Regioselective synthesis of water-soluble monophosphate derivatives of combretastatin A-1

Rajendra P. Tanpure, Benson L. Nguyen, Tracy E. Strecker, Savannah Aguirre, Suman Sharma, David J. Chaplin, Bronwyn G. Siim, Ernest Hamel, John W. Lippert, George Pettit, Mary Lynn Trawick, Kevin G. Pinney

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The natural products combretastatin A-4 (CA4) and combretastatin A-1 (CA1) are potent cancer vascular disrupting agents and inhibitors of tubulin assembly (IC 50 = 1-2 μM). The phosphorylated prodrugs CA4P and CA1P are undergoing human clinical trials against cancer. CA1 is unique due to its incorporation of a vicinal phenol, which has afforded the opportunity to prepare both diphosphate and regioisomeric monophosphate derivatives. Here, we describe the first synthetic routes suitable for the regiospecific preparation of the CA1-monophosphates CA1MPA (8a/b) and CA1MPB (4a/b). The essential regiochemistry necessary to distinguish between the two vicinal phenolic groups was accomplished with a tosyl protecting group strategy. Each of the four monophosphate analogues (including Z and E isomers) demonstrated in vitro cytotoxicity against selected human cancer cell lines comparable to their corresponding diphosphate congeners. Furthermore, Z-CA1MPA (8a) and Z-CA1MPB (4a) were inactive as inhibitors of tubulin assembly (IC 50 > 40 μM), as anticipated in this pure protein assay.

Original languageEnglish (US)
Pages (from-to)1568-1574
Number of pages7
JournalJournal of Natural Products
Volume74
Issue number7
DOIs
StatePublished - Jul 22 2011

Fingerprint

Tubulin Modulators
Diphosphates
Derivatives
Water
Neoplasms
Prodrugs
Cytotoxicity
Phenol
Biological Products
Isomers
Blood Vessels
Assays
Cells
Clinical Trials
Cell Line
combretastatin A-1
Proteins

ASJC Scopus subject areas

  • Complementary and alternative medicine
  • Molecular Medicine
  • Organic Chemistry
  • Analytical Chemistry
  • Pharmaceutical Science
  • Pharmacology
  • Drug Discovery

Cite this

Tanpure, R. P., Nguyen, B. L., Strecker, T. E., Aguirre, S., Sharma, S., Chaplin, D. J., ... Pinney, K. G. (2011). Regioselective synthesis of water-soluble monophosphate derivatives of combretastatin A-1. Journal of Natural Products, 74(7), 1568-1574. https://doi.org/10.1021/np200104t

Regioselective synthesis of water-soluble monophosphate derivatives of combretastatin A-1. / Tanpure, Rajendra P.; Nguyen, Benson L.; Strecker, Tracy E.; Aguirre, Savannah; Sharma, Suman; Chaplin, David J.; Siim, Bronwyn G.; Hamel, Ernest; Lippert, John W.; Pettit, George; Trawick, Mary Lynn; Pinney, Kevin G.

In: Journal of Natural Products, Vol. 74, No. 7, 22.07.2011, p. 1568-1574.

Research output: Contribution to journalArticle

Tanpure, RP, Nguyen, BL, Strecker, TE, Aguirre, S, Sharma, S, Chaplin, DJ, Siim, BG, Hamel, E, Lippert, JW, Pettit, G, Trawick, ML & Pinney, KG 2011, 'Regioselective synthesis of water-soluble monophosphate derivatives of combretastatin A-1', Journal of Natural Products, vol. 74, no. 7, pp. 1568-1574. https://doi.org/10.1021/np200104t
Tanpure RP, Nguyen BL, Strecker TE, Aguirre S, Sharma S, Chaplin DJ et al. Regioselective synthesis of water-soluble monophosphate derivatives of combretastatin A-1. Journal of Natural Products. 2011 Jul 22;74(7):1568-1574. https://doi.org/10.1021/np200104t
Tanpure, Rajendra P. ; Nguyen, Benson L. ; Strecker, Tracy E. ; Aguirre, Savannah ; Sharma, Suman ; Chaplin, David J. ; Siim, Bronwyn G. ; Hamel, Ernest ; Lippert, John W. ; Pettit, George ; Trawick, Mary Lynn ; Pinney, Kevin G. / Regioselective synthesis of water-soluble monophosphate derivatives of combretastatin A-1. In: Journal of Natural Products. 2011 ; Vol. 74, No. 7. pp. 1568-1574.
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