A guanine-rich strand within the promoter of the KRAS gene can fold into an intra-molecular G-qua... more A guanine-rich strand within the promoter of the KRAS gene can fold into an intra-molecular G-quadruplex structure (G4), which has an important role in the regulation of KRAS transcription. We have previously identified indolo[3,2-b]quinolines with a 7-carboxylate group and three alkylamine side chains (IQ3A) as effective G4 stabilizers and promising selective anticancer leads. Herein we investigated the anticancer mechanism of action of these compounds, which we hypothesized due to stabilization of the G4 sequence in the KRAS promoter and subsequent down-regulation of gene expression. IQ3A compounds showed greater stabilization of G4 compared to duplex DNA structures and reduced KRAS promoter activity in a dual luciferase reporter assay. Moreover, IQ3A compounds showed high anti-proliferative activity in HCT116 and SW620 colon cancer cells (IC50 < 2.69 μM), without eliciting cell death in non-malignant HEK293T human embryonic kidney, and human colon fibroblasts CCD18co. IQ3A com...
Journal of the Chemical Society, Perkin Transactions 2, 1991
... Acyloxymethyl as a drug protecting group. Kinetics and mechanism of the hydrolysis of N-acylo... more ... Acyloxymethyl as a drug protecting group. Kinetics and mechanism of the hydrolysis of N-acyloxymethylbenzamides. Jim Iley, Rui Moreira and Eduarda Rosa J. Chem. Soc., Perkin Trans. 2, 1991, 563-570. DOI: 10.1039/P29910000563 ...
A guanine-rich strand within the promoter of the KRAS gene can fold into an intra-molecular G-qua... more A guanine-rich strand within the promoter of the KRAS gene can fold into an intra-molecular G-quadruplex structure (G4), which has an important role in the regulation of KRAS transcription. We have previously identified indolo[3,2-b]quinolines with a 7-carboxylate group and three alkylamine side chains (IQ3A) as effective G4 stabilizers and promising selective anticancer leads. Herein we investigated the anticancer mechanism of action of these compounds, which we hypothesized due to stabilization of the G4 sequence in the KRAS promoter and subsequent down-regulation of gene expression. IQ3A compounds showed greater stabilization of G4 compared to duplex DNA structures and reduced KRAS promoter activity in a dual luciferase reporter assay. Moreover, IQ3A compounds showed high anti-proliferative activity in HCT116 and SW620 colon cancer cells (IC50 < 2.69 μM), without eliciting cell death in non-malignant HEK293T human embryonic kidney, and human colon fibroblasts CCD18co. IQ3A com...
Journal of the Chemical Society, Perkin Transactions 2, 1991
... Acyloxymethyl as a drug protecting group. Kinetics and mechanism of the hydrolysis of N-acylo... more ... Acyloxymethyl as a drug protecting group. Kinetics and mechanism of the hydrolysis of N-acyloxymethylbenzamides. Jim Iley, Rui Moreira and Eduarda Rosa J. Chem. Soc., Perkin Trans. 2, 1991, 563-570. DOI: 10.1039/P29910000563 ...
O-(N-alkylamido)methyl esters of penicillin G were studied as a new class of prodrugs. The hydrol... more O-(N-alkylamido)methyl esters of penicillin G were studied as a new class of prodrugs. The hydrolysis in aqueous buffers containing 20 % (v/v) of acetonitrile was investigated by HPLC. A U-shaped pH-rate profile was seen with a pH-independent process extending from pH ca. 2 to pH ca. 10. This pathway is characterised by kinetic data that are consistent with a unimolecular mechanism involving rate-limiting iminium ion formation and penicillinoate expulsion. Penicillin G and the corresponding amide are the ultimate products detected and isolated, indicating that beta-lactam ring opening is much slower than ester hydrolysis. The O-(N-alkylamido)methyl esters of penicillin G displayed similar in vitro antibacterial activity to penicillin G itself. Compared to the penicillin G derivatives, the much higher stability of the O-(N-methylbenzamido)methyl benzoate, acetate and valproate esters (which gave rise to a Bronsted Beta 1g value of ca. -1) suggests that tertiary N-acyloxymethylamides may be useful prodrugs for carboxylic acid drugs with pKa &gt; 4.
... Lugo and Peter G. Jones entro de Productos Naturales Organicos &quot;Antonio Gonzalez&... more ... Lugo and Peter G. Jones entro de Productos Naturales Organicos &quot;Antonio Gonzalez&quot;, CSICUniversidad de ... 11 AG Gonzalez, G. de la Fuente, and RD Acosta, Heterocygles, 22, 17 ... Press pic SYNTHESIS OF THE 12HYDROXY G1BBERELLINS GApGA AND GAQ Alex Chu and ...
... Synthesis of Tertiary NAcyloxymethylamide Prod rugs of Carboxylic Acid Drugs Rui Moreira*1, E... more ... Synthesis of Tertiary NAcyloxymethylamide Prod rugs of Carboxylic Acid Drugs Rui Moreira*1, Eduarda Mendes&#x27;, Teresa Calheiros1, Maria J. Bacelo&#x27;, Jim ... secondary amides with paraformaldehyde MeaSiCI Compound Rl R2 Yield() EIMSr I (M+2) M+ (MC1)4 2a Me Me 100 ...
