title: Design, synthesis, and biological evaluation of water-soluble amino acid prodrug conjugates derived from combretastatin, dihydronaphthalene, and benzosuberene-based parent vascular disrupting agents.
abstract: 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=0.11-40nM) across all evaluated cell lines, and they were strong inhibitors of tubulin polymerization (IC50=0.62-1.5μM). 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 1.0μM) 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 2h post treatment (80mg/kg), with similar results observed upon treatment (15mg/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.
authors: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United States.
authors: Laxman
authors: L
authors: Devkota
authors: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United States.
authors: Chen-Ming
authors: CM
authors: Lin
authors: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United States.
authors: Tracy E
authors: TE
authors: Strecker
authors: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United States.
authors: Yifan
authors: Y
authors: Wang
authors: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United States.
authors: Justin K
authors: JK
authors: Tidmore
authors: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United States.
authors: Zhi
authors: Z
authors: Chen
authors: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United States.
authors: Rajsekhar
authors: R
authors: Guddneppanavar
authors: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United States.
authors: Christopher J
authors: CJ
authors: Jelinek
authors: Department of Radiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9058, United States.
authors: Ramona
authors: R
authors: Lopez
authors: Department of Radiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9058, United States.
authors: Li
authors: L
authors: Liu
authors: Screening 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, MD 21702, United States.
authors: Ernest
authors: E
authors: Hamel
authors: Department of Radiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9058, United States.
authors: Ralph P
authors: RP
authors: Mason
authors: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United States.|OXiGENE Inc., 701 Gateway Boulevard, Suite 210, South San Francisco, California 94080, United States.
authors: David J
authors: DJ
authors: Chaplin
authors: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United States.
authors: Mary Lynn
authors: ML
authors: Trawick
authors: Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United States.
authors: Kevin G
authors: KG
authors: Pinney
mesh_terms: D000596:Amino Acids / Q000737:chemistry / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D001632:Bibenzyls / Q000737:chemistry / Q000627:therapeutic use*; D001940:Breast / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D003374:Coumarins / Q000737:chemistry / Q000627:therapeutic use*; D015195:Drug Design; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009281:Naphthalenes / Q000737:chemistry / Q000627:therapeutic use*; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D061848:Optical Imaging; D011355:Prodrugs / Q000737:chemistry / Q000627:therapeutic use*; D012995:Solubility; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism; D014867:Water / Q000737:chemistry
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D001632:Bibenzyls; D003374:Coumarins; D009281:Naphthalenes; D011355:Prodrugs; D014404:Tubulin; C000611462:benzosuberene; D014867:Water; C086079:1,2-dihydronaphthalene; C040105:combretastatin
keywords: Amino acid prodrug salts; Anti-cancer agents; Benzosuberene analogs; Combretastatin analogs; Dihydronaphthalene analogs; Inhibitors of tubulin polymerization; Small-molecule synthesis; Vascular disrupting agents