Novel Water-Soluble Substituted Pyrrolo[3,2-d]pyrimidines: Design, Synthesis, and Biological Evaluation as Antitubulin Antitumor Agents
- 429 Downloads
To study the effects of a regioisomeric change on the biological activities of previously reported water soluble, colchicine site binding, microtubule depolymerizing agents.
Nine pyrrolo[3,2-d]pyrimidines were designed and synthesized. The importance of various substituents was evaluated. Their abilities to cause cellular microtubule depolymerization, inhibit proliferation of MDA-MB-435 tumor cells and inhibit colchicine binding to tubulin were studied. One of the compounds was also evaluated in the National Cancer Institute preclinical 60 cell line panel.
Pyrrolo[3,2-d]pyrimidine analogs were more potent than their pyrrolo[2,3-d]pyrimidine regioisomers. We identified compounds with submicromolar potency against cellular proliferation. The structure-activity relationship study gave insight into substituents that were crucial for activity and those that improved activity. The compound tested in the NCI 60 cell line is a 2-digit nanomolar (GI50) inhibitor of 8 tumor cell lines.
We have identified substituted pyrrolo[3,2-d]pyrimidines that are water-soluble colchicine site microtubule depolymerizing agents. These compounds serve as leads for further optimization.
KEY WORDSantitubulin colchicine-site binders drug design microtubule depolymerizer pyrrolo[3,2-d]pyrimidines
Acknowledgments and Disclosures
National Cancer Institute for performing the in vitro antitumor evaluation in their 60 tumor preclinical screening program.
Grant from the National Institute of Health, National Cancer Institute, CA142868 (AG,SLM).
NSF equipment grant for the NMR (NMR: CHE 0614785) and the CTRC Cancer Center Support Grant, P30 CA054174
- 2.Gangjee A, Zhao Y, Lin L, Raghavan S, Roberts EG, Risinger AL, et al. Corrections to synthesis and discovery of water-soluble microtubule targeting agents that bind to the colchicine site on tubulin and circumvent Pgp mediated resistance. J Med Chem 2011;54(3):913.Google Scholar
- 10.Sizova OS, Modnikova GA, Glushkov RG, Solov'eva NP, Ryabokon NA, Chernov VA, et al. Synthesis and biological activity of 4,7-substituted pyrrolo[3,2-d]pyrimidines. Khim-Farm Zh. 1984;18:958–62.Google Scholar
- 11.Gangjee A, Li W, Yang J, Kisliuk RL. Design, synthesis, and biological evaluation of classical and nonclassical 2-amino-4-oxo-5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors. J Med Chem. 2008;51(1):68–76.PubMedCrossRefGoogle Scholar
- 13.Stadlwieser J, Schmidt B, Bernsmann H, Dunkern T, Benediktus E, Pahl A, et al. inventors; Nycomed GmbH, Germany. assignee. Methylpyrrolopyrimidinecarboxamides as phosphodiesterase type 5 inhibitors and their preparation and use in the treatment of diseases. Patent WO2011023693A1. 2011.Google Scholar
- 22.Verdier-Pinard P, Lai J-Y, Yoo H-D, Yu J, Marquez B, Nagle DG, et al. Structure-activity analysis of the interaction of curacin A, the potent colchicine site antimitotic agent, with tubulin and effects of analogs on the growth of MCF-7 breast cancer cells. Mol Pharmacol. 1998;53(1):62–76.PubMedGoogle Scholar