Anticancer Properties of Halogenated Pyrrolo[3,2-d]pyrimidines with Decreased Toxicity via N5 Substitution
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Cawrse, Brian M., Rena S. Lapidus, Brandon Cooper, Eun Yong Choi, and Katherine L. Seley-Radtke. “Anticancer Properties of Halogenated Pyrrolo[3,2-d]Pyrimidines with Decreased Toxicity via N5 Substitution.” ChemMedChem 13, no. 2 (2018): 178–85. https://doi.org/10.1002/cmdc.201700641.
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This is the peer reviewed version of the following article: Cawrse, Brian M., Rena S. Lapidus, Brandon Cooper, Eun Yong Choi, and Katherine L. Seley-Radtke. “Anticancer Properties of Halogenated Pyrrolo[3,2-d]Pyrimidines with Decreased Toxicity via N5 Substitution.” ChemMedChem 13, no. 2 (2018): 178–85. https://doi.org/10.1002/cmdc.201700641., which has been published in final form at https://doi.org/10.1002/cmdc.201700641. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited
Abstract
Halogenated pyrrolo[3,2-d]pyrimidine analogues have shown antiproliferative activity in recent studies, with cell accumulation occurring in the G₂/M stage without apoptosis. However, the mechanism of action and pharmacokinetic (PK) profile of these compounds has yet to be determined. To investigate the PK profile of these compounds, a series of halogenated pyrrolo[3,2-d]pyrimidine compounds was synthesized and first tested for activity in various cancer cell lines followed by a mouse model. EC₅₀ values ranged from 0.014 to 14.5 μm, and maximum tolerated doses (MTD) in mice were between 5 and 10 mg kg⁻¹. This indicates a wide variance in activity and toxicity that necessitates further study. To decrease toxicity, a second series of compounds was synthesized with N5-alkyl substitutions in an effort to slow the rate of metabolism, which was thought to be leading to the toxicity. The N-substituted compounds demonstrated comparable cell line activity (EC₅₀ values between 0.83–7.3 μm) with significantly decreased toxicity (MTD=40 mg kg⁻¹). Finally, the PK profile of the active N5-substituted compound shows a plasma half-life of 32.7 minutes, and rapid conversion into the parent unsubstituted analogue. Together, these data indicate that halogenated pyrrolo[3,2-d]pyrimidines present a promising lead into potent antiproliferative agents with tunable activity and toxicity, and rapid metabolism.