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1.
J Biol Chem ; 288(48): 34746-54, 2013 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-24158442

RESUMEN

The survival and proliferation of Plasmodium falciparum parasites and human cancer cells require de novo pyrimidine synthesis to supply RNA and DNA precursors. Orotate phosphoribosyltransferase (OPRT) is an indispensible component in this metabolic pathway and is a target for antimalarials and antitumor drugs. P. falciparum (Pf) and Homo sapiens (Hs) OPRTs are characterized by highly dissociative transition states with ribocation character. On the basis of the geometrical and electrostatic features of the PfOPRT and HsOPRT transition states, analogues were designed, synthesized, and tested as inhibitors. Iminoribitol mimics of the ribocation transition state in linkage to pyrimidine mimics using methylene or ethylene linkers gave dissociation constants (Kd) as low as 80 nM. Inhibitors with pyrrolidine groups as ribocation mimics displayed slightly weaker binding affinities for OPRTs. Interestingly, p-nitrophenyl riboside 5'-phosphate bound to OPRTs with Kd values near 40 nM. Analogues designed with a C5-pyrimidine carbon-carbon bond to ribocation mimics gave Kd values in the range of 80-500 nM. Acyclic inhibitors with achiral serinol groups as the ribocation mimics also displayed nanomolar inhibition against OPRTs. In comparison with the nucleoside derivatives, inhibition constants of their corresponding 5'-phosphorylated transition state analogues are largely unchanged, an unusual property for a nucleotide-binding site. In silico docking of the best inhibitor into the HsOPRT active site supported an extensive hydrogen bond network associated with the tight binding affinity. These OPRT transition state analogues identify crucial components of potent inhibitors targeting OPRT enzymes. Despite their tight binding to the targets, the inhibitors did not kill cultured P. falciparum.


Asunto(s)
Malaria/enzimología , Redes y Vías Metabólicas , Orotato Fosforribosiltransferasa/química , Plasmodium falciparum/química , Pirimidinas/biosíntesis , Antimaláricos/química , Sitios de Unión , Humanos , Enlace de Hidrógeno , Cinética , Malaria/tratamiento farmacológico , Malaria/parasitología , Nucleósidos , Orotato Fosforribosiltransferasa/genética , Orotato Fosforribosiltransferasa/metabolismo , Plasmodium falciparum/enzimología , Plasmodium falciparum/metabolismo , Conformación Proteica , Pirimidinas/química , Pirrolidinas/farmacología , Especificidad por Sustrato
2.
Bioorg Med Chem ; 21(17): 5629-46, 2013 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-23810424

RESUMEN

The pathogenic protozoa responsible for malaria lack enzymes for the de novo synthesis of purines and rely on purine salvage from the host. In Plasmodium falciparum (Pf), hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) converts hypoxanthine to inosine monophosphate and is essential for purine salvage making the enzyme an anti-malarial drug target. We have synthesized a number of simple acyclic aza-C-nucleosides and shown that some are potent inhibitors of Pf HGXPRT while showing excellent selectivity for the Pf versus the human enzyme.


Asunto(s)
Antimaláricos/química , Inhibidores Enzimáticos/química , Nucleósidos/química , Pentosiltransferasa/antagonistas & inhibidores , Plasmodium falciparum/enzimología , Antimaláricos/síntesis química , Antimaláricos/farmacología , Compuestos Aza/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Cinética , Nucleósidos/síntesis química , Nucleósidos/farmacología , Pentosiltransferasa/metabolismo , Plasmodium falciparum/efectos de los fármacos , Unión Proteica
3.
J Med Chem ; 65(7): 5462-5494, 2022 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-35324190

RESUMEN

Hypermethylation of CpG regions by human DNA methyltransferase 1 (DNMT1) silences tumor-suppression genes, and inhibition of DNMT1 can reactivate silenced genes. The 5-azacytidines are approved inhibitors of DNMT1, but their mutagenic mechanism limits their utility. A synthon approach from the analogues of S-adenosylhomocysteine, methionine, and deoxycytidine recapitulated the chemical features of the DNMT1 transition state in the synthesis of 16 chemically stable transition-state mimics. Inhibitors causing both full and partial inhibition of purified DNMT1 were characterized. The inhibitors show modest selectivity for DNMT1 versus DNMT3b. Active-site docking predicts inhibitor interactions with S-adenosyl-l-methionine and deoxycytidine regions of the catalytic site, validated by direct binding analysis. Inhibitor action with purified DNMT1 is not reflected in cultured cells. A partial inhibitor activated cellular DNA methylation, and a full inhibitor had no effect on cellular DNA methylation. These compounds provide chemical access to a new family of noncovalent DNMT chemical scaffolds for use in DNA methyltransferases.


Asunto(s)
ADN (Citosina-5-)-Metiltransferasas , Metilación de ADN , Línea Celular , ADN/metabolismo , ADN (Citosina-5-)-Metiltransferasa 1/metabolismo , Metilasas de Modificación del ADN/metabolismo , Desoxicitidina/metabolismo , Humanos
4.
Chem Biol ; 19(6): 721-30, 2012 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-22726686

RESUMEN

Plasmodium falciparum, the primary cause of deaths from malaria, is a purine auxotroph and relies on hypoxanthine salvage from the host purine pool. Purine starvation as an antimalarial target has been validated by inhibition of purine nucleoside phosphorylase. Hypoxanthine depletion kills Plasmodium falciparum in cell culture and in Aotus monkey infections. Hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) from P. falciparum is required for hypoxanthine salvage by forming inosine 5'-monophosphate, a branchpoint for all purine nucleotide synthesis in the parasite. Here, we present a class of HGXPRT inhibitors, the acyclic immucillin phosphonates (AIPs), and cell permeable AIP prodrugs. The AIPs are simple, potent, selective, and biologically stable inhibitors. The AIP prodrugs block proliferation of cultured parasites by inhibiting the incorporation of hypoxanthine into the parasite nucleotide pool and validates HGXPRT as a target in malaria.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Organofosfonatos/farmacología , Pentosiltransferasa/antagonistas & inhibidores , Plasmodium falciparum/efectos de los fármacos , Profármacos/farmacología , Dominio Catalítico/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Eritrocitos/efectos de los fármacos , Humanos , Modelos Moleculares , Conformación Molecular , Organofosfonatos/síntesis química , Organofosfonatos/química , Pentosiltransferasa/genética , Pentosiltransferasa/metabolismo , Plasmodium falciparum/enzimología , Plasmodium falciparum/metabolismo , Profármacos/síntesis química , Profármacos/química , Relación Estructura-Actividad
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