RESUMEN
@#Phosphatidylinositol-3-kinase (PI3K) inhibitors can increase the sensitivity of tumor cells to Poly ADP-ribose polymerase-1 (PARP-1) inhibitors. Therefore, the simultaneous inhibition of the PARP-1 and PI3K activities are expected to overcome the drug resistance of PARP-1 inhibitors.In our previous work, two compounds XW-1 and WZ-1 with excellent activities against PARP-1 and PI3K were obtained with the limitation to further study due to their poor water solubility.Therefore, XW-1 and WZ-1 were chosen as lead compounds to optimize their solubility by introducing a salt-forming site via a urea group, and 11 novel compounds were designed and synthesized. The structure of all target compounds was confirmed by 1H NMR, 13C NMR, and HRMS.The enzyme activities of the compounds against PARP-1 and PI3K were measured, and the results showed that most of the compounds demonstrated good inhibitory activities against PARP-1 and PI3K.Based on the above result, the inhibitory activities of compounds 8b, 8e, and 8f against MDA-MB-231, MDA-MB-468, HCC1937, HCT116, and olaparib-resistant HCT116R were determined by MTT, respectively.Additionally, the structure-activity relationship was discussed. The results showed that these compounds displayed excellent antiproliferation activity.Among them, compound 8f demonstrated antiproliferation remarkably against all five tumor cells, which was more potent than that of olaparib, and was comparable to that of BKM120.Furthermore, the solubility of hydrochloride salts of compound 8b and 8f was significantly improved compared to the lead compounds.The results of this study will provide a theoretical basis for the further development of PARP-1 and PI3K dual-target inhibitors with good pharmaceutical properties and strong inhibitory activities.
RESUMEN
Histone deacetylase (HDAC) is usually abnormally overexpressed, which mainly leads to the transcriptional repression of tumor suppressor genes. Histone deacetylase inhibitors (HDIs) exert anti-tumor biological effects by regulating nucleosome structure, inhibiting HDAC activity, and controlling the expression of tumor suppressor genes. There are currently 5 drugs on the market, but only for peripheral T-cell lymphoma and cutaneous T-cell lymphoma. In solid tumors, most of the HDAC inhibitors used have failed to achieve effective therapeutic effects. Phosphoinositide 3-kinase (PI3K) is the starting node of the PI3K-AKT-mTOR signaling pathway, which plays a very important role in the proliferation, migration, invasion, and differentiation of tumor cells. The abnormal activation of PI3K is closely related to the occurrence and development of tumors, and the combined use of HDAC and PI3K inhibitors and HDAC/PI3K dual-target inhibitors show synergistic anticancer activity. This article introduces the anti-tumor clinical and preclinical research progress of representative HDAC inhibitors and PI3K inhibitors, as well as HDAC/PI3K dual-target inhibitors.
RESUMEN
OBJECTIVE: To study the distribution, excretion and other pharmacokinetic characteristics of dual target ligand-based lidamycin (DTLL) in rats. METHODS: [125l] radioactivity isotope tracing method was used to determine the pharmacokinetic parameters of DTLL which was injected intravenously via the tail vein of healthy Wistar rats at a single dose of [125l] DTLL 2625 kBq · 0.05 mg-1· kg-1. The samples from rat plasma, tissue, feces, urine and bile were obtained to analyze the distributions of DTLL in rats after administration and to calculate the cumulative excretion scores by using a liquid scintillation counting analyzer with the WinNolin program. RESULTS: The area under the concentration-time curve (AUC0-∞) of DTLL was (184±33) h·μg·L-1, with half time (t1/2) and cleanrance (Cl) at (3.98±0.75) h and (278±41) mL·h-1· kg-1, respectively. DTLL was mainly distributed in whole body tissues without any accumulation observed. The excretion rate of DTLL was (82.5±2.6)% for urine, compared with (10.4±6.6)% in feces and (92.9±7.4)% in total. CONCLUSION: DTLL is distributed rapidly in the whole body without obvious accumulation. Most of the DTLL administered is excreted through feces and urine.