Bioreductively Activatable Prodrug Conjugates of Combretastatin A-1 and Combretastatin A-4 as Anticancer Agents Targeted toward Tumor-Associated Hypoxia
- Blake A. Winn
Blake A. WinnDepartment of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United StatesMore by Blake A. Winn
- ,
- Laxman Devkota
Laxman DevkotaDepartment of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United StatesMore by Laxman Devkota
- ,
- Bunnarack Kuch
Bunnarack KuchDepartment of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United StatesMore by Bunnarack Kuch
- ,
- Matthew T. MacDonough
Matthew T. MacDonoughDepartment of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United StatesMore by Matthew T. MacDonough
- ,
- Tracy E. Strecker
Tracy E. StreckerDepartment of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United StatesMore by Tracy E. Strecker
- ,
- Yifan Wang
Yifan WangDepartment of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United StatesMore by Yifan Wang
- ,
- Zhe Shi
Zhe ShiDepartment of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United StatesMore by Zhe Shi
- ,
- Jeni L. Gerberich
Jeni L. GerberichPredictive Imaging Research Laboratory, Department of Radiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9058, United StatesMore by Jeni L. Gerberich
- ,
- Deboprosad Mondal
Deboprosad MondalDepartment of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United StatesMore by Deboprosad Mondal
- ,
- Alejandro J. Ramirez
Alejandro J. RamirezMass Spectrometry Center, Baylor University, One Bear Place #97046, Waco, Texas 76798-7046, United StatesMore by Alejandro J. Ramirez
- ,
- Ernest Hamel
Ernest HamelScreening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, Maryland 21702, United StatesMore by Ernest Hamel
- ,
- David J. Chaplin
David J. ChaplinDepartment of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United StatesFast Biopharma Ltd., 10 Aston Park, Aston Rowant, OX49 5SW, United KingdomMore by David J. Chaplin
- ,
- Peter Davis
Peter DavisFast Biopharma Ltd., 10 Aston Park, Aston Rowant, OX49 5SW, United KingdomMore by Peter Davis
- ,
- Ralph P. Mason
Ralph P. MasonPredictive Imaging Research Laboratory, Department of Radiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9058, United StatesMore by Ralph P. Mason
- ,
- Mary Lynn Trawick*
Mary Lynn Trawick*Tel: (254) 710-6857. Fax: (254) 710-4272. E-mail: [email protected]Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United StatesMore by Mary Lynn Trawick
- , and
- Kevin G. Pinney*
Kevin G. Pinney*Tel: (254) 710-4117. Fax: (254) 710-4272. E-mail: [email protected]Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United StatesMore by Kevin G. Pinney
Abstract
The natural products combretastatin A-1 (CA1) and combretastatin A-4 (CA4) function as potent inhibitors of tubulin polymerization and as selective vascular disrupting agents (VDAs) in tumors. Bioreductively activatable prodrug conjugates (BAPCs) can enhance selectivity by serving as substrates for reductase enzymes specifically in hypoxic regions of tumors. A series of CA1-BAPCs incorporating nor-methyl, mono-methyl, and gem-dimethyl nitrothiophene triggers were synthesized together with corresponding CA4-BAPCs, previously reported by Davis (Mol. Cancer Ther.2006, 5 (11), 2886), for comparison. The CA4-gem-dimethylnitrothiophene BAPC 45 proved exemplary in comparison to its nor-methyl 43 and mono-methyl 44 congeners. It was stable in phosphate buffer (pH 7.4, 24 h), was cleaved (25%, 90 min) by NADPH-cytochrome P450 oxidoreductase (POR), was inactive (desirable prodrug attribute) as an inhibitor of tubulin polymerization (IC50 > 20 μM), and demonstrated hypoxia-selective activation in the A549 cell line [hypoxia cytotoxicity ratio (HCR) = 41.5]. The related CA1-gem-dimethylnitrothiophene BAPC 41 was also promising (HCR = 12.5) with complete cleavage (90 min) upon treatment with POR. In a preliminary in vivo dynamic bioluminescence imaging study, BAPC 45 (180 mg/kg, ip) induced a decrease (within 4 h) in light emission in a 4T1 syngeneic mouse breast tumor model, implying activation and vascular disruption.
Cited By
This article is cited by 15 publications.
