791724-87-3Relevant academic research and scientific papers
In-vitro antitumor activity of new quaternary phosphonium salts, derivatives of 3-hydroxypyridine
Iksanova, Alfiya G.,Gabbasova, Raylya R.,Kupriyanova, Tatyana V.,Akhunzyanov, Almaz A.,Pugachev, Michail V.,Vafiva, Ruzalia M.,Shtyrlin, Nikita V.,Balakin, Konstantin V.,Shtyrlin, Yurii G.
, p. 682 - 690 (2018)
This work presents the results of in-vitro biological activity studies of three novel anticancer agents, phosphonium salts based on the 3-hydroxypyridine scaffold, including one derivative of 4-deoxypyridoxine. Proliferation and viability of cells treated with these compounds was assessed by the colony formation and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Effects of the compounds on apoptosis and cell cycle were studied by flow cytometry using annexin V-FITC/propidium iodide and propidium iodide staining, respectively. The influence of the compounds on mitochondrial membrane potential and intracellular reactive oxygen species was evaluated using tetramethyl rhodamine ethyl and DCFHA staining. Western blot analysis was used to study the changes in the expression of Bcl-xL, Bax, and caspase-3 apoptotic proteins. The treatment of ovarian adenocarcinoma cells OVCAR-4 with the tested compounds inhibited the growth and induced cell cycle arrest in the G1 phase. 3-Hydroxypyridine derivatives induced apoptosis by hyperexpression of Bax and caspase-3, whereas 4-deoxypyridoxine derivative induced cell death partly by reactive oxygen species generation and caspase-3 hyperexpression. These results indicate that the quaternary phosphonium salts studied represent potential therapeutic agents for the treatment of ovarian cancer.
Rationally designed high-affinity 2-amino-6-halopurine heat shock protein 90 inhibitors that exhibit potent antitumor activity
Kasibhatla, Srinivas R.,Hong, Kevin,Biamonte, Marco A.,Busch, David J.,Karjian, Patricia L.,Sensintaffar, John L.,Kamal, Adeela,Lough, Rachel E.,Brekken, John,Lundgren, Karen,Grecko, Roy,Timony, Gregg A.,Ran, Yingqing,Mansfield, Robert,Fritz, Lawrence C.,Ulm, Edgar,Burrows, Francis J.,Boehm, Marcus F.
, p. 2767 - 2778 (2008/02/06)
Heat shock protein 90 (Hsp90) is a molecular chaperone protein implicated in stabilizing the conformation and maintaining the function of many cell-signaling proteins. Many oncogenic proteins are more dependent on Hsp90 in maintaining their conformation, stability, and maturation than their normal counterparts. Furthermore, recent data show that Hsp90 exists in an activated form in malignant cells but in a latent inactive form in normal tissues, suggesting that inhibitors selective for the activated form could provide a high therapeutic index. Hence, Hsp90 is emerging as an exciting new target for the treatment of cancer. We now report on a novel series of 2-amino-6-halopurine Hsp90 inhibitors exemplified by 2-amino-6-chloro-9-(4-iodo-3,5-dimethylpyridin- 2-ylmethyl)purine (30). These highly potent inhibitors (IC50 of 30 = 0.009 μM in a HER-2 degradation assay) also display excellent antiproliferative activity against various tumor cell lines (IC50 of 30 = 0.03 μM in MCF7 cells). Moreover, this class of inhibitors shows higher affinity for the activated form of Hsp90 compared to our earlier 8-sulfanylpurine Hsp90 inhibitor series. When administered orally to mice, these compounds exhibited potent tumor growth inhibition (>80%) in an N87 xenograft model, similar to that observed with 17-allylamino-17- desmethoxygeldanamycin (17-AAG), which is a compound currently in phase I/II clinical trials.
