Pyridine-substituted thiazolylphenol derivatives: Synthesis, modeling studies, aromatase inhibition, and antiproliferative activity evaluation (original) (raw)
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Turkish Computational and Theoretical Chemistry, 2020
Aromatase is an estrogen biosynthesis enzyme belonging to the cytochrome P450 family that catalyzes the rate-limiting step of converting androgens to estrogens. As it is pertinent toward tumor cell growth promotion aromatase is a lucrative therapeutic target for breast cancer. In the pursuit of robust aromatase inhibitors, a set of thirty 1-substituted mono-and bis-benzonitrile or phenyl analogs of 1.2.3triazole letrozole were employed in quantitative structure activity relationship (QSAR) study using multiple linear regression (MLR).The results demonstrated good predictive ability for the MLR model. After dividing the dataset into training and test set. The models were statistically robust internally (R 2 = 0.982) and the model predictability was tested by several parameters, including the external criteria (R 2 pred = 0.851. CCC= 0.946). Insights gained from the present study are anticipated to provide pertinent information contributing to the origins of aromatase inhibitory activity and therefore aid in our ongoing quest for aromatase inhibitors with robust properties.
Synthesis and molecular docking of 1,2,3-triazole-based sulfonamides as aromatase inhibitors
Bioorganic & Medicinal Chemistry, 2015
A series of 1,4-disubstituted-1,2,3-triazoles (13-35) containing sulfonamide moiety were synthesized and evaluated for their aromatase inhibitory effects. Most triazoles with open-chain sulfonamide showed significant aromatase inhibitory activity (IC 50 = 1.3-9.4 lM). Interestingly, the meta analog of triazolebenzene-sulfonamide (34) bearing 6,7-dimethoxy substituents on the isoquinoline ring displayed the most potent aromatase inhibitory activity (IC 50 = 0.2 lM) without affecting normal cell. Molecular docking of these triazoles against aromatase revealed that the compounds could snugly occupy the active site of the enzyme through hydrophobic, p-p stacking, and hydrogen bonding interactions. The potent compound 34 was able to form hydrogen bonds with Met374 and Ser478 which were suggested to be the essential residues for the promising inhibition. The study provides compound 34 as a potential lead molecule of anti-aromatase agent for further development.
Research in Pharmaceutical Sciences, 2017
Aromatase inhibitors (AIs) as effective candidates have been used in the treatment of hormone-dependent breast cancer. In this study, we have proposed 300 structures as potential AIs and filtered them by Lipinski's rule of five using DrugLito software. Subsequently, they were subjected to docking simulation studies to select the top 20 compounds based on their Gibbs free energy changes and also to perform more studies on the protein-ligand interaction fingerprint by AuposSOM software. In this stage, anastrozole and letrozole were used as positive control to compare their interaction fingerprint patterns with our proposed structures. Finally, based on the binding energy values, one active structure (ligand 15) was selected for molecular dynamic simulation in order to get information for the binding mode of these ligands within the enzyme cavity. The triazole of ligand 15 pointed to HEM group in aromatase active site and coordinated to Fe of HEM through its N4 atom. In addition, two π-cation interactions was also observed, one interaction between triazole and porphyrin of HEM group, and the other was 4-chloro phenyl moiety of this ligand with Arg115 residue.
QSAR modeling of aromatase inhibitory activity of 1-substituted 1,2,3-triazole analogs of letrozole
European Journal of Medicinal Chemistry, 2013
Aromatase is an estrogen biosynthesis enzyme belonging to the cytochrome P450 family that catalyzes the rate-limiting step of converting androgens to estrogens. As it is pertinent toward tumor cell growth promotion, aromatase is a lucrative therapeutic target for breast cancer. In the pursuit of robust aromatase inhibitors, a set of fifty-four 1-substituted mono-and bis-benzonitrile or phenyl analogs of 1,2,3triazole letrozole were employed in quantitative structureeactivity relationship (QSAR) study using multiple linear regression (MLR), artificial neural network (ANN) and support vector machine (SVM). Such QSAR models were developed using a set of descriptors providing coverage of the general characteristics of a molecule encompassing molecular size, flexibility, polarity, solubility, charge and electronic properties. Important physicochemical properties giving rise to good aromatase inhibition were obtained by means of exploring its chemical space as a function of the calculated molecular descriptors. The optimal subset of 3 descriptors (i.e. number of rings, ALogP and HOMOeLUMO) was further used for QSAR model construction. The predicted pIC 50 values were in strong correlation with their experimental values displaying correlation coefficient values in the range of 0.72e0.83 for the cross-validated set (Q CV ) while the external test set (Q Ext ) afforded values in the range of 0.65e0.66. Insights gained from the present study are anticipated to provide pertinent information contributing to the origins of aromatase inhibitory activity and therefore aid in our on-going quest for aromatase inhibitors with robust properties.
