5657-51-2Relevant articles and documents
Design and synthesis of novel PARP-1 inhibitors based on pyridopyridazinone scaffold
Elmasry, Ghada F.,Aly, Enayat E.,Awadallah, Fadi M.,El-Moghazy, Samir M.
, p. 655 - 666 (2019)
Various pyridopyridazinone derivatives were designed as Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. The pyridopyridazinone scaffold was used as an isostere of the phthalazine nucleus of the lead compound Olaparib in addition to some modifications in the tail part of the molecule. Preliminary biological evaluation indicated that most compounds possessed inhibitory potencies comparable to Olaparib in nanomolar level. The best PARP-1 inhibitory activity was observed for compound 8a with (IC50 = 36 nM) compared to Olaparib as a reference drug (IC50 = 34 nM). Molecular modeling simulation revealed that, the designed compounds docked well into PARP-1 active site and their complexes are stabilized by three key hydrogen bond interactions with both Gly863 and Ser904 as well as other favorable π-π and hydrogen-π stacking interactions with Tyr907 and Tyr896, respectively. Computational ADME study predicted that the target compounds 8a and 8e have proper pharmacokinetic and drug-likeness properties. These outcomes afford a new structural framework for the design of novel inhibitors for PARP-1.
ADENOSINE RECEPTOR BINDING COMPOUNDS
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, (2020/02/06)
The present invention relates to pharmaceutical compounds and compositions of Formula (I) and methods of treatment using the compounds and compositions, especially for the treatment and/or prevention of a proliferation disorder, such as cancer. Compounds of Formula (I) as further described herein are shown modulators of the adenosine A2A receptor and exhibit antiproliferative activity. Accordingly, these compounds are useful to treat proliferative disorders such as cancer, and other adenosine receptor-related conditions including an inflammatory disease, renal disease, diabetes, vascular disease, lung disease, or an autoimmune disease.
Investigation of the Structure-Activity Relationships of Aza-A-Ring Indenoisoquinoline Topoisomerase i Poisons
Beck, Daniel E.,Reddy, P. V. Narasimha,Lv, Wei,Abdelmalak, Monica,Tender, Gabrielle S.,Lopez, Sophia,Agama, Keli,Marchand, Christophe,Pommier, Yves,Cushman, Mark
, p. 3840 - 3853 (2016/05/24)
Several indenoisoquinolines have shown promise as anticancer agents in clinical trials. Incorporation of a nitrogen atom into the indenoisoquinoline scaffold offers the possibility of favorably modulating ligand-binding site interactions, physicochemical properties, and biological activities. Four series of aza-A-ring indenoisoquinolines were synthesized in which the nitrogen atom was systematically rotated through positions 1, 2, 3, and 4. The resulting compounds were tested to establish the optimal nitrogen position for topoisomerase IB (Top1) enzyme poisoning activity and cytotoxicity to human cancer cells. The 4-aza compounds were the most likely to yield derivatives with high Top1 inhibitory activity. However, the relationship between structure and cytotoxicity was more complicated since the potency was influenced strongly by the side chains on the lactam nitrogen. The most cytotoxic azaindenoisoquinolines 45 and 46 had nitrogen in the 2- or 3-positions and a 3′-dimethylaminopropyl side chain, and they had MGM GI50 values that were slightly better than the corresponding indenoisoquinoline 64.
