2212-05-7Relevant articles and documents
Synthesis of the novel PARP-1 inhibitor AG-690/11026014 and its protective effects on angiotensin II-induced mouse cardiac remodeling
Feng, Guo-Shuai,Zhu, Cui-Ge,Li, Zhuo-Ming,Wang, Pan-Xia,Huang, Yi,Liu, Min,He, Ping,Lou, Lan-Lan,Chen, Shao-Rui,Liu, Pei-Qing
, p. 638 - 650 (2017)
We previously identified AG-690/11026014 (6014) as a novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor that effectively prevented angiotensin II (Ang II)-induced cardiomyocyte hypertrophy. In the present study, we reported a new synthesis route for 6014, and investigated its protective effects on Ang II-induced cardiac remodeling and cardiac dysfunction and the underlying mechanisms in mice. We designed a new synthesis route to obtain a sufficient quantity of 6014 for this in vivo study. C57BL/6J mice were infused with Ang II and treated with 6014 (10, 30, 90 mg·kg-1 ·d-1, ig) for 4 weeks. Then two-dimensional echocardiography was performed to assess the cardiac function and structure. Histological changes of the hearts were examined with HE staining and Masson's trichrome staining. The protein expression was evaluated by Western blot, immunohistochemistry and immunofluorescence assays. The activities of sirtuin-1 (SIRT-1) and the content of NAD+ were detected with the corresponding test kits. Treatment with 6014 dose-dependently improved cardiac function, including LVEF, CO and SV and reversed the changes of cardiac structure in Ang II-infused mice: it significantly ameliorated Ang II-induced cardiac hypertrophy evidenced by attenuating the enlargement of cardiomyocytes, decreased HW/BW and LVW/BW, and decreased expression of hypertrophic markers ANF, BNP and β-MHC; it also prevented Ang II-induced cardiac fibrosis, as implied by the decrease in excess accumulation of extracellular matrix (ECM) components collagen I, collagen III and FN. Further studies revealed that treatment with 6014 did not affect the expression levels of PARP-1, but dose-dependently inhibited the activity of PARP-1 and subsequently restored the activity of SIRT-1 in heart tissues due to the decreased consumption of NAD+ and attenuated Poly-ADP-ribosylation (PARylation) of SIRT-1. In conclusion, the novel PARP-1 inhibitor 6014 effectively protects mice against AngII-induced cardiac remodeling and improves cardiac function. Thus, 6014 might be a potential therapeutic agent for heart diseases.
Design, Synthesis, and Structural Analysis of Cladosporin-Based Inhibitors of Malaria Parasites
Babbar, Palak,Das, Pronay,Manickam, Yogavel,Mankad, Yash,Yadav, Swati,Parvez, Suhel,Sharma, Amit,Reddy, D. Srinivasa
, p. 1777 - 1794 (2021/05/10)
Here we have described a systematic structure activity relationship (SAR) of a set of compounds inspired from cladosporin, a tool compound that targets parasite (Plasmodium falciparum) lysyl tRNA synthetase (KRS). Four sets of analogues, synthesized based on point changes in the chemical scaffold of cladosporin and other logical modifications and hybridizations, were assessed using high throughput enzymatic and parasitic assays along with in vitro pharmacokinetics. Co-crystallization of the most potent compound in our series (CL-2) with PfKRS revealed its structural basis of enzymatic binding and potency. Further, we report that CL-2 has performed better than cladosporin in terms of metabolic stability. It thus represents a new lead for further optimization toward the development of antimalarial drugs. Collectively, along with a lead compound, the series offers insights on how even the slightest chemical modification might play an important role in enhancing or decreasing the potency of a chemical scaffold.
Chlorination Reaction of Aromatic Compounds and Unsaturated Carbon-Carbon Bonds with Chlorine on Demand
Liu, Feng,Wu, Na,Cheng, Xu
supporting information, p. 3015 - 3020 (2021/05/05)
Chlorination with chlorine is straightforward, highly reactive, and versatile, but it has significant limitations. In this Letter, we introduce a protocol that could combine the efficiency of electrochemical transformation and the high reactivity of chlorine. By utilizing Cl3CCN as the chloride source, donating up to all three chloride atom, the reaction could generate and consume the chlorine in situ on demand to achieve the chlorination of aromatic compounds and electrodeficient alkenes.
