72155-09-0Relevant academic research and scientific papers
Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis
Golani, Lalit K.,Wallace-Povirk, Adrianne,Deis, Siobhan M.,Wong, Jennifer,Ke, Jiyuan,Gu, Xin,Raghavan, Sudhir,Wilson, Mike R.,Li, Xinxin,Polin, Lisa,De Waal, Parker W.,White, Kathryn,Kushner, Juiwanna,O'Connor, Carrie,Hou, Zhanjun,Xu, H. Eric,Melcher, Karsten,Dann, Charles E.,Matherly, Larry H.,Gangjee, Aleem
, p. 7856 - 7876 (2016/10/12)
Targeted antifolates with heteroatom replacements of the carbon vicinal to the phenyl ring in 1 by N (4), O (8), or S (9), or with N-substituted formyl (5), acetyl (6), or trifluoroacetyl (7) moieties, were synthesized and tested for selective cellular uptake by folate receptor (FR) α and β or the proton-coupled folate transporter. Results show increased in vitro antiproliferative activity toward engineered Chinese hamster ovary cells expressing FRs by 4-9 over the CH2 analogue 1. Compounds 4-9 inhibited de novo purine biosynthesis and glycinamide ribonucleotide formyltransferase (GARFTase). X-ray crystal structures for 4 with FRα and GARFTase showed that the bound conformations of 4 required flexibility for attachment to both FRα and GARFTase. In mice bearing IGROV1 ovarian tumor xenografts, 4 was highly efficacious. Our results establish that heteroatom substitutions in the 3-atom bridge region of 6-substituted pyrrolo[2,3-d]pyrimidines related to 1 provide targeted antifolates that warrant further evaluation as anticancer agents.
Novel histamine H3 receptor antagonists based on the 4-[(1H-imidazol-4-yl)methyl]piperidine scaffold
Vaccaro, Wayne D.,Sher, Rosy,Berlin, Michael,Shih, Neng-Yang,Aslanian, Robert,Schwerdt, John H.,McCormick, Kevin D.,Piwinski, John J.,West Jr., Robert E.,Anthes, John C.,Williams, Shirley M.,Wu, Ren-Long,She, H. Susan,Rivelli, Maria A.,Mutter, Jennifer C.,Corboz, Michel R.,Hey, John A.,Favreau, Leonard
, p. 395 - 399 (2007/10/03)
We report the discovery of novel histamine H3 receptor antagonists based on 4-[(1H-imidazol-4-yl)methyl]piperidine. The most potent compounds in the series (e.g., 7) result from the attachment of a substituted aniline amide to the main pharmaco
Folate Analogues in the C9-N10 Bridge Region. 14. 11-Oxahomofolic Acid, a Potential Antitumor Agent
Nair, M. G.,Saunders, Colleen,Chen, Shiang-Yuan,Kisliuk, Roy L.,Gaumont, Y.
, p. 59 - 65 (2007/10/02)
The chemical synthesis of 11-oxahomofolic acid (2) has been carried out using an unambiguous procedure.Reaction of methyl p-hydroxybenzoate with β-propiolactone gave 3-propionic acid (7), which was converted to 1-bromo-4--2-butanone (8) by the Arndt-Eistert procedure.Protection of the carbonyl group of 8 as the oxime resulted in the formation of 10, which on reaction with potassium phthalimide in the presence of crown-18 ether as a catalyst gave 1-phthalimido-4--2-butanone oxime (11).Hydrazinolysis of 11 gave 1-amino-4--2-butanone oxime (4), which was used as the key intermediate for the construction of 11-oxahomofolic acid (2) by modifications of the Boon and Leigh procedure.The dithionite reduction product of 2, 7,8-dihydro-11-oxahomofolic acid, served as a substrate of Lactobacillus casei dihydrofolate reductase and exhibited a relative rate of 50percent of the natural substrate under identical conditions.The catalytic reduction product of 11-oxahomofolic acid consisting of a mixture of diastereomers exhibited powerful antifolate activity against both MTX-sensitive and -resistant L. casei and Streptococcus faecium.The enzymatic reduction product of 7,8-dihydro-11-oxahomofolate having the "natural" configuration at C6 exhibited good antifolate activity against both MTX-sensitive and -resistant strains of L. casei and S. faecium.This paper details the synthesis and preliminary biological evaluation of an antifol, which is a substarate of L. casei dihydrofolate reductase in its 7,8-dihydro form and the resulting enzymatic reduction product capable of inhibiting the growth of the same organism from which the enzyme was derived.Thus, 7,8-dihydro-11-oxahomofolic acid has been showh to be potentially capable of inducing a "lethal synthesis" in L. casei.
