Anti-epileptic activity, toxicity and teratogenicity in CD1 mice of a novel valproic acid arylamide derivative, N-(2-hydroxyphenyl)-2-propylpentanamide

Untargeted LC-MS/MS Metabolomics Study of HO-AAVPA and VPA on Breast Cancer Cell Lines

“…Then, the IC 15 values were calculated from IC 50 values (Table 1) and compared with those of previous reports. By observing the range of concentrations tested for both compounds (140 µM to 36 mM VPA and 9 µM to 2 mM HO-AAVPA), it is clear that HO-AAVPA has a higher potency, attributed to the 2-hydroxybenzamide fragment that functions as a zinc-binding group [35][36][37]. In their published study of HO-AAVPA, Prestegui-Martel et al ( 2016) calculated IC 50 values of 280 and 190 µM for MDA-MB-231 and MCF-7 cells, respectively [37]; according to our results, the calculated IC 50 value was quite similar for MDA-MB-231 cells (291.8 µM) but not for MCF-7 cells (476.1 µM), although it was in the same order of magnitude.…”

“…HO-AAVPA exerts similar effects to VPA in different experimental contexts. For example, HO-AAVPA possesses an anticonvulsant effect comparable to VPA but with lower toxicity and teratogenic effects in an in vivo model [35]. Additionally, HO-AAVPA modifies HMGB1 acetylation, a nonhistone protein involved in DNA stability, repair, transcription, and recombination processes and in the generation of reactive oxygen species (ROS), activities which are also found in VPA with lower potency [36].…”

“…In their original publication, Prestegui-Martlel et al (2016) demonstrated that HO-AAVPA has antiproliferative activity against BC cells at lower concentrations compared to VPA [37]. Accumulating evidence supports the similar effects produced by HO-AAVPA and VPA, as well as the discrepancies between the molecular target for which it was designed and the findings obtained in vitro [35][36][37]. Furthermore, many pharmacological properties of HO-AAVPA remain to be elucidated, particularly its impact on intracellular metabolism of distinct subtypes of BC cells, such as LA and TNBC, two cell lines with varying levels of aggressiveness and distinct biological targets, including HDACs [9] and metabolomic profiles [38].…”

N-(2′-Hydroxyphenyl)-2-Propylpentanamide (HO-AAVPA) Inhibits HDAC1 and Increases the Translocation of HMGB1 Levels in Human Cervical Cancer Cells

“…N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA) is a VPA derivative designed by in silico studies to target HDAC (Scheme 1), showing better antiproliferative effects than VPA on the rhabdomyosarcoma cell line (A204), cervical cancer cells (HeLa cells), and breast cancer cells (MCF-7, MDA-MB-231, and SKBr3) [2]. Additionally, HO-AAVPA depicted lesser toxicity and teratogenic effects that VPA and also showed better pharmacokinetic properties than VPA in a rat model (half-life for VPA 1 h and for HO-AAVPA 4 h) [19][20][21]. However, the HDAC inhibitory effects of HO-AAVPA have not been experimentally tested, and the mechanism that explains its antiproliferative effect must be elucidated.…”

PAMAM-G4 protect the N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA) and maintain its antiproliferative effects on MCF-7

“…HO-AAVPA showed antiproliferative effects on cancer cell lines (HeLa, rhabdomyosarcoma, MCF-7, MDA-MB-231 and SKBr3) 13 . Some toxicity studies in a rat model show that HO-AAVPA does not cause liver damage in acute and subchronic treatment, it does not affect organogenesis, and its lethal dose 50 (LD 50 ) 14 is inside the drug toxicity limits recommended 15 . However, during the development and validation of analytical method of HO-AAVPA on reversed-phase high-performance liquid chromatography (RP-HPLC) there was identified a metabolite from a metabolism study into rat liver microsomes 16 which yield two metabolites 17 .…”