TY - JOUR
T1 - Design, synthesis, and biological evaluation of water-soluble amino acid prodrug conjugates derived from combretastatin, dihydronaphthalene, and benzosuberene-based parent vascular disrupting agents
AU - Devkota, Laxman
AU - Lin, Chen Ming
AU - Strecker, Tracy E.
AU - Wang, Yifan
AU - Tidmore, Justin K.
AU - Chen, Zhi
AU - Guddneppanavar, Rajsekhar
AU - Jelinek, Christopher J.
AU - Lopez, Ramona
AU - Liu, Li
AU - Hamel, Ernest
AU - Mason, Ralph P.
AU - Chaplin, David J.
AU - Trawick, Mary Lynn
AU - Pinney, Kevin G.
N1 - Funding Information:
The authors are grateful to the National Cancer Institute of the National Institutes of Health (Grant No. 5R01CA140674 to K.G.P., M.L.T., and R.P.M.), the Cancer Prevention and Research Institute of Texas (CPRIT, Grant No. RP140399 to K.G.P., M.L.T., and R.P.M.), and OXiGENE, Inc. (Grant to K.G.P. and M.L.T.) for their financial support of this project. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health. The authors also thank Dr. Michelle Nemec (Director) for the use of the shared Molecular Biosciences Center at Baylor University and Dr. Alejandro Ramirez (Mass Spectrometry Core Facility, Baylor University). The authors are grateful to Mr. Jarrod Tunnell (Baylor University) for his contributions to the synthesis of an advanced intermediate, and to Jeni Gerberich (UTSW) for valuable technical assistance. Imaging (at UTSW) was facilitated with the assistance of Resources of the Harold C. Simmons Cancer Center supported through an National Institutes of Health National Cancer Institute Cancer Center Support Grant [Grant 1P30 CA142543], specifically, the Southwestern Small Animal Imaging Resource, and Live Cell Imaging Resource. The IVIS Spectrum was purchased with support of 1S10RR024757.
Publisher Copyright:
© 2016 Elsevier Ltd. All rights reserved.
PY - 2016/3/1
Y1 - 2016/3/1
N2 - Targeting tumor vasculature represents an intriguing therapeutic strategy in the treatment of cancer. In an effort to discover new vascular disrupting agents with improved water solubility and potentially greater bioavailability, various amino acid prodrug conjugates (AAPCs) of potent amino combretastatin, amino dihydronaphthalene, and amino benzosuberene analogs were synthesized along with their corresponding water-soluble hydrochloride salts. These compounds were evaluated for their ability to inhibit tubulin polymerization and for their cytotoxicity against selected human cancer cell lines. The amino-based parent anticancer agents 7, 8, 32 (also referred to as KGP05) and 33 (also referred to as KGP156) demonstrated potent cytotoxicity (GI50 = 0.11-40 nM) across all evaluated cell lines, and they were strong inhibitors of tubulin polymerization (IC50 = 0.62-1.5 μM). The various prodrug conjugates and their corresponding salts were investigated for cleavage by the enzyme leucine aminopeptidase (LAP). Four of the glycine water-soluble AAPCs (16, 18, 44 and 45) showed quantitative cleavage by LAP, resulting in the release of the highly cytotoxic parent drug, whereas partial cleavage (<10-90%) was observed for other prodrugs (15, 17, 24, 38 and 39). Eight of the nineteen AAPCs (13-16, 42-45) showed significant cytotoxicity against selected human cancer cell lines. The previously reported CA1-diamine analog and its corresponding hydrochloride salt (8 and 10, respectively) caused extensive disruption (at a concentration of 1.0 μM) of human umbilical vein endothelial cells growing in a two-dimensional tubular network on matrigel. In addition, compound 10 exhibited pronounced reduction in bioluminescence (greater than 95% compared to saline control) in a tumor bearing (MDA-MB-231-luc) SCID mouse model 2 h post treatment (80 mg/kg), with similar results observed upon treatment (15 mg/kg) with the glycine amino-dihydronaphthalene AAPC (compound 44). Collectively, these results support the further pre-clinical development of the most active members of this structurally diverse collection of water-soluble prodrugs as promising anticancer agents functioning through a mechanism involving vascular disruption.
AB - Targeting tumor vasculature represents an intriguing therapeutic strategy in the treatment of cancer. In an effort to discover new vascular disrupting agents with improved water solubility and potentially greater bioavailability, various amino acid prodrug conjugates (AAPCs) of potent amino combretastatin, amino dihydronaphthalene, and amino benzosuberene analogs were synthesized along with their corresponding water-soluble hydrochloride salts. These compounds were evaluated for their ability to inhibit tubulin polymerization and for their cytotoxicity against selected human cancer cell lines. The amino-based parent anticancer agents 7, 8, 32 (also referred to as KGP05) and 33 (also referred to as KGP156) demonstrated potent cytotoxicity (GI50 = 0.11-40 nM) across all evaluated cell lines, and they were strong inhibitors of tubulin polymerization (IC50 = 0.62-1.5 μM). The various prodrug conjugates and their corresponding salts were investigated for cleavage by the enzyme leucine aminopeptidase (LAP). Four of the glycine water-soluble AAPCs (16, 18, 44 and 45) showed quantitative cleavage by LAP, resulting in the release of the highly cytotoxic parent drug, whereas partial cleavage (<10-90%) was observed for other prodrugs (15, 17, 24, 38 and 39). Eight of the nineteen AAPCs (13-16, 42-45) showed significant cytotoxicity against selected human cancer cell lines. The previously reported CA1-diamine analog and its corresponding hydrochloride salt (8 and 10, respectively) caused extensive disruption (at a concentration of 1.0 μM) of human umbilical vein endothelial cells growing in a two-dimensional tubular network on matrigel. In addition, compound 10 exhibited pronounced reduction in bioluminescence (greater than 95% compared to saline control) in a tumor bearing (MDA-MB-231-luc) SCID mouse model 2 h post treatment (80 mg/kg), with similar results observed upon treatment (15 mg/kg) with the glycine amino-dihydronaphthalene AAPC (compound 44). Collectively, these results support the further pre-clinical development of the most active members of this structurally diverse collection of water-soluble prodrugs as promising anticancer agents functioning through a mechanism involving vascular disruption.
KW - Amino acid prodrug salts
KW - Anti-cancer agents
KW - Benzosuberene analogs
KW - Combretastatin analogs
KW - Dihydronaphthalene analogs
KW - Inhibitors of tubulin polymerization
KW - Small-molecule synthesis
KW - Vascular disrupting agents
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U2 - 10.1016/j.bmc.2016.01.007
DO - 10.1016/j.bmc.2016.01.007
M3 - Article
C2 - 26852340
AN - SCOPUS:84957975307
SN - 0968-0896
VL - 24
SP - 938
EP - 956
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 5
ER -