Discovery of isoquinolinone and naphthyridinone-based inhibitors of poly(ADP-ribose) polymerase-1 (PARP1) as anticancer agents: Structure activity relationship and preclinical characterization was written by Karche, Navnath P.;Bhonde, Mandar;Sinha, Neelima;Jana, Gourhari;Kukreja, Gagan;Kurhade, Sanjay P.;Jagdale, Arun R.;Tilekar, Ajay R.;Hajare, Anil K.;Jadhav, Ganesh R.;Gupta, Nishant R.;Limaye, Rohan;Khedkar, Nilesh;Thube, Baban R.;Shaikh, Javed S.;Rao Irlapati, Nageswara;Phukan, Samiron;Gole, Gopal;Bommakanti, Apparao;Khanwalkar, Harshal;Pawar, Yogesh;Kale, Ramesh;Kumar, Rakesh;Gupta, Rajesh;Praveen Kumar, V. R.;Wahid, Saif;Francis, Albi;Bhat, Tariq;Kamble, Nivrutti;Patil, Vinod;Nigade, Prashant B.;Modi, Dipak;Pawar, Shashikant;Naidu, Sneha;Volam, Harish;Pagdala, Vamsi;Mallurwar, Sadanand;Goyal, Hemant;Bora, Pushpak;Ahirrao, Prajakta;Singh, Minakshi;Kamalakannan, Prabhakaran;Naik, Kumar Ram;Kumar, Pradipta;Powar, Rajendra G.;Shankar, Rajesh B.;Bernstein, Peter R.;Gundu, Jayasagar;Nemmani, Kumar;Narasimham, Lakshmi;George, Kochumalayil Shaji;Sharma, Sharad;Bakhle, Dhananjay;Kamboj, Rajender Kumar;Palle, Venkata P.. And the article was included in Bioorganic & Medicinal Chemistry in 2020.Recommanded Product: 3939-12-6 This article mentions the following:
The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone and naphthyridinone analogs is described. Compounds of structure I have good biochem. and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure into a cyclopentene ring offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure naphthyridinones. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor I, which was further characterized as preclin. candidate mol. Compound I is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound I demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Addnl., compound I also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing’s sarcoma models. In the experiment, the researchers used many compounds, for example, 6-Fluoronicotinonitrile (cas: 3939-12-6Recommanded Product: 3939-12-6).
6-Fluoronicotinonitrile (cas: 3939-12-6) belongs to pyridine derivatives. Pyridine is diamagnetic and has a diamagnetic susceptibility of −48.7 × 10−6 cm3·mol−1.The molecular electric dipole moment is 2.2 debyes. The standard enthalpy of formation is 100.2 kJ·mol−1 in the liquid phase and 140.4 kJ·mol−1 in the gas phase. One of the examples of pyridines is the well-known alkaloid lithoprimidine, which is an A3 adenosine receptor antagonist and N,N-dimethylaminopyridine (DMAP) analog, commonly used in organic synthesis.Recommanded Product: 3939-12-6