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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The enediynes (Figure 5.57) are a class of bacterial natural products characterized by either nine- or ten-membered rings containing two triple bonds separated by a double bond. These compounds are capable of undergoing a unique internal chemical reaction known as the Bergman cyclization. The resulting di-radical formed, a 1,4-dehydrobenzene species, is capable of abstracting hydrogen atoms from the sugar backbone of DNA. This results in double-strand breaks in the double helix which are problematic for the cell to repair, thus rendering the compounds extremely cytotoxic. Examples of structures of the enediyne family of DNA-cleaving bacterial natural products: Neocarzinostatin, Calicheamicin γ1, Esperimicin. and Dynemicin A.
Characterization and initial demonstration of in vivo efficacy of a novel heat-activated metalloenediyne anti-cancer agent
Published in International Journal of Hyperthermia, 2022
Joy Garrett, Erin Metzger, Mark W. Dewhirst, Karen E. Pollok, John J. Turchi, Isabelle C. Le Poole, Kira Couch, Logan Lew, Anthony Sinn, Jeffrey M. Zaleski, Joseph R. Dynlacht
Enediynes are a class of natural products that were first recognized for their potent anti-tumor activities in the late 1980s. Since then, several derivatives have been synthesized, but common to all enediynes are two acetylenic groups conjugated to a double bond commonly situated within a nine- or ten-membered ring [1]. It is this uniquely strained structure that confers the cytotoxic tendencies of these compounds, as an appropriate chemical or physical trigger will induce the enediyne core to undergo Bergman cyclization. This cycloaromatization results in the production of a benzenoid 1,4-diradical intermediate that may go on to abstract H-atoms from DNA, resulting in strand breakage. While the DNA-damaging aspects of enediynes are tantalizing, their clinical utility has been limited due to challenges in controlling the initiation of diradical formation; the mild activation temperatures for enediyne cyclization (generally less than 37 °C) lead to toxicity. Combined with difficulties of synthetic accessibility, these factors discouraged their further development.
Intensive fibrosarcoma-binding capability of the reconstituted analog and its antitumor activity
Published in Drug Delivery, 2018
Jian Xu, Yue Du, Wen-Juan Liu, Liang Li, Yi Li, Xiao-Fei Wang, Hong-Fei Yi, Chuan-Kun Shan, Gui-Min Xia, Xiu-Jun Liu, Yong-Su Zhen
To investigate the cytotoxicity of protein LT (LDP, served as the control), and enediyne-integrated analog LTE (LDM, served as the control) to HT1080 and A549 cells, Cell Counting Kit-8 assay was performed. Different concentrations of protein LT and LDP (0 µM, 1.3 µM, 2.5 µM, 5 µM, 10 µM, and 20 µM) as well as the LTE and LDM (0 nM, 0.0001 nM, 0.001 nM, 0.01 nM, 0.1 nM, and 1 nM) were employed for analyses. As shown in Figure 4(a), when treated with 20 µM of protein LT, both the growth of HT1080 (upper left) and A549 cells (upper right) were inhibited moderately, and significant difference was shown as compared with the control (0 µM), respectively. Additionally, in Figure 4(a) (lower left and right), more striking inhibitory potency was confirmed, which also demonstrated the successful reconstitution of active enediyne to the protein LT.