Synthesis and Evaluation of Folate-Conjugated Phenanthraquinones for Tumor-Targeted Oxidative ChemotherapyReport as inadecuate




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Almost all cells are easily killed by exposure to potent oxidants. Indeed, major pathogen defense mechanisms in both animal and plant kingdoms involve production of an oxidative burst, where host defense cells show an invading pathogen with reactive oxygen species ROS. Although cancer cells can be similarly killed by ROS, development of oxidant-producing chemotherapies has been limited by their inherent nonspecificity and potential toxicity to healthy cells. In this paper, we describe the targeting of an ROS-generating molecule selectively to tumor cells using folate as the tumor-targeting ligand. For this purpose, we exploit the ability of 9,10-phenanthraquinone PHQ to enhance the continuous generation of H2O2 in the presence of ascorbic acid to establish a con-stitutive source of ROS within the tumor mass. We report here that incubation of folate receptor-expressing KB cells in culture with folate-PHQ plus ascorbate results in the death of the cancer cells with an IC50 of ~10 nM folate-PHQ. We also demonstrate that a cleavable spacer linking folate to PHQ is significantly inferior to a noncleavable spacer, in contrast to most other folate-targeted therapeutic agents. Unfortunately, no evidence for folate-PHQ mediated tumor regression in murine tumor models is obtained, suggesting that unanticipated impediments to generation of cytotoxic quantities of ROS in vivo are encountered. Possible mechanisms and potential solutions to these unanticipated results are offered.

KEYWORDS

Cancer, Folate Receptor, Reactive Oxygen Species

Cite this paper

Kumar, A. , Chelvam, V. , Sakkarapalayam, M. , Li, G. , Sanchez-Cruz, P. , Piñero, N. , Low, P. and Alegria, A. 2016 Synthesis and Evaluation of Folate-Conjugated Phenanthraquinones for Tumor-Targeted Oxidative Chemotherapy. Open Journal of Medicinal Chemistry, 6, 1-17. doi: 10.4236-ojmc.2016.61001.





Author: Ajay Kumar1,2*, Venkatesh Chelvam3,4, Mahalingam Sakkarapalayam3, Guo Li3, Pedro Sanchez-Cruz2, Natasha S. Piñero2, Philip S. Lo

Source: http://www.scirp.org/



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