Structural interrogation of benzosuberene-based inhibitors of tubulin polymerization

Christine A. Herdman, Laxman Devkota, Chen Ming Lin, Haichan Niu, Tracy E. Strecker, Ramona Lopez, Li Liu, Clinton S. George, Rajendra P. Tanpure, Ernest Hamel, David J. Chaplin, Ralph P. Mason, Mary Lynn Trawick, Kevin G. Pinney

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The discovery of 3-methoxy-9-(3′,4′,5′-trimethoxyphenyl)-6,7-dihydro-5H-benzo[7]annulen-4-ol (a benzosuberene-based analogue referred to as KGP18) was originally inspired by the natural products colchicine and combretastatin A-4 (CA4). The relative structural simplicity and ease of synthesis of KGP18, coupled with its potent biological activity as an inhibitor of tubulin polymerization and its cytotoxicity (in vitro) against human cancer cell lines, has resulted in studies focused on new analogue design and synthesis. Our goal was to probe the relationship of structure to function in this class of anticancer agents. A series of twenty-two new benzosuberene-based analogues of KGP18 was designed and synthesized. These compounds vary in their methoxylation pattern and separately incorporate trifluoromethyl groups around the pendant aryl ring for the evaluation of the effect of functional group modifications on the fused six-membered aromatic ring. In addition, the 8,9-saturated congener of KGP18 has been synthesized to assess the necessity of unsaturation at the carbon atom bearing the pendant aryl ring. Six of the molecules from this benzosuberene-series of compounds were active (IC50 <5 μM) as inhibitors of tubulin polymerization while four analogues were comparable (IC50 approximately 1 μM) in their tubulin inhibitory activity to CA4 and KGP18. The potency of a bis-trifluoromethyl analogue 74 and the unsaturated KGP18 derivative 73 as inhibitors of tubulin assembly along with their moderate cytotoxicity suggested the potential utility of these compounds as vascular disrupting agents (VDAs) to selectively target microvessels feeding tumors. Accordingly, water-soluble and DMSO-soluble phosphate prodrug salts of each were synthesized for preliminary in vivo studies to assess their potential efficacy as VDAs.

Original languageEnglish (US)
Pages (from-to)7497-7520
Number of pages24
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number24
DOIs
StatePublished - Dec 15 2015

Fingerprint

Tubulin Modulators
Cytotoxicity
Inhibitory Concentration 50
Blood Vessels
Bearings (structural)
Prodrugs
Colchicine
Tubulin
Dimethyl Sulfoxide
Microvessels
Bioactivity
Biological Products
Antineoplastic Agents
Functional groups
Tumors
Neoplasms
Carbon
Salts
Phosphates
Cells

Keywords

  • Benzosuberene analogues
  • 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

Herdman, C. A., Devkota, L., Lin, C. M., Niu, H., Strecker, T. E., Lopez, R., ... Pinney, K. G. (2015). Structural interrogation of benzosuberene-based inhibitors of tubulin polymerization. Bioorganic and Medicinal Chemistry, 23(24), 7497-7520. https://doi.org/10.1016/j.bmc.2015.10.012

Structural interrogation of benzosuberene-based inhibitors of tubulin polymerization. / Herdman, Christine A.; Devkota, Laxman; Lin, Chen Ming; Niu, Haichan; Strecker, Tracy E.; Lopez, Ramona; Liu, Li; George, Clinton S.; Tanpure, Rajendra P.; Hamel, Ernest; Chaplin, David J.; Mason, Ralph P.; Trawick, Mary Lynn; Pinney, Kevin G.

In: Bioorganic and Medicinal Chemistry, Vol. 23, No. 24, 15.12.2015, p. 7497-7520.

Research output: Contribution to journalArticle

Herdman, CA, Devkota, L, Lin, CM, Niu, H, Strecker, TE, Lopez, R, Liu, L, George, CS, Tanpure, RP, Hamel, E, Chaplin, DJ, Mason, RP, Trawick, ML & Pinney, KG 2015, 'Structural interrogation of benzosuberene-based inhibitors of tubulin polymerization', Bioorganic and Medicinal Chemistry, vol. 23, no. 24, pp. 7497-7520. https://doi.org/10.1016/j.bmc.2015.10.012
Herdman, Christine A. ; Devkota, Laxman ; Lin, Chen Ming ; Niu, Haichan ; Strecker, Tracy E. ; Lopez, Ramona ; Liu, Li ; George, Clinton S. ; Tanpure, Rajendra P. ; Hamel, Ernest ; Chaplin, David J. ; Mason, Ralph P. ; Trawick, Mary Lynn ; Pinney, Kevin G. / Structural interrogation of benzosuberene-based inhibitors of tubulin polymerization. In: Bioorganic and Medicinal Chemistry. 2015 ; Vol. 23, No. 24. pp. 7497-7520.
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