5334-59-8Relevant articles and documents
New pyrazolopyrimidine derivatives as Leishmania amazonensis arginase inhibitors
Feitosa, Livia M.,da Silva, Edson R.,Hoelz, Lucas V.B.,Souza, Danielle L.,Come, Julio A.A.S.S.,Cardoso-Santos, Camila,Batista, Marcos M.,Soeiro, Maria de Nazare C.,Boechat,Pinheiro, Luiz C.S.
, p. 3061 - 3069 (2019/06/08)
Arginase performs the first enzymatic step in polyamine biosynthesis in Leishmania and represents a promising target for drug development. Polyamines in Leishmania are involved in trypanothione synthesis, which neutralize the oxidative burst of reactive oxygen species (ROS) and nitric oxide (NO) that are produced by host macrophages to kill the parasite. In an attempt to synthesize arginase inhibitors, six 1-phenyl-1H-pyrazolo[3,4-d]pyrimidine derivatives with different substituents at the 4-position of the phenyl group were synthesized. All compounds were initially tested at 100 μM concentration against Leishmania amazonensis ARG (LaARG), showing inhibitory activity ranging from 36 to 74%. Two compounds, 1 (R=H) and 6 (R=CF3), showed arginase inhibition >70% and IC50 values of 12 μM and 47 μM, respectively. Thus, the kinetics of LaARG inhibition were analyzed for compounds 1 and 6 and revealed that these compounds inhibit the enzyme by an uncompetitive mechanism, showing Kis values, and dissociation constants for ternary complex enzyme-substrate-inhibitor, of 8.5 ± 0.9 μM and 29 ± 5 μM, respectively. Additionally, the molecular docking studies proposed that these two uncompetitive inhibitors interact with different LaARG binding sites, where compound 1 forms more H-bond interactions with the enzyme than compound 6. These compounds showed low activity against L. amazonensis free amastigotes obtained from mice lesions when assayed with as much as 30 μM. The maximum growth inhibition reached was between 20 and 30% after 48 h of incubation. These results suggest that this system can be promising for the design of potential antileishmanial compounds.
Synthesis and in vitro antiproliferative activity of novel pyrazolo[3,4-d]pyrimidine derivatives
Abdou, Nermin S.,Serya, Rabah A. T.,Esmat, Ahmed,Tolba, Mai F.,Ismail, Nasser S. M.,Abouzid, Khaled A. M.
supporting information, p. 1518 - 1534 (2015/08/18)
A novel series of pyrazolo[3,4-d]pyrimidine derivatives were designed, synthesized and evaluated for their antiproliferative activity. Among the five compounds selected by NCI, compound 11a showed a distinctive pattern of selectivity on cell line panels and was further screened for a 5-log dose range, where it showed potent antiproliferative activity with median growth inhibition (GI50) equal to 1.71 μM against the CNS cancer SNB-75 cell line. The tested derivative showed remarkably the highest cell growth inhibition against non-small cell lung cancer HOP-62, CNS cancer SNB-75, breast cancer HS578T, and melanoma MALME-3M cell lines. Flow cytometric analysis revealed that compound 11a could significantly induce apoptosis in A549 cells in vitro at low micromolar concentrations. Further investigation showed that compound 11a induced significant cell cycle arrest at G0/G1 phase partly due to its ability to downregulate cyclin D1 and upregulate p27kip1 levels.
Selective synthesis of 1-substituted 4-chloropyrazolo[3,4-d]pyrimidines
Babu, Suresh,Morrill, Christie,Almstead, Neil G.,Moon, Young-Choon
supporting information, p. 1882 - 1885 (2013/06/05)
Strategies for carrying out the reaction of 4,6-dichloropyrimidine-5- carboxaldehyde with various hydrazines to generate 1-substituted 4-chloropyrazolo[3,4-d]pyrimidines in a selective and high-yielding manner are presented. For aromatic hydrazines, the reaction is performed in the absence of an external base, which promotes exclusive hydrazone formation. The hydrazones subsequently cyclize at an elevated temperature to form the desired pyrazolo[3,4-d]pyrimidine products. For aliphatic hydrazines, the reaction sequence proceeds as a single step in the presence of an external base.
