2. Academic Validation
  3. Simple monocyclic pyrimidine analogs as microtubule targeting agents binding to the colchicine site

Simple monocyclic pyrimidine analogs as microtubule targeting agents binding to the colchicine site

  • Bioorg Med Chem. 2023 Mar 15:82:117217. doi: 10.1016/j.bmc.2023.117217.
Shruti Choudhary 1,  Krishna Kaku 1,  Andrew J Robles 2,  Ernest Hamel 3,  Susan L Mooberry 4,  Aleem Gangjee 5
Affiliations

Affiliations

  • 1 Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh PA 15282, United States.
  • 2 Department of Pharmacology and the Mays Cancer Center, University of Texas Health Science Center, San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States.
  • 3 Molecular Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, United States.
  • 4 Department of Pharmacology and the Mays Cancer Center, University of Texas Health Science Center, San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, United States. Electronic address: mooberry@uthscsa.edu.
  • 5 Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh PA 15282, United States. Electronic address: gangjee@duq.edu.
PMID: 36889150 DOI: 10.1016/j.bmc.2023.117217
Abstract

Complex Natural Products that bind to tubulin/microtubules come under the broad category of microtubule binding agents. The design of simplified analogs of previously reported bicyclic, microtubule depolymerizer, pyrrolo[2,3-d]pyrimidine, provided valuable structure-activity relationship data and led to the identification of novel monocyclic pyrimidine analogs of which 12 was 47-fold more potent (EC50 123 nM) for cellular microtubule depolymerization activity and 7.5-fold more potent (IC50 24.4 nM) at inhibiting the growth of MDA-MB-435 Cancer cells, suggesting significantly better binding of the target within the colchicine site of tubulin compared to lead compound 1. This compound and Others of this series of monocyclic pyrimidine analogs were able to overcome multidrug resistance due to the expression of the βIII-isotype of tubulin and P-glycoprotein. In vivo evaluation of the most potent analog 12 in an MDA-MB-435 xenograft mouse model indicated, along with paclitaxel, that both compounds showed a trend towards lower tumor volume however neither compound showed significant antitumor activity in the trial. To our knowledge these are the first examples of simple substituted monocyclic pyrimidines as colchicine site binding antitubulin compounds with potent antitumor activity.

Keywords

Colchicine site agents; Cytotoxins; Microtubule targeting agents; Pyrimidines.

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