Novel Microtubule-Targeting 7-Deazahypoxanthines Derived from Marine Alkaloid Rigidins with Potent in Vitro and in Vivo Anticancer Activities

  • J Med Chem. 2016 Jan 14;59(1):480-5. doi: 10.1021/acs.jmedchem.5b01426.
Derek C Medellin  1 ,  Qiong Zhou  2 ,  Robert Scott  1 ,  R Matthew Hill  1 ,  Sarah K Frail  3 ,  Ramesh Dasari  1 ,  Steven J Ontiveros  4 ,  Stephen C Pelly  5 ,  Willem A L van Otterlo  5 ,  Tania Betancourt  1  6 ,  Charles B Shuster  4 ,  Ernest Hamel  7 ,  Ruoli Bai  7 ,  Daniel V LaBarbera  2 ,  Snezna Rogelj  3 ,  Liliya V Frolova  3 ,  Alexander Kornienko  1
Affiliations
  • 1. Department of Chemistry and Biochemistry, Texas State University , San Marcos, Texas 78666, United States.
  • 2. Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus , Aurora, Colorado 80045, United States.
  • 3. Departments of Chemistry and Biology, New Mexico Tech , Socorro, New Mexico 87801, United States.
  • 4. Department of Biology, New Mexico State University , Las Cruces, New Mexico 88003, United States.
  • 5. Department of Chemistry and Polymer Science, Stellenbosch University , Stellenbosch, Western Cape, South Africa.
  • 6. Materials Science, Engineering, and Commercialization Program, Texas State University , San Marcos, Texas 78666, United States.
  • 7. Screening Technologies Branch, Developmental Therapeutics Program, National Cancer Institute, Frederick National Laboratory of Cancer Research, National Institutes of Health, Frederick, Maryland 21702, United States.
PMID: 26641132 DOI: 10.1021/acs.jmedchem.5b01426
Abstract

Docking studies of tubulin-targeting C2-substituted 7-deazahypoxanthine analogues of marine alkaloid rigidins led to the design and synthesis of compounds containing linear C2-substituents. The C2-alkynyl analogue was found to have double- to single-digit nanomolar antiproliferative IC50 values and showed statistically significant tumor size reduction in a colon Cancer mouse model at nontoxic concentrations. These results provide impetus and further guidance for the development of these rigidin analogues as Anticancer agents.

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