Synthesis and biological evaluation of benzocyclooctene-based and indene-based anticancer agents that function as inhibitors of tubulin polymerization

Christine A. Herdman, Tracy E. Strecker, Rajendra P. Tanpure, Zhi Chen, Alex Winters, Jeni Gerberich, Li Liu, Ernest Hamel, Ralph P. Mason, David J. Chaplin, Mary Lynn Trawick, Kevin G. Pinney

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The natural products colchicine and combretastatin A-4 (CA4) have been inspirational for the design and synthesis of structurally related analogues and spin-off compounds as inhibitors of tubulin polymerization. The discovery that a water-soluble phosphate prodrug salt of CA4 (referred to as CA4P) is capable of imparting profound and selective damage to tumor-associated blood vessels paved the way for the development of a new therapeutic approach for cancer treatment utilizing small-molecule inhibitors of tubulin polymerization that also act as vascular disrupting agents (VDAs). Combination of salient structural features associated with colchicine and CA4 led to the design and synthesis of a variety of fused aryl-cycloalkyl and aryl-heterocyclic compounds that function as inhibitors of tubulin polymerization. Prominent among these compounds is a benzosuberene analogue (referred to as KGP18), which demonstrates sub-nM cytotoxicity against human cancer cell lines and functions (when administered as a water-soluble prodrug salt) as a VDA in mouse models. Structure activity relationship considerations led to the evaluation of benzocyclooctyl [6,8 fused] and indene [6,5 fused] ring systems. Four benzocyclooctene and four indene analogues were prepared and evaluated biologically. Three of the benzocyclooctene analogues were active as inhibitors of tubulin polymerization (IC50 < 5 μM), and benzocyclooctene phenol 23 was comparable to KGP18 in terms of potency. The analogous indene-based compound 31 also functioned as an inhibitor of tubulin polymerization (IC50 = 11 μM) with reduced potency. The most potent inhibitor of tubulin polymerization from this group was benzocyclooctene analogue 23, and it was converted to its water-soluble prodrug salt 24 to assess its potential as a VDA. Preliminary in vivo studies, which utilized the MCF7-luc-GFP-mCherry breast tumor in a SCID mouse model, demonstrated that treatment with 24 (120 mg kg−1) resulted in significant vascular shutdown, as evidenced by bioluminescence imaging at 4 h post administration, and that the effect continued at both 24 and 48 h. Contemporaneous studies with CA4P, a clinically relevant VDA, were carried out as a positive control.

Original languageEnglish (US)
Pages (from-to)2418-2427
Number of pages10
JournalMedChemComm
Volume7
Issue number12
DOIs
StatePublished - 2016

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Tubulin Modulators
Antineoplastic Agents
Blood Vessels
Prodrugs
Salts
Colchicine
Inhibitory Concentration 50
Water
Tumors
Vascular Tissue Neoplasms
Bioluminescence
Heterocyclic Compounds
Oncology
SCID Mice
Blood vessels
Structure-Activity Relationship
Cytotoxicity
Phenol
Biological Products
indene

ASJC Scopus subject areas

  • Biochemistry
  • Pharmaceutical Science

Cite this

Herdman, C. A., Strecker, T. E., Tanpure, R. P., Chen, Z., Winters, A., Gerberich, J., ... Pinney, K. G. (2016). Synthesis and biological evaluation of benzocyclooctene-based and indene-based anticancer agents that function as inhibitors of tubulin polymerization. MedChemComm, 7(12), 2418-2427. https://doi.org/10.1039/c6md00459h

Synthesis and biological evaluation of benzocyclooctene-based and indene-based anticancer agents that function as inhibitors of tubulin polymerization. / Herdman, Christine A.; Strecker, Tracy E.; Tanpure, Rajendra P.; Chen, Zhi; Winters, Alex; Gerberich, Jeni; Liu, Li; Hamel, Ernest; Mason, Ralph P.; Chaplin, David J.; Trawick, Mary Lynn; Pinney, Kevin G.

In: MedChemComm, Vol. 7, No. 12, 2016, p. 2418-2427.

Research output: Contribution to journalArticle

Herdman, CA, Strecker, TE, Tanpure, RP, Chen, Z, Winters, A, Gerberich, J, Liu, L, Hamel, E, Mason, RP, Chaplin, DJ, Trawick, ML & Pinney, KG 2016, 'Synthesis and biological evaluation of benzocyclooctene-based and indene-based anticancer agents that function as inhibitors of tubulin polymerization', MedChemComm, vol. 7, no. 12, pp. 2418-2427. https://doi.org/10.1039/c6md00459h
Herdman, Christine A. ; Strecker, Tracy E. ; Tanpure, Rajendra P. ; Chen, Zhi ; Winters, Alex ; Gerberich, Jeni ; Liu, Li ; Hamel, Ernest ; Mason, Ralph P. ; Chaplin, David J. ; Trawick, Mary Lynn ; Pinney, Kevin G. / Synthesis and biological evaluation of benzocyclooctene-based and indene-based anticancer agents that function as inhibitors of tubulin polymerization. In: MedChemComm. 2016 ; Vol. 7, No. 12. pp. 2418-2427.
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