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.
Zinc and Cadmium Complexes of Pyridinemethanol Carboxylates: Metal Carboxylate Zwitterions and Metal–Organic Frameworks
Lin, Shi-Xin,Liu, Quan,Liu, Yan,Niu, Ru-Jie,Young, David J.,Zhang, Wen-Hua
, p. 832 - 837 (2020/06/03)
The heterofunctional lactone furo[3,4-b]pyridin-5(7H)-one (L1) undergoes a coordination-induced ring-opening reaction with Zn(NO3)2 ? 6H2O to yield the zwitterionic [Zn(L1′)2(H2O)2] (1, L1′=2-(hydroxymethyl)nicotinate) with an uncoordinated carboxylate. The same reaction with Cd(NO3)2 ? 4H2O provides a two-dimensional (2D) network of [Cd(L1′)2]n (3) with the carboxylates coordinated to cadmium(II) propagating the assembly. The corresponding reactions of Zn(NO3)2 ? 6H2O and Cd(NO3)2 ? 4H2O with 2-(hydroxymethyl)isonicotinic acid (HL2) generated zwitterionic [Zn(L2)2(H2O)2] (2) and a 2D network [Cd(L2)2]n?nDMF (4, DMF=N,N′-dimethylformamide), respectively. Complexes 1–4 are weakly emissive, giving ligand-centered emissions at 409 nm (1), 412/436 nm (2), 404 nm (3), and 412/436 nm (4) in CHCl3 solutions upon excitation at 330 nm. This work points to the potential of using ‘hidden’ functionalities widely found in small organic molecules and natural products for the construction of coordination complexes with new functionality and potential applications.
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.
