Design, Synthesis and Anticancer Activity Against the MCF-7 Cell Line of Benzo-Fused 1,4-Dihetero Seven- and Six-Membered Tethered Pyrimidines and Purines

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Abstract:

Having previously reported the synthesis and anticancer activities of cyclic 5-fluorouracil (5-FU) O,N-acetalic compounds, the decision was made to change 5-FU for uracil (U), with the prospect of finding an antiproliferative agent endowed with a new mechanism of action. The use of a reverse transcription-PCR-based assay decreased cyclin D1 mRNA, suggesting that this cyclic U O,N-acetalic compound exerts its regulatory action on cyclin D1 at the level of transcription. Following the ongoing Anticancer Drug Programme we planned the synthesis of compounds bearing a natural pyrimidine base and also, the oxygen atom at position 1 of the seven-membered cycle was replaced by its isosteric sulfur atom, and its oxidized states. Next, the pyrimidine base was substituted for the purine one, with the objective of increasing both the lipophilicity and the structural diversity of the target molecules. If the previously described compounds were not prodrugs, it would not be necessary to maintain the O,N-acetalic characteristic. Therefore, molecules were designed in which both structural entities (such as the benzoheterocyclic ring and the purine base) were linked by a heteroatom-C-C-N bond. A series of (RS)-9-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-9H-purine derivatives was obtained and the anticancer activity for the most active compounds was correlated with their capability to induce apoptosis. Finally, completing a SAR study, a series of (RS)-6-substituted-7- or 9-(1,2,3,5-tetrahydro-4,1-benzoxazepine-3-yl)-7H- or 9H-purines was prepared. The studies by microarray technology showed that the main molecular targets of some of these compounds are proapoptotic genes with protein kinase activity such as GP132, ERN1 or RAC1, which prevent the metastatic progression.

Keywords: Antitumour compounds; benzoxadioxepins; benzoxathiepins; benzoxathiins; benzoxazepines; breast cancer; purines; pyrimidines

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986708785909021

Affiliations: Departamento de Quimica Farmaceutica y Organica, Facultad de Farmacia, c/ Campus de Cartuja, s/n, 18071 Granada, Spain.

Publication date: October 1, 2008

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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