- EIF4E-INHIBITING 4-OXO-3,4-DIHYDROPYRIDO[3,4-D]PYRIMIDINE COMPOUNDS
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The present invention provides synthesis, pharmaceutically acceptable formulations and uses of compounds in accordance with Formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. For Formula I compounds X1, X2, X3, X4, X5, X6, Q, L1, L2, Y, R1, R2, R3, R4, R5, R6, R7, R8 and rings A, B and C are as defined in the specification. The inventive Formula I compounds are inhibitors of eIF4e and find utility in any number of therapeutic applications, including but not limited to treatment of inflammation and various cancers.
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Paragraph 0405; 0442
(2021/01/23)
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- Anticancer Properties of Halogenated Pyrrolo[3,2-d]pyrimidines with Decreased Toxicity via N5 Substitution
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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.
- Cawrse, Brian M.,Lapidus, Rena S.,Cooper, Brandon,Choi, Eun Yong,Seley-Radtke, Katherine L.
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p. 178 - 185
(2017/12/26)
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- THIENO- AND PYRROLOPYRIMIDINE ANALOGUES AS ANTICANCER AGENTS AND METHODS OF USE THEREOF
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The present invention provides for the design and synthesis of halogenated thieno- and pyrrolopyrimidine compounds that exhibit cancer proliferation inhibitory activity and the use thereof for cancer treatment.
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Paragraph 0071-0072
(2016/09/26)
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- Antiproliferative activities of halogenated pyrrolo[3,2-d]pyrimidines
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In vitro evaluation of the halogenated pyrrolo[3,2-d]pyrimidines identified antiproliferative activities in compounds 1 and 2 against four different cancer cell lines. Upon screening of a series of pyrrolo[3,2-d]pyrimidines, the 2,4-Cl compound 1 was foun
- Temburnikar, Kartik W.,Ross, Christina R.,Wilson, Gerald M.,Balzarini, Jan,Cawrse, Brian M.,Seley-Radtke, Katherine L.
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p. 4354 - 4363
(2015/08/03)
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- C-Functionalization of 9-deazapurines by cross-coupling reactions
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C-Functionalization of pyrrolo[3,2-d]pyrimidine scaffold in positions 2, 4, and 7 using cross-coupling reactions was performed. Thus, 2-(5-(benzyloxymethyl)-2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)ethanol, a versatile synthetic precursor for 9-deazapurines and?4,6-diazaindoles, was prepared by vinylation of the corresponding iodide followed by hydroboration of the double bond. A synthesis of 9-(1,2-dihydroxyethyl)-9-deazaadenine, a 9-deaza-1′-nor congener to antiviral DHPA, was developed. In addition, an abnormal regioselectivity in methylalumination of the terminal triple bond in position 7 of the pyrrolo[3,2-d]pyrimidine scaffold leading to a transformation into (Z)-prop-1-enyl was observed.
- Bambuch, Vítězslav,Otmar, Miroslav,Pohl, Radek,Masojídková, Milena,Holy, Antonín
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p. 1589 - 1601
(2007/10/03)
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