A guanine-rich strand within the promoter of the KRAS gene can fold into an intra-molecular G-qua... more A guanine-rich strand within the promoter of the KRAS gene can fold into an intra-molecular G-quadruplex structure (G4), which has an important role in the regulation of KRAS transcription. We have previously identified indolo[3,2-b]quinolines with a 7-carboxylate group and three alkylamine side chains (IQ3A) as effective G4 stabilizers and promising selective anticancer leads. Herein we investigated the anticancer mechanism of action of these compounds, which we hypothesized due to stabilization of the G4 sequence in the KRAS promoter and subsequent down-regulation of gene expression. IQ3A compounds showed greater stabilization of G4 compared to duplex DNA structures and reduced KRAS promoter activity in a dual luciferase reporter assay. Moreover, IQ3A compounds showed high anti-proliferative activity in HCT116 and SW620 colon cancer cells (IC50 < 2.69 μM), without eliciting cell death in non-malignant HEK293T human embryonic kidney, and human colon fibroblasts CCD18co. IQ3A com...
Journal of the Chemical Society, Perkin Transactions 2, 1991
... Acyloxymethyl as a drug protecting group. Kinetics and mechanism of the hydrolysis of N-acylo... more ... Acyloxymethyl as a drug protecting group. Kinetics and mechanism of the hydrolysis of N-acyloxymethylbenzamides. Jim Iley, Rui Moreira and Eduarda Rosa J. Chem. Soc., Perkin Trans. 2, 1991, 563-570. DOI: 10.1039/P29910000563 ...
A guanine-rich strand within the promoter of the KRAS gene can fold into an intra-molecular G-qua... more A guanine-rich strand within the promoter of the KRAS gene can fold into an intra-molecular G-quadruplex structure (G4), which has an important role in the regulation of KRAS transcription. We have previously identified indolo[3,2-b]quinolines with a 7-carboxylate group and three alkylamine side chains (IQ3A) as effective G4 stabilizers and promising selective anticancer leads. Herein we investigated the anticancer mechanism of action of these compounds, which we hypothesized due to stabilization of the G4 sequence in the KRAS promoter and subsequent down-regulation of gene expression. IQ3A compounds showed greater stabilization of G4 compared to duplex DNA structures and reduced KRAS promoter activity in a dual luciferase reporter assay. Moreover, IQ3A compounds showed high anti-proliferative activity in HCT116 and SW620 colon cancer cells (IC50 < 2.69 μM), without eliciting cell death in non-malignant HEK293T human embryonic kidney, and human colon fibroblasts CCD18co. IQ3A com...
Journal of the Chemical Society, Perkin Transactions 2, 1991
... Acyloxymethyl as a drug protecting group. Kinetics and mechanism of the hydrolysis of N-acylo... more ... Acyloxymethyl as a drug protecting group. Kinetics and mechanism of the hydrolysis of N-acyloxymethylbenzamides. Jim Iley, Rui Moreira and Eduarda Rosa J. Chem. Soc., Perkin Trans. 2, 1991, 563-570. DOI: 10.1039/P29910000563 ...
O-(N-alkylamido)methyl esters of penicillin G were studied as a new class of prodrugs. The hydrol... more O-(N-alkylamido)methyl esters of penicillin G were studied as a new class of prodrugs. The hydrolysis in aqueous buffers containing 20 % (v/v) of acetonitrile was investigated by HPLC. A U-shaped pH-rate profile was seen with a pH-independent process extending from pH ca. 2 to pH ca. 10. This pathway is characterised by kinetic data that are consistent with a unimolecular mechanism involving rate-limiting iminium ion formation and penicillinoate expulsion. Penicillin G and the corresponding amide are the ultimate products detected and isolated, indicating that beta-lactam ring opening is much slower than ester hydrolysis. The O-(N-alkylamido)methyl esters of penicillin G displayed similar in vitro antibacterial activity to penicillin G itself. Compared to the penicillin G derivatives, the much higher stability of the O-(N-methylbenzamido)methyl benzoate, acetate and valproate esters (which gave rise to a Bronsted Beta 1g value of ca. -1) suggests that tertiary N-acyloxymethylamides may be useful prodrugs for carboxylic acid drugs with pKa &gt; 4.
... Lugo and Peter G. Jones entro de Productos Naturales Organicos &quot;Antonio Gonzalez&... more ... Lugo and Peter G. Jones entro de Productos Naturales Organicos &quot;Antonio Gonzalez&quot;, CSICUniversidad de ... 11 AG Gonzalez, G. de la Fuente, and RD Acosta, Heterocygles, 22, 17 ... Press pic SYNTHESIS OF THE 12HYDROXY G1BBERELLINS GApGA AND GAQ Alex Chu and ...
... Synthesis of Tertiary NAcyloxymethylamide Prod rugs of Carboxylic Acid Drugs Rui Moreira*1, E... more ... Synthesis of Tertiary NAcyloxymethylamide Prod rugs of Carboxylic Acid Drugs Rui Moreira*1, Eduarda Mendes&#x27;, Teresa Calheiros1, Maria J. Bacelo&#x27;, Jim ... secondary amides with paraformaldehyde MeaSiCI Compound Rl R2 Yield() EIMSr I (M+2) M+ (MC1)4 2a Me Me 100 ...
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