Design, synthesis, and biological evaluation of water-soluble amino acid prodrug conjugates derived from combretastatin, dihydronaphthalene, and benzosuberene-based parent vascular disrupting agents

Laxman Devkota, Chen Ming Lin, Tracy E. Strecker, Yifan Wang, Justin K. Tidmore, Zhi Chen, Rajsekhar Guddneppanavar, Christopher J. Jelinek, Ramona Lopez, Li Liu, Ernest Hamel, Ralph P. Mason, David J. Chaplin, Mary Lynn Trawick, Kevin G. Pinney

Research output: Contribution to journalArticle

20 Citations (Scopus)

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 = 0.11-40 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 (

Original languageEnglish (US)
Pages (from-to)938-956
Number of pages19
JournalBioorganic and Medicinal Chemistry
Volume24
Issue number5
DOIs
StatePublished - Mar 1 2016

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Prodrugs
Leucyl Aminopeptidase
Blood Vessels
Cytotoxicity
Amino Acids
Water
Tubulin Modulators
Salts
Cells
Cell Line
Neoplasms
Tubulin
Polymerization
Antineoplastic Agents
Solubility
Glycine
Biological Availability
Inhibitory Concentration 50
Tumors
Enzymes

Keywords

  • Amino acid prodrug salts
  • Anti-cancer agents
  • Benzosuberene analogs
  • Combretastatin analogs
  • Dihydronaphthalene analogs
  • Inhibitors of tubulin polymerization
  • Small-molecule synthesis
  • Vascular disrupting agents

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Design, synthesis, and biological evaluation of water-soluble amino acid prodrug conjugates derived from combretastatin, dihydronaphthalene, and benzosuberene-based parent vascular disrupting agents. / Devkota, Laxman; Lin, Chen Ming; Strecker, Tracy E.; Wang, Yifan; Tidmore, Justin K.; Chen, Zhi; Guddneppanavar, Rajsekhar; Jelinek, Christopher J.; Lopez, Ramona; Liu, Li; Hamel, Ernest; Mason, Ralph P.; Chaplin, David J.; Trawick, Mary Lynn; Pinney, Kevin G.

In: Bioorganic and Medicinal Chemistry, Vol. 24, No. 5, 01.03.2016, p. 938-956.

Research output: Contribution to journalArticle

Devkota, L, Lin, CM, Strecker, TE, Wang, Y, Tidmore, JK, Chen, Z, Guddneppanavar, R, Jelinek, CJ, Lopez, R, Liu, L, Hamel, E, Mason, RP, Chaplin, DJ, Trawick, ML & Pinney, KG 2016, 'Design, synthesis, and biological evaluation of water-soluble amino acid prodrug conjugates derived from combretastatin, dihydronaphthalene, and benzosuberene-based parent vascular disrupting agents', Bioorganic and Medicinal Chemistry, vol. 24, no. 5, pp. 938-956. https://doi.org/10.1016/j.bmc.2016.01.007
Devkota, Laxman ; Lin, Chen Ming ; Strecker, Tracy E. ; Wang, Yifan ; Tidmore, Justin K. ; Chen, Zhi ; Guddneppanavar, Rajsekhar ; Jelinek, Christopher J. ; Lopez, Ramona ; Liu, Li ; Hamel, Ernest ; Mason, Ralph P. ; Chaplin, David J. ; Trawick, Mary Lynn ; Pinney, Kevin G. / Design, synthesis, and biological evaluation of water-soluble amino acid prodrug conjugates derived from combretastatin, dihydronaphthalene, and benzosuberene-based parent vascular disrupting agents. In: Bioorganic and Medicinal Chemistry. 2016 ; Vol. 24, No. 5. pp. 938-956.
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AU - Strecker, Tracy E.

AU - Wang, Yifan

AU - Tidmore, Justin K.

AU - Chen, Zhi

AU - Guddneppanavar, Rajsekhar

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AU - Liu, Li

AU - Hamel, Ernest

AU - Mason, Ralph P.

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