56-05-3Relevant articles and documents
A modular approach towards functionalized highly stable self-complementary quadruple hydrogen bonded systems
Rayavarapu, Suresh,Kheria, Sanjeev,Shinde, Dinesh R.,Gonnade, Rajesh G.,Sanjayan, Gangadhar J.
, p. 10087 - 10094 (2017)
Self-complementary quadruple hydrogen bonded systems have shown potential as key building blocks for developing various supramolecular polymers. Opportunities for the introduction of multiple functionalities would further augment, in principle, their application potential. Herein, we report a novel modular approach to simultaneously introduce two closely aligned side chains into AADD-type self-complementary quadruple hydrogen-bonding systems. Dithiane-tethered ureidopyrimidinone has been used as a reactive intermediate to efficiently attach closely aligned side chains by simply reacting with amines to form highly stable molecular duplexes. These duplexes featuring AADD-type arrays of hydrogen bonding codes are highly stable in non-polar solvents (Kdim > 1.9 × 107 M-1 in CDCl3) as well as in polar solvents (Kdim > 105 in 10% DMSO-d6/CDCl3). Another notable feature of these self-assembling systems is their insensitivity to prototropy-related issues owing to their prototropic degeneracy, which will enhance their application potential in supramolecular chemistry.
Developing novel classes of protein kinase CK1δ inhibitors by fusing [1,2,4]triazole with different bicyclic heteroaromatic systems
Grieco, Ilenia,Bissaro, Maicol,Tiz, Davide Benedetto,Perez, Daniel I.,Perez, Conception,Martinez, Ana,Redenti, Sara,Mariotto, Elena,Bortolozzi, Roberta,Viola, Giampietro,Cozza, Giorgio,Spalluto, Giampiero,Moro, Stefano,Federico, Stephanie
, (2021/03/16)
Protein kinase CK1δ expression and activity is involved in different pathological situations that include neuroinflammatory and neurodegenerative diseases. For this reason, protein kinase CK1δ has become a possible therapeutic target for these conditions. 5,6-fused bicyclic heteroaromatic systems that resemble adenine of ATP represent optimal scaffolds for the development of a new class of ATP competitive CK1δ inhibitors. In particular, a new series of [1,2,4]triazolo[1,5-c]pyrimidines and [1,2,4]triazolo[1,5-a][1,3,5]triazines was developed. Some crucial interactors have been identified, such as the presence of a free amino group able to interact with the residues of the hinge region at the 5- and 7- positions of the [1,2,4]triazolo[1,5-c]pyrimidine and [1,2,4]triazolo[1,5-a][1,3,5]triazine scaffolds, respectively; or the presence of a 3-hydroxyphenyl or 3,5-dihydroxyphenyl moiety at the 2- position of both nuclei. Molecular modeling studies identified the key interactions involved in the inhibitor-protein recognition process that appropriately fit with the outlined structure-activity relationship. Considering the fact that the CK1 protein kinase is involved in various pathologies in particular of the central nervous system, the interest in the development of new inhibitors permeable to the blood-brain barrier represents today an important goal in the pharmaceutical field. The best potent compound of the series is the 5-(7-amino-5-(benzylamino)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-2-yl)benzen-1,3-diol (compound 51, IC50 = 0.18 μM) that was predicted to have an intermediate ability to cross the membrane in our in vitro assay and represents an optimal starting point to both studies the therapeutic value of protein kinase CK1δ inhibition and to develop new more potent derivatives.
Exploration of carbamide derived pyrimidine-thioindole conjugates as potential VEGFR-2 inhibitors with anti-angiogenesis effect
Bhandari, Sonal,Bhargava, Suresh K.,Reddy, T. Srinivasa,Reddy, Velma Ganga,Sakla, Akash P.,Sana, Sravani,Shankaraiah, Nagula,Tokala, Ramya
, (2020/05/18)
The development of new small molecules from known structural motifs through molecular hybridization is one of the trends in drug discovery. In this connection, we have combined the two pharmacophoric units (pyrimidine and thioindole) in a single entity via molecular hybridization strategy along with introduction of urea functionality at C2 position of pyrimidine to increase the efficiency of H-bonding interactions. Among the synthesized conjugates 12a-aa, compound 12k was found to exhibit significant IC50 values 5.85, 7.87, 6.41 and 10.43 μM against MDA-MB-231 (breast), HepG2 (liver), A549 (lung) and PC-3 (prostate) cancer cell lines, respectively. All these compounds were further evaluated for their inhibitory activities against VEGFR-2 protein. The results specified that among the tested compounds, 12d, 12e, 12k, 12l, 12p, 12q, 12t and 12u prominently suppressed VEGFR-2, with IC50 values of 310–920 nM in association to the positive control (210 nM). Angiogenesis inhibition was evident by tube formation assay in HUVECs and cell-invasion by transwell assay. The mechanism of cellular toxicity on MDA-MB-231 was found through depolarisation of mitochondrial membrane potential, increased ROS production and subsequent DNA damage resulting in apoptosis induction. Moreover, clonogenic and wound healing assays designated the inhibition of colony formation and cell migration by 12k in a dose-dependent manner. Molecular docking studies also shown that compound 12k capably intermingled with catalytically active residues GLU-885, ASP-1046 of the VEGFR-2 through hydrogen-bonding interactions.
