Effect of two series of isoindolines over HDAC8 activity and expression

Trejo-Muñoz, Cynthia R.; Jimenez, Elvía Mera; Pinto‐Almazán, Rodolfo; Gandarilla, José Alfredo Díaz; Correa‐Basurto, José; Trujillo‐Ferrara, José G.; Guerra‐Araiza, Christian; Talamás-Rohana, Patricia; Percino, Teresa Mancilla

doi:10.1007/s00044-013-0903-y

Cited by 7 publications

(8 citation statements)

References 19 publications

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“…The isoindolines 1 – 14 (Scheme ; see also the Supporting Information) were synthetized according to the method developed in our laboratory; from these 1 – 4 , 6 , 7 , 8 – 11 , 13 , and 14 were identified by spectroscopic methods, data obtained corresponding to the previously reported . Because spectral data of 5 and 12 have not been previously reported, in this paper we provide them, as well as the procedure for their synthesis .…”

Section: Methodsmentioning

confidence: 99%

“…Therefore, they have been used in the treatment of diverse diseases such as Alzheimer's disease and anxiety disorders , osteoporosis , cardiovascular diseases , rheumatoid arthritis, inflammation , autoimmune disease , and cancer . In this regard, we have been interested in the synthesis of isoindoline 2‐substituted derivatives of α‐amino acids, as well as their theoretical and biological evaluation . Consequently, in this work we report the determination of IC 50 values of two series of isoindolines 1 – 7 and 8 – 14 over COX‐1 and COX‐2 enzymes, as well as a statistical study, using MLR and LS‐SVM correlation methods, of the relation of the inhibitory activity with some relevant physicochemical parameters and the free energy thermodynamic parameter of ligands‐COX1 and COX2 complexes obtained by docking.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Isoindoline Derivatives of α‐Amino Acids as Cyclooxygenase 1 and 2 Inhibitors

Percino

Trejo-Muñoz

Díaz-Gandarilla

et al. 2016

Archiv der Pharmazie

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IC50 values were obtained for two series of isoindolines derived from α-amino acids over cyclooxygenase 1 and 2 (COX-1 and COX-2). In order to explain the biological activity observed, a structure-activity relationship (SAR) model was achieved for the tested compounds and 19 reference compounds with known selective inhibitory activity, through the correlation of the binding energies calculated from rigid docking of the best conformations into the catalytic sites of COX-1 and COX-2, as well as their molecular descriptors: Log P, molecular weight (MW), volume (V), and solvation energy (Esol) versus their experimental IC50 values by MLR and LS-SVM methods. The model probed whether the COX-1 and COX-2 inhibitory activities of the isoindolines correlate with steric, hydrophobic, and thermodynamic parameters. The correlation values with MLR for COX-1 and COX-2 (r(2) = 0.4193 and r(2) = 0.5929) were optimized with LS-SVM until r(2) = 0.6818 for COX-1 and r(2) = 0.8985 for COX-2, resulting in a good predictive ability for COX-1 and -2 inhibition with this model. In conclusion, the data suggests that the physicochemical descriptors evaluated have an impact on the inhibitory activity and selectivity of isoindolines over COX-1 and COX-2.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Isoindoline Derivatives of α‐Amino Acids as Cyclooxygenase 1 and 2 Inhibitors

Percino

Trejo-Muñoz

Díaz-Gandarilla

et al. 2016

Archiv der Pharmazie

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“…Regarding the anticancer activity of isoindolines, it has been probed their antiproliferative activity of some of their derivate over colon cancer, [11] for treating multiple myeloma, [21) as well as cell lines from hepatocarcinoma, prostate, and pancreatic [22] . This biological effect seems to be related mainly to the inhibition of enzymes like HDACs that participate in the cancer progression [11,23] . Cancer is the leading cause of death worldwide, [24] and its incidence is expected to increase by 70 % over the next two decades.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of New Isoindolines Derived from L‐Α‐Amino Acids and their Selectivity on Cancer Cell Lines

Mancilla Percino,

Hernández Rodríguez,

Mera Jiménez

2024

ChemistrySelect

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Isoindolines are essential from the point of view of synthesis and their biological properties, so this work is focused on the synthesis of new isoindolines derived from the following L‐α‐amino acids, aspartic acid (1), arginine (2), glutamic acid (3‐5), serine (6), and lysine (7). All compounds were characterized by 1H and 13C NMR, infrared, and high‐resolution mass spectrometry. In addition, the synthesized compounds were screened to investigate their antiproliferative activities against five human cancer cell lines, A549, U373, MDA‐MB‐231, MCF‐7, and HeLa, as well as on primary cell culture healthy, MGC, EC, and Vero cells lines. All tested compounds exhibited activity against cancer cell lines at mM concentrations. Notably, compounds 6 derived from Ser, and 7 derived from Lys exhibited remarkable effects on the A549 and U373. The IC50 values for these compounds were determined to be 0.001 and 0.007 mM, respectively. These findings indicate a significantly higher potency of compounds 6 and 7 than the other tested compounds. Among the tested compounds, only compound 5 displayed significant cytotoxic activity against the Vero cell line.

