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

Derek C Medellin; Qiong Zhou; Robert Scott; R Matthew Hill; Sarah K Frail; Ramesh Dasari; Steven J Ontiveros; Stephen C Pelly; Willem A L van Otterlo; Tania Betancourt; Charles B Shuster; Ernest Hamel; Ruoli Bai; Daniel V LaBarbera; Snezna Rogelj; Liliya V Frolova; Alexander Kornienko

doi:10.1021/acs.jmedchem.5b01426

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. Epub 2015 Dec 17.

Authors

Derek C Medellin¹, Qiong Zhou², Robert Scott¹, R Matthew Hill¹, Sarah K Frail³, Ramesh Dasari¹, Steven J Ontiveros⁴, Stephen C Pelly⁵, Willem A L van Otterlo⁵, Tania Betancourt^{1

6}, Charles B Shuster⁴, Ernest Hamel⁷, Ruoli Bai⁷, Daniel V LaBarbera², Snezna Rogelj³, Liliya V Frolova³, Alexander Kornienko¹

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Colchicine / metabolism
Colonic Neoplasms / drug therapy
Drug Design
Drug Screening Assays, Antitumor
Female
Humans
Marine Toxins / chemistry*
Marine Toxins / pharmacology*
Mice
Mice, Nude
Models, Molecular
Molecular Docking Simulation
Structure-Activity Relationship
Tubulin / drug effects
Tubulin / metabolism
Tubulin Modulators / pharmacology
Xanthines / chemical synthesis*
Xanthines / pharmacology*

Substances

Antineoplastic Agents
Marine Toxins
Tubulin
Tubulin Modulators
Xanthines
Colchicine

Abstract

Publication types

MeSH terms

Substances

Grants and funding