- Wen Ren, Yuling Deng, Jacob D. Ward, Rebecca Vairin, Ruoli Bai, Hashini I. Wanniarachchi, Khagendra B. Hamal, Pouguiniseli E. Tankoano, Caleb S. Tamminga, Lorena M.A. Bueno, Ernest Hamel, Ralph P. Mason, Mary Lynn Trawick, Kevin G. Pinney. Synthesis and biological evaluation of structurally diverse 6-aryl-3-aroyl-indole analogues as inhibitors of tubulin polymerization. European Journal of Medicinal Chemistry 2024, 263 , 115794. https://doi.org/10.1016/j.ejmech.2023.115794
- Zhi-Lin Liu, Xi-Tong Ren, Yue Huang, Jia-Li Sun, Xiao-Shuang Wang, Meng-Fei Zheng, Lin-Jie Cui, Xue-Fei Zhang, Zhao-Hui Tang. A Novel CA4P Polymeric Nanoparticle for Murine Hepatoma Therapy. Chinese Journal of Polymer Science 2023, 41 (8) , 1223-1229. https://doi.org/10.1007/s10118-023-2921-7
- Muhannad N Fadhel, Sila Appak Baskoy, Yanjie Wang, Eno Hysi, Michael C. Kolios. Use of photoacoustic imaging for monitoring vascular disrupting cancer treatments. Journal of Biophotonics 2023, 16 (4) https://doi.org/10.1002/jbio.202000209
- Baodong Hu, Xinrui Zhao, Endao Wang, Jingwen Zhou, Jianghua Li, Jian Chen, Guocheng Du. Efficient heterologous expression of cytochrome P450 enzymes in microorganisms for the biosynthesis of natural products. Critical Reviews in Biotechnology 2023, 43 (2) , 227-241. https://doi.org/10.1080/07388551.2022.2029344
- Dongmei Guo, Yue Huang, Kun Wang, Chenguang Yang, Lili Ma, Yu Zhang, Haiyang Yu, Manhua Cui, Zhaohui Tang. Preparation and Characterization Evaluation of Poly(L-Glutamic Acid)-g-Methoxy Poly(Ethylene Glycol)/Combretastatin A4/BLZ945 Nanoparticles for Cervical Cancer Therapy. International Journal of Nanomedicine 2023, Volume 18 , 6901-6914. https://doi.org/10.2147/IJN.S441131
- Alessandra Ammazzalorso, Trond Vidar Hansen. Combretastatin Derivatives as Tubulin Inhibitors: A Fascinating Journey from Nature to Drug Discovery Strategies. 2022, 112-144. https://doi.org/10.2174/9789815079098122010007
- Zhonglei Wang, Liyan Yang, Yake Li, Shaohua Song, Juan Qu, Rui He, Shanshan Ren, Peiwei Gong. An activatable, carrier-free, triple-combination nanomedicine for ALK/EGFR-mutant non-small cell lung cancer highly permeable targeted chemotherapy. New Journal of Chemistry 2022, 46 (37) , 17673-17677. https://doi.org/10.1039/D2NJ03231G
- Li Liu, Regan Schuetze, Jeni L. Gerberich, Ramona Lopez, Samuel O. Odutola, Rajendra P. Tanpure, Amanda K. Charlton-Sevcik, Justin K. Tidmore, Emily A.-S. Taylor, Payal Kapur, Hans Hammers, Mary Lynn Trawick, Kevin G. Pinney, Ralph P. Mason. Demonstrating Tumor Vascular Disrupting Activity of the Small-Molecule Dihydronaphthalene Tubulin-Binding Agent OXi6196 as a Potential Therapeutic for Cancer Treatment. Cancers 2022, 14 (17) , 4208. https://doi.org/10.3390/cancers14174208
- Zhilin Liu, Yu Zhang, Na Shen, Jiali Sun, Zhaohui Tang, Xuesi Chen. Destruction of tumor vasculature by vascular disrupting agents in overcoming the limitation of EPR effect. Advanced Drug Delivery Reviews 2022, 183 , 114138. https://doi.org/10.1016/j.addr.2022.114138
- Lijiang Huang, Yan Peng, Xuetao Tao, Xiaoxiao Ding, Rui Li, Yongsheng Jiang, Wei Zuo, . Microtubule Organization Is Essential for Maintaining Cellular Morphology and Function. Oxidative Medicine and Cellular Longevity 2022, 2022 , 1-15. https://doi.org/10.1155/2022/1623181
- William A. Denny. Nitroaromatic Hypoxia-Activated Prodrugs for Cancer Therapy. Pharmaceuticals 2022, 15 (2) , 187. https://doi.org/10.3390/ph15020187
- Dean C. Singleton, Andrew Macann, William R. Wilson. Therapeutic targeting of the hypoxic tumour microenvironment. Nature Reviews Clinical Oncology 2021, 18 (12) , 751-772. https://doi.org/10.1038/s41571-021-00539-4
- Yihang Guo, Honghong Wang, Jeni L. Gerberich, Samuel O. Odutola, Amanda K. Charlton-Sevcik, Maoping Li, Rajendra P. Tanpure, Justin K. Tidmore, Mary Lynn Trawick, Kevin G. Pinney, Ralph P. Mason, Li Liu. Imaging-Guided Evaluation of the Novel Small-Molecule Benzosuberene Tubulin-Binding Agent KGP265 as a Potential Therapeutic Agent for Cancer Treatment. Cancers 2021, 13 (19) , 4769. https://doi.org/10.3390/cancers13194769
- Li Liu, Devin O’Kelly, Regan Schuetze, Graham Carlson, Heling Zhou, Mary Lynn Trawick, Kevin G. Pinney, Ralph P. Mason. Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors. Molecules 2021, 26 (9) , 2551. https://doi.org/10.3390/molecules26092551
- Natalie J. Serkova, Kristine Glunde, Chad R. Haney, Mohammed Farhoud, Alexandra De Lille, Elizabeth F. Redente, Dmitri Simberg, David C. Westerly, Lynn Griffin, Ralph P. Mason. Preclinical Applications of Multi-Platform Imaging in Animal Models of Cancer. Cancer Research 2021, 81 (5) , 1189-1200. https://doi.org/10.1158/0008-5472.CAN-20-0373