PubMed · 10703328
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K A Hoyer. 1999. Fluorouracil.. https://pubmed.ncbi.nlm.nih.gov/10703328/
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Exposure of lung cancer cells to gemcitabine (2',2'-difluorodeoxycytidine) arrests cells in S phase and induces secondary apoptotic cell death. Gemcitabine treatment decreased the expression of IkappaB-alpha protein and, concomitantly, increased the activity of nuclear factor-kappaB (NF-kappaB) transcription factor, a known inhibitor of the apoptotic response. This increase was accompanied by a similar increment in the expression of inhibitor of apoptosis-1 (IAP-1) protein and mRNA, a caspase inhibitor responsive to NF-kappaB. These changes were important to the final destiny of the cells, since overexpression of a dominant negative version of IkappaB-alpha, which suppresses NF-kappaB activation, blocks the increase of IAP-1 protein and potentiates the action of gemcitabine. Additionally, overexpression of IAP-1 protein in A549 cells expressing the IkappaB-alpha mutant restored the initial sensitivity to gemcitabine and demonstrated that this protein was responsible for the inhibitory effect of NF-kappaB. These results support the notion of IAP-1 as an important antiapoptotic protein mediating sensitivity to deoxynucleotides analogs in non-small-cell lung cancer cells.
Alkylation of various primary amines with crotyl bromide, followed by DMAP-promoted acylation with methyl malonyl chloride to 4 and then manganic triacetate dihydrate/cupric acetate induced radical cyclization, gave 1-substituted-4-vinyl-3-carbomethoxy-2-pyrrolidinones (5). Thiation to the thiolactams 6 and guanidine cyclization then gave a series of 2-amino-3,4-dihydro-4-oxo-5-vinyl-7-substituted pyrrolo[2,3-d]pyrimidines (7). Palladium-catalyzed C-C coupling with diethyl 4-iodobenzoylglutamate led in one step via an unexpected redox reaction to the diethyl esters 9 of a series of 7-substituted derivatives of ALIMTA (LY231514, MTA), from which the target analogues 10 were readily prepared by saponification. Attempted deprotection at position 7 was successful in only one case (9d, R = CH(2)C(6)H(3)(OMe)(2)(-3',4'), which resulted in a known pentultimate precursor (9, R = H) of ALIMTA. The 7-substituted derivatives 10 proved to be inactive in vitro as inhibitors of cell division.
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