TY - JOUR
T1 - Bioreductively Activatable Prodrug Conjugates of Combretastatin A-1 and Combretastatin A-4 as Anticancer Agents Targeted toward Tumor-Associated Hypoxia
AU - Winn, Blake A.
AU - Devkota, Laxman
AU - Kuch, Bunnarack
AU - Macdonough, Matthew T.
AU - Strecker, Tracy E.
AU - Wang, Yifan
AU - Shi, Zhe
AU - Gerberich, Jeni L.
AU - Mondal, Deboprosad
AU - Ramirez, Alejandro J.
AU - Hamel, Ernest
AU - Chaplin, David J.
AU - Davis, Peter
AU - Mason, Ralph P.
AU - Trawick, Mary Lynn
AU - Pinney, Kevin G.
N1 - Funding Information:
Dedicated to Professor George R. Pettit on the occasion of his most recent birthday and in celebration of his lifetime scientific accomplishments that continue to define and advance the fields of natural products chemistry, medicinal chemistry, and synthetic organic chemistry. The authors are grateful to the Cancer Prevention and Research Institute of Texas (CPRIT, Grant No. RP140399 to K.G.P., M.L.T., and R.P.M.), the National Cancer Institute of the National Institutes of Health (Grant No. 5R01CA140674 to K.G.P., M.L.T., and R.P.M.), Mateon Therapeutics, Inc. (grant to K.G.P. and M.L.T.), and the Undergraduate Research and Scholarly Activity Small Grant Program, the University Research Committee (URC), and the Vice Provost for Research at Baylor University (grants to M.L.T.) for their financial support of this project. BLI was facilitated by the Southwestern Small Animal Imaging Resource supported in part by the NIH Comprehensive Cancer Center Grant P30 CA142543 and a Shared Instrumentation Grant 1S10 RR024757. The authors also thank Dr. Michelle Nemec (Director) for the use of the shared Molecular Biosciences Center at Baylor University, the Mass Spectrometry Core Facility, Baylor University, and Dr. Kevin Klausmeyer (X-ray analysis, Baylor University). The authors are grateful to Mr. David Ross IV (Baylor University), Ms. Taylor Deushane (Baylor University), Mr. Benji Gomez (Baylor University), and Ms. Evelyn Le (Baylor University) for their contributions to the synthesis of advanced intermediates. We appreciate the technical support of Alex Winters and valuable discussions with Dr. Li Liu (UT Southwestern) and Dr. Edward Graves (Stanford University). Histology was performed by Dr. John Shelton in the Histo Pathology Core at UT Southwestern. We thank the Whole Brain Microscopy Facility (WBMF) in the UT Southwestern Department of Neurology and Neurotherapeutics for use of high-resolution scanning equipment used to obtain histological images of the 4T1-luc tumors. The WBMF is supported by the Texas Institute for Brain Injury and Repair. This research was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute, which includes federal funds under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
Funding Information:
Dedicated to Professor George R. Pettit on the occasion of his most recent birthday and in celebration of his lifetime scientific accomplishments that continue to define and advance the fields of natural products chemistry, medicinal chemistry, and synthetic organic chemistry. The authors are grateful to the Cancer Prevention and Research Institute of Texas (CPRIT, Grant No. RP140399 to K.G.P., M.L.T., and R.P.M.), the National Cancer Institute of the National Institutes of Health (Grant No. 5R01CA140674 to K.G.P., M.L.T., and R.P.M.) Mateon Therapeutics, Inc. (grant to K.G.P. and M.L.T.), and the Undergraduate Research and Scholarly Activity Small Grant Program, the University Research Committee (URC), and the Vice Provost for Research at Baylor University (grants to M.L.T.) for their financial support of this project. BLI was facilitated by the Southwestern Small Animal Imaging Resource supported in part by the NIH Comprehensive Cancer Center Grant P30 CA142543 and a Shared Instrumentation Grant 1S10 RR024757. The authors also thank Dr. Michelle Nemec (Director) for the use of the shared Molecular Biosciences Center at Baylor University, the Mass Spectrometry Core Facility, Baylor University, and Dr. Kevin Klausmeyer (X-ray analysis, Baylor University). The authors are grateful to Mr. David Ross IV (Baylor University), Ms. Taylor Deushane (Baylor University), Mr. Benji Gomez (Baylor University), and Ms. Evelyn Le (Baylor University) for their contributions to the synthesis of advanced intermediates. We appreciate the technical support of Alex Winters and valuable discussions with Dr. Li Liu (UT Southwestern) and Dr. Edward Graves (Stanford University). Histology was performed by Dr. John Shelton in the Histo Pathology Core at UT Southwestern. We thank the Whole Brain Microscopy Facility (WBMF) in the UT Southwestern Department of Neurology and Neurotherapeutics for use of high-resolution scanning equipment used to obtain histological images of the 4T1-luc tumors. The WBMF is supported by the Texas Institute for Brain Injury and Repair. This research was supported in part by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute, which includes federal funds under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
Publisher Copyright:
Copyright © 2020 American Chemical Society and American Society of Pharmacognosy.
PY - 2020/4/24
Y1 - 2020/4/24
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jnatprod.9b00773
DO - 10.1021/acs.jnatprod.9b00773
M3 - Article
C2 - 32196334
AN - SCOPUS:85082341475
SN - 0163-3864
VL - 83
SP - 937
EP - 954
JO - Journal of Natural Products
JF - Journal of Natural Products
IS - 4
ER -