- Benzimidazole derivatives as potential dual inhibitors for PARP-1 and DHODH
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Poly (ADP-ribose) polymerases (PARPs) play diverse roles in various cellular processes that involve DNA repair and programmed cell death. Amongst these polymerases is PARP-1 which is the key DNA damage-sensing enzyme that acts as an initiator for the DNA
- Abdullah, Iskandar,Chee, Chin Fei,Lee, Yean-Kee,Thunuguntla, Siva Sanjeeva Rao,Satish Reddy,Nellore, Kavitha,Antony, Thomas,Verma, Jitender,Mun, Kong Wai,Othman, Shatrah,Subramanya, Hosahalli,Rahman, Noorsaadah Abd.
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p. 4669 - 4680
(2015/08/03)
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- Synthesis and evaluation of a new generation of orally efficacious benzimidazole-based poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors as anticancer agents
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Small molecule inhibitors of PARP-1 have been pursued by various organizations as potential therapeutic agents either capable of sensitizing cytotoxic treatments or acting as stand-alone agents to combat cancer. As one of the strategies to expand our portfolio of PARP-1 inhibitors, we pursued unsaturated heterocycles to replace the saturated cyclic amine derivatives appended to the benzimidazole core. Not only did a variety of these new generation compounds maintain high enzymatic potency, many of them also displayed robust cellular activity. For example, the enzymatic IC50 and cellular EC50 values were as low as 1 nM or below. Compounds 24 (EC50 = 3.7 nM) and 44 (EC50 = 7.8 nM), featuring an oxadiazole and a pyridine moiety, respectively, demonstrated balanced potency and PK profiles. In addition, these two molecules exhibited potent oral in vivo efficacy in potentiating the cytotoxic agent temozolomide in a B16F10 murine melanoma model.
- Tong, Yunsong,Bouska, Jennifer J.,Ellis, Paul A.,Johnson, Eric F.,Leverson, Joel,Liu, Xuesong,Marcotte, Patrick A.,Olson, Amanda M.,Osterling, Donald J.,Przytulinska, Magdalena,Rodriguez, Luis E.,Shi, Yan,Soni, Nirupama,Stavropoulos, Jason,Thomas, Sheela,Donawho, Cherrie K.,Frost, David J.,Luo, Yan,Giranda, Vincent L.,Penning, Thomas D.
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experimental part
p. 6803 - 6813
(2010/04/06)
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