potent anticancer activity. The mode of action is the same for current drugs and the compounds tested. The difference is that topoisomerase 1-DNA complexes remain trapped for a longer time when the compounds are used and so have greater ability to kill cancer cells.
Researchers at Kolkata’s the Indian Institute of Chemical Biology (CSIR-IICB) and the Indian Association for the Cultivation of Science (IACS) have designed and synthesised about 25 quinoline derivatives that show potent anticancer activity. The compounds were tested in vitro against human Topoisomerase 1 (topo1) activity and their efficacy to kill cancer cells was carried out using breast, ovarian, cervical and colon cancer cell lines. The results of topo1 inhibition activity, cellular mechanisms and the cancer cell line studies carried out at IACS and the compounds designed and synthesised by IICB researchers were published in the Journal of Medicinal Chemistry.
“Preliminary data based on cell line studies suggest that the compounds from IICB might be effective against breast and colon cancer,” says Srijita Paul Chowdhuri from the School of Biological Sciences at IACS and one of the first authors of the paper.
“We designed the compounds through computational analysis followed by synthesis and X-ray crystallography before biological validation began,” says Biswajit Kundu from the Medicinal Chemistry Laboratory at IICB and one the first authors of the paper.
Topoisomerase 1 is a fundamental enzyme that is essential for replication. DNA is in a supercoiled state and has to be unwound before replication can take place. For the DNA to uncoil, the topo1 enzyme has to first bind to the DNA and form a complex. Once the complex is formed, the topo1 enzyme cleaves one strand of the DNA thus allowing the DNA to uncoil. Once uncoiling is completed, the topo1 enzyme rejoins the cleaved DNA strand for replication to take place.
How the compounds work
Existing drugs and the quinoline derivatives synthesised by the IICB team have the ability to trap the complex thereby not freeing the topo1 to rejoin the cleaved DNA strand. As the number of trapped complexes in the DNA increases, the amount of free topo1 enzyme available to repair the cleaved DNA strand reduces. Also, other enzymes involved in replication and transcription (where DNA is converted into RNA) come and collide with the trapped topo1 and this causes more DNA breaks. As a result, replication gets affected leading to DNA break and cancer cell death.
The mode of action of the existing drugs and the synthesised compounds is the same. The difference lies in the time the complexes remain trapped when the drugs or the synthesised compounds are used and therefore the ability to kill cancer cells.
Compared with normal cells, topo1 enzyme is produced in far excess amount in cancer cells and so more complexes are formed. As a result, though topo1 enzyme is found even in normal cells, there is greater likelihood of the drugs specifically targeting the cancer cells.
How the compounds differ from the drugs
“The existing drugs bind to the complex and trap it only transiently. This is because the drugs can be easily removed by body fluids. So within about 20 minutes, all the DNA breaks are repaired,” says Dr. Benu Brata Das from the School of Biological Sciences and DBT-Wellcome India Alliance fellow at IACS and one of the corresponding authors of the paper. “So the existing drugs have less ability to kill cancer cells.”
“The existing drugs are not metabolically stable and so become inactive very fast. So using the existing drugs, the complexes can be trapped only for a brief period,” says Dr. Arindam Talukdar from IICB and the other corresponding author. “But our compound can trap the complex for as long as five hours. All the 25 quinoline derivatives we synthesised show similar efficacy towards human topo1 inhibition.”
The ability of the synthesised derivatives to trap the complex for a much longer time might translate into better efficacy in killing cancer cells.
“The speciality of our compound is that they do not react with or bind to topo1 or the DNA when they are in isolation. They bind only when topo1 and the DNA form a complex. Thus, our designed compounds can be seen as targeted therapies,” says Dr. Talukdar.
IICB jointly with IACS has already filed a patent in India for all the 25 quinoline derivatives.
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