56-09-7Relevant articles and documents
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Ounn,Skinner
, p. 3713,3715,3716 (1975)
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Cinnamide derived pyrimidine-benzimidazole hybrids as tubulin inhibitors: Synthesis, in silico and cell growth inhibition studies
Sana, Sravani,Reddy, Velma Ganga,Srinivasa Reddy,Tokala, Ramya,Kumar, Rahul,Bhargava, Suresh K.,Shankaraiah, Nagula
, (2021/03/15)
An approach in modern medicinal chemistry to discover novel bioactive compounds is by mimicking diverse complementary pharmacophores. In extension of this strategy, a new class of piperazine-linked cinnamide derivatives of benzimidazole-pyrimidine hybrids have been designed and synthesized. Their in vitro cytotoxicity profiles were explored on selected human cancer cell lines. Specifically, structural comparison of target hybrids with tubulin-DAMA-colchicine and tubulin-nocodazole complexes has exposed a deep position of benzimidazole ring into the αT5 loop. All the synthesized compounds were demonstrated modest to interesting cytotoxicity against different cancer cell lines. The utmost cytotoxicity has shown with an amine linker of benzimidazole-pyrimidine series, with specificity toward A549 (lung cancer) cell line. The most potent compound in this series was 18i, which inhibited cancer cell growth at micromolar concentrations ranging 2.21–7.29 μM. Flow cytometry studies disclosed that 18i inhibited the cells in G2/M phase of cell cycle. The potent antitumor activity of 18i resulted from enhanced microtubule disruption at a similar level as nocodazole on β-tubulin antibody, explored using immunofluorescence staining. The most active compound 18i also inhibited tubulin polymerization with an IC50 of 5.72 ± 0.51 μM. In vitro biological analysis of 18i presented apoptosis induction on A549 cells with triggering of ROS generation and loss of mitochondrial membrane potential, resulting in DNA injury. In addition, 18i displayed impairment in cellular migration and inhibited the colony formation. Notably, the safety profile of most potent compound 18i was revealed by screening against normal human pulmonary epithelial cells (L132: IC50: 69.25 ± 5.95 μM). The detailed binding interactions of 18i with tubulin was investigated by employing molecular docking, superimposition and free energy analyses. Thus remarks made in this study established that pyrimidine-benzimidazole hybrids as a new class of tubulin polymerization inhibitors with significant anticancer activity.
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.
Preparation method of famciclovir
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Paragraph 0022-0024, (2019/03/28)
The invention relates to a preparation method of famciclovir. The preparation method comprises the following steps of: adopting guanidine nitrate and diethyl malonate as raw materials, carrying out ring-closing reaction under an alkaline condition to obtain 2-amino-4,6-pyrimidinediol, then obtaining 2-amino-4,6-dichloropyrimidine by hydroxyl chlorination, reacting with 2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl-1-amine to generate 6-chloro-N(i)4(/i)-(2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl)pyrimidine-2,4-diamine, then reacting with sodium nitrite under the acidic condition to obtain 2-(2-((2-amino-6-chloro-5-nitrosopyrimidin-4-yl)amino)ethyl)propane-1,3-diol, and finally carrying out reduction/dechloridation, ring-closing and esterification reaction to obtain the famciclovir. The preparation method has the beneficial effects that the problems of poor N-alkylation reaction selectivity and need of additional purification of reaction intermediates and the like in the current process are solved.