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“…On this background, our research has been interesting in the synthesis of compounds derived from α‐amino acids and in researching their biological properties, for instance, we have synthesized and carried out docking studies and in vitro assays of some 2,3‐dihydro‐1 H ‐isoindole derived from α‐amino acids as channel blockers, Cox‐1 and ‐2 inhibitors, effect over HDAC8 activity and expression, and HDACs inhibitors, as well as effect on the K14E6 transgenic mouse model (Mancilla et al, 2001; Mancilla‐Percino et al, 2010, 2016; Rodríguez‐Uribe et al, 2018, 2020; Santamaria‐Herrera et al, 2016; Trejo Muñoz et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…On this background, our research has been interesting in the synthesis of compounds derived from αamino acids and in researching their biological properties, for instance, we have synthesized and carried out docking studies and in vitro assays of some 2,3-dihydro-1H-isoindole derived from αamino acids as channel blockers, Cox-1 and -2 inhibitors, effect over HDAC8 activity and expression, and HDACs inhibitors, as well as effect on the K14E6 transgenic mouse model (Mancilla et al, 2001;Mancilla-Percino et al, 2010Rodríguez-Uribe et al, 2018, 2020Santamaria-Herrera et al, 2016;Trejo Muñoz et al, 2014). Thus, continuing with our studies, in this work, we present the synthesis of novel N-aminophalimides 5(ac) and 6(a-c) derived from αamino acids, which have the phthalimide moiety as analogous compounds studied as anticancer agents and HDAC inhibitors, as well as new 3(a-c), 4(a-c) acetamides as precursors of Naminophalimides.…”

mentioning

confidence: 99%

Synthesis of N‐aminophalimides derived from α‐amino acids: Theoretical study to find them as HDAC8 inhibitors by docking simulations and in vitro assays

Guzmán Ramírez,

Mancilla Percino

2023

Chem Biol Drug Des

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Phthalimides are valuable for synthesis and biological properties. New acetamides 3(a–c) and 4(a–c) were synthesized and characterized as precursors for novel N‐aminophalimides 5(a–c) and 6(a–c). Structures of 4a, 5(a–b), and 6(a–b) were confirmed by single crystal X‐ray. Docking studies identified compounds with favorable Gibbs free energy values for binding to histone deacetylase 8 (HDAC8), an enzyme targeted for anticancer drug development. These compounds bound to both the orthosteric and allosteric pockets of HDAC8, similar to Trichostatin A (TSA), an HDAC8 inhibitor. 6(a–c) contain hydroxyacetamide moiety as a zinc‐binding group, a phthalimide moiety as a capping group, and aminoacetamide moiety as a linker group, which are important for ligand‐receptor binding. ΔG values indicated that compounds 5b, 6b, and 6c had higher affinity for HDAC8 in the allosteric pocket compared to TSA. In vitro evaluation of inhibitory activities on HDAC8 revealed that compounds 3(a–c) and 5(a–c) showed similar inhibitory effects (IC50) ranging from 0.445 to 0.751 μM. Compounds 6(a–c) showed better affinity, with 6a (IC50 = 28 nM) and 6b (IC50 = 0.18 μM) showing potent inhibitory effects slightly lower than TSA (IC50 = 26 nM). These findings suggest that the studied compounds hold promise as potential candidates for further biological investigations.

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Effect of two series of isoindolines over HDAC8 activity and expression

Cited by 7 publications

References 19 publications

Isoindoline Derivatives of α‐Amino Acids as Cyclooxygenase 1 and 2 Inhibitors

Isoindoline Derivatives of α‐Amino Acids as Cyclooxygenase 1 and 2 Inhibitors

Synthesis of New Isoindolines Derived from L‐Α‐Amino Acids and their Selectivity on Cancer Cell Lines

Synthesis of N‐aminophalimides derived from α‐amino acids: Theoretical study to find them as HDAC8 inhibitors by docking simulations and in vitro assays

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