Abstract
A- and D-ring-modified luotonin-inspired heterocycles have been synthesized and were evaluated for their activity against the viability of four cancer cell lines in vitro, namely, MCF7, HCT116, JURKAT, and NCI-H460. The analysis of results indicated that two of the synthesized derivatives displayed good inhibition against the growth of the human colon cancer HCT116 cell line, with potencies lower than but in the same order of magnitude as camptothecin (CPT). These two luotonin analogues also showed an activity similar to that of the highly potent alkaloid CPT as inhibitors of topoisomerase I and also inhibited topoisomerase II. These results show that complete planarity is not a strict requirement for topoisomerase inhibition by luotonin-related compounds, paving the way to the design of analogues with improved solubility.
Highlights
Cancer and related diseases are mainly caused by a number of genetic, environmental, and lifestyle-associated factors and the disease is characterized by a shift in the controlled mechanisms that govern cell proliferation and differentiation, and normal physiological activity [1]
In 2012, there were 14.1 million new cases of cancer worldwide and 8.2 million cancer-related deaths, and it is estimated that about 32.6 million patients have survived after 5 years of a cancer diagnosis [2]. erefore, the development of novel, more effective anticancer agents with good pharmacokinetic profiles remains an important and challenging goal in medicinal chemistry [3]. e NIH (National Institutes of Health) database describes a large number of anticancer compounds, organized according to their targets and mechanisms of action [4]
BioMed Research International inhibition or poisoning is an important strategy in cancer chemotherapy [7,8,9,10]
Summary
Cancer and related diseases are mainly caused by a number of genetic, environmental, and lifestyle-associated factors and the disease is characterized by a shift in the controlled mechanisms that govern cell proliferation and differentiation, and normal physiological activity [1]. Topoisomerase II is the target of a number of anticancer agents in clinical use, including etoposide, amsacrine, and doxorubicin [3, 11]. Dual inhibition of topoisomerases I and II by a single agent leads to compounds that are able to target a larger population of cells in comparison with selective inhibitors and increase antitumor activity and has been proposed as a worthwhile goal in the discovery of anticancer agents [21]. Luotonin A, an alkaloid from Peganum nigelastrum, can be viewed as a hydrolysis-stable CPT analogue. While both compounds share the same mechanism of action, namely, stabilization of the topoisomerase I− DNA complex, luotonin shows a much lower level of activity. Due to limitations in synthetic methodology, the least explored one is the manipulation of the D-ring of luotonin; in this regard, only two examples of D-ring-contracted luotonin analogues have been described [26, 37]
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