Synthesis and biological activity of 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl regioisomers as inhibitors of de novo purine biosynthesis with selectivity for cellular uptake by high affinity folate receptors and the proton-coupled folate transporter over the reduced folate carrier.
J Med Chem
; 55(4): 1758-70, 2012 Feb 23.
Article
em En
| MEDLINE
| ID: mdl-22243528
ABSTRACT
We previously reported the selective transport of classical 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidines with a thienoyl-for-benzoyl-substituted side chain and a three- (3a) and four-carbon (3b) bridge. Compound 3a was more potent than 3b against tumor cells. While 3b was completely selective for transport by folate receptors (FRs) and the proton-coupled folate transporter (PCFT) over the reduced folate carrier (RFC), 3a was not. To determine if decreasing the distance between the bicyclic scaffold and l-glutamate in 3b would preserve transport selectivity and potency against human tumor cells, 3b regioisomers with [1,3] (7 and 8) and [1,2] (4, 5, and 6) substitutions on the thienoyl ring and with acetylenic insertions in the four-atom bridge were synthesized and evaluated. Compounds 7 and 8 were potent nanomolar inhibitors of KB and IGROV1 human tumor cells with complete selectivity for FRα and PCFT over RFC.
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Base de dados:
MEDLINE
Assunto principal:
Purinas
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Pirimidinas
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Pirróis
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Tiofenos
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Receptor 1 de Folato
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Transportador de Folato Acoplado a Próton
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Proteína Carregadora de Folato Reduzido
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Antineoplásicos
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article