2. Academic Validation
  3. Synthesis and biological evaluation of structurally diverse 6-aryl-3-aroyl-indole analogues as inhibitors of tubulin polymerization

Synthesis and biological evaluation of structurally diverse 6-aryl-3-aroyl-indole analogues as inhibitors of tubulin polymerization

  • Eur J Med Chem. 2024 Jan 5:263:115794. doi: 10.1016/j.ejmech.2023.115794.
Wen Ren 1,  Yuling Deng 2,  Jacob D Ward 3,  Rebecca Vairin 4,  Ruoli Bai 5,  Hashini I Wanniarachchi 6,  Khagendra B Hamal 7,  Pouguiniseli E Tankoano 8,  Caleb S Tamminga 9,  Lorena M A Bueno 10,  Ernest Hamel 11,  Ralph P Mason 12,  Mary Lynn Trawick 13,  Kevin G Pinney 14
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, Baylor University, One Bear Place, No. 97348, Waco, TX, 76798-7348, United States. Electronic address: Wen_Ren1@baylor.edu.
  • 2 Department of Chemistry and Biochemistry, Baylor University, One Bear Place, No. 97348, Waco, TX, 76798-7348, United States. Electronic address: Yuling_Deng@baylor.edu.
  • 3 Department of Chemistry and Biochemistry, Baylor University, One Bear Place, No. 97348, Waco, TX, 76798-7348, United States. Electronic address: Jake_Ward1@alumni.baylor.edu.
  • 4 Department of Chemistry and Biochemistry, Baylor University, One Bear Place, No. 97348, Waco, TX, 76798-7348, United States. Electronic address: Rebecca_Vairin@baylor.edu.
  • 5 Molecular Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, MD, 21702, United States. Electronic address: bair@nih.gov.
  • 6 Department of Radiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390-9058, United States. Electronic address: Hashini.Wanniarachchi@UTSouthwestern.edu.
  • 7 Department of Chemistry and Biochemistry, Baylor University, One Bear Place, No. 97348, Waco, TX, 76798-7348, United States. Electronic address: Khagendra_Hamal@baylor.edu.
  • 8 Department of Chemistry and Biochemistry, Baylor University, One Bear Place, No. 97348, Waco, TX, 76798-7348, United States. Electronic address: Elyse_Tankoano1@baylor.edu.
  • 9 Department of Chemistry and Biochemistry, Baylor University, One Bear Place, No. 97348, Waco, TX, 76798-7348, United States. Electronic address: Caleb_Tamminga1@baylor.edu.
  • 10 Department of Radiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390-9058, United States. Electronic address: Lorena.Arango@UTSouthwestern.edu.
  • 11 Molecular Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, MD, 21702, United States. Electronic address: hamele@dc37a.nci.nih.gov.
  • 12 Department of Radiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390-9058, United States. Electronic address: Ralph.Mason@UTSouthwestern.edu.
  • 13 Department of Chemistry and Biochemistry, Baylor University, One Bear Place, No. 97348, Waco, TX, 76798-7348, United States. Electronic address: Mary_Lynn_Trawick@baylor.edu.
  • 14 Department of Chemistry and Biochemistry, Baylor University, One Bear Place, No. 97348, Waco, TX, 76798-7348, United States. Electronic address: Kevin_Pinney@baylor.edu.
PMID: 37984295 DOI: 10.1016/j.ejmech.2023.115794
Abstract

The synthesis and evaluation of small-molecule inhibitors of tubulin polymerization remains a promising approach for the development of new therapeutic agents for Cancer treatment. The natural products colchicine and combretastatin A-4 (CA4) inspired significant drug discovery campaigns targeting the colchicine site located on the beta-subunit of the tubulin heterodimer, but so far these efforts have not yielded an approved drug for Cancer treatment in human patients. Interest in the colchicine site was enhanced by the discovery that a subset of colchicine site agents demonstrated dual functionality as both potent antiproliferative agents and effective vascular disrupting agents (VDAs). Our previous studies led to the discovery and development of a 2-aryl-3-aroyl-indole analogue (OXi8006) that inhibited tubulin polymerization and demonstrated low nM IC50 values against a variety of human Cancer cell lines. A water-soluble phosphate prodrug salt (OXi8007), synthesized from OXi8006, displayed promising vascular disrupting activity in mouse models of Cancer. To further extend structure-activity relationship correlations, a series of 6-aryl-3-aroyl-indole analogues was synthesized and evaluated for their inhibition of tubulin polymerization and cytotoxicity against human Cancer cell lines. Several structurally diverse molecules in this small library were strong inhibitors of tubulin polymerization and of MCF-7 and MDA-MB-231 human breast Cancer cells. One of the most promising analogues (KGP591) caused significant G2/M arrest of MDA-MB-231 cells, disrupted microtubule structure and cell morphology in MDA-MB-231 cells, and demonstrated significant inhibition of MDA-MB-231 cell migration in a wound healing (scratch) assay. A phosphate prodrug salt, KGP618, synthesized from its parent phenolic precursor, KGP591, demonstrated significant reduction in bioluminescence signal when evaluated in vivo against an orthotopic model of kidney Cancer (RENCA-luc) in BALB/c mice, indicative of VDA efficacy. The most active compounds from this series offer promise as Anticancer therapeutic agents.

Keywords

Antiproliferative agents; Indole synthesis; Inhibitors of cell migration; Inhibitors of tubulin polymerization; Molecular docking; Vascular disrupting agents.

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