ArticleBioorganic & medicinal chemistry2016
Design, synthesis, and biological evaluation of water-soluble amino acid prodrug conjugates derived from combretastatin, dihydronaphthalene, and benzosuberene-based parent vascular disrupting agents.
Article in Bioorganic & medicinal chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 47 citations in OpenAlex.
- Recent Overview on the Molecular Hybrids Integrated With Benzosuberone/Benzo[7]annulene Derivatives as Multi-Target Therapeutics.Archiv der Pharmazie · 2026Review
- Targeting Tumor-Associated Hypoxia with Bioreductively Activatable Prodrug Conjugates Derived from Dihydronaphthalene, Benzosuberene, and Indole-based Inhibitors of Tubulin Polymerization.RSC medicinal chemistry · 2025Article
- Benzosuberene and Tetracyclic Analogues as Colchicine Site Inhibitors of Tubulin Polymerization.ACS medicinal chemistry letters · 2025Article
- Drug-Linker Constructs Bearing Unique Dual-Mechanism Tubulin Binding Payloads Tethered through Cleavable and Non-Cleavable Linkers.Tetrahedron · 2025Article
- Chemical synthesis and application of aryldihydronaphthalene derivatives.RSC advances · 2024Review
- 3,4-Diarylisoxazoles-Analogues of Combretastatin A-4: Design, Synthesis, and Biological EvaluationACS pharmacology & translational science · 2024Article
- Synthesis and biological evaluation of structurally diverse 6-aryl-3-aroyl-indole analogues as inhibitors of tubulin polymerization.European journal of medicinal chemistry · 2024Article
- Antiproliferative and Tubulin-Destabilising Effects of 3-(Prop-1-en-2-yl)azetidin-2-Ones and Related Compounds in MCF-7 and MDA-MB-231 Breast Cancer Cells.Pharmaceuticals (Basel, Switzerland) · 2023Article
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- Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors.Molecules (Basel, Switzerland) · 2021Review
- Design and Synthesis of New 6-Nitro and 6-Amino-3,3a,4,5-Tetrahydro-2Molecules (Basel, Switzerland) · 2019Article
- Synthesis and biological evaluation of structurally diverse α-conformationally restricted chalcones and related analogues.MedChemComm · 2019Article
- 3-Vinylazetidin-2-Ones: Synthesis, Antiproliferative and Tubulin Destabilizing Activity in MCF-7 and MDA-MB-231 Breast Cancer Cells.Pharmaceuticals (Basel, Switzerland) · 2019Article
- Efficient Synthetic Methodology for the Construction of Dihydronaphthalene and Benzosuberene Molecular Frameworks.Tetrahedron letters · 2019Article
- Discovery of Novel 4-Arylisochromenes as Anticancer Agents Inhibiting Tubulin Polymerization.ACS medicinal chemistry letters · 2018Article
- Improved Methodology for the Synthesis of a Cathepsin B Cleavable Dipeptide Linker, Widely Used in Antibody-Drug Conjugate Research.Tetrahedron letters · 2018Article
- Synthesis of dihydronaphthalene analogues inspired by combretastatin A-4 and their biological evaluation as anticancer agents.MedChemComm · 2018Article
- Recent advances in combretastatin based derivatives and prodrugs as antimitotic agents.MedChemComm · 2017Review
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Authors and funding
15 authors at 3 institutions in 1 country.
Funding
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.
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