QSAR analysis of some azole derivatives as potent aromatase inhibitors
2018
A high proportion of breast tumors are hormone-dependent, implying that endogenous estrogens play a critical role in cancer cell proliferation. One of the most effective strategies for the treatment of breast cancer is reduction of estrogens level by inhibiting aromatase enzyme which is responsible for catalyzing the rate-limiting step in estrogen biosynthesis. A series of azole derivatives as potential aromatase inhibitors were subjected to two different drug design methodologies, QSAR and molecular docking simulation. MLR, FA-MLR, PCR and GA-PLS were employed to make connections between the structural parameters and aromatase inhibitory activity. GA-PLS represented superior results and a model with a high statistical quality (R2 = 0.86 and Q2 = 0.83) for predicting the inhibitory activity. The results can provide useful information for the development of more potent aromatase inhibitors.
Acta Chimica Slovenica, 2016
This article demonstrates the synthesis of 1,2,4-triazole derivatives and their applications in medicine particularly as anti-breast cancer agents which is a major issue of the present. The synthesized compounds were characterized by elemental analysis, FT-IR and NMR. DFT was used to study the quantum chemical calculations of geometries and vibrational wave numbers of 3-hydroxynaphthyl and p-tolyl substituted 1,2,4-triazoles in the ground state. The scaled harmonic vibrational frequencies obtained from the DFT method were compared with those of the FT-IR spectra and found good agreement. The synthesized 1,2,4-triazole-naphthyl hybrids were screened for the anticancer activity against MCF-7 breast cancer lines. Among them compounds 3 and 7 showed broad spectrum anticancer activity with IC 50 values 9.7 μM and 7.10 μM, respectively and their activity is comparable to that of the standard drugs. The molecular model for binding between the compounds (1-8) and the active site of BRCA2 was obtained on the basis of the computational docking results and the structure-activity relationship.
Optimization of the aromatase inhibitory activities of pyridylthiazole analogues of resveratrol
Bioorganic & Medicinal Chemistry, 2012
Aromatase is an established target not only for breast cancer chemotherapy, but also for breast cancer chemoprevention. The moderate and non-selective aromatase inhibitory activity of resveratrol (1) was improved about 100-fold by replacement of the ethylenic bridge with a thiadiazole and the phenyl rings with pyridines (e.g., compound 3). The aromatase inhibitory activity was enhanced over 6000-fold by using a 1,3-thiazole as the central ring and modifying the substituents on the 'A' ring to target the Met374 residue of aromatase. On the other hand, targeting the hydroxyl group of Thr310 by a hydrogen-bond acceptor on the 'B' ring did not improve the aromatase inhibitory activity.
Biochemical and Biophysical Research Communications, 2002
The synthesis, biochemical evaluation and molecular modelling of a series of N-alkylated 4-(4 0 -aminobenzyl)-2-oxazolidinones is described involving the derivatisation of the starting R-or S-enantiomer of 4-benzyl-2-oxazolidinones. The compounds were tested for human placental aromatase (AR) inhibition in vitro and were found, in general, to be more potent than the standard compound, aminoglutethimide (AG). The inhibitory activity of the compounds was rationalised through the use of the novel substrate-heme complex (SHC) approach and suggests that the S-enantiomer based compounds protrude beyond the C(13), C(17), and C(16) area of the steroid backbone, resulting in steric hindrance with the active site of AR and thus reduced inhibitory activity. The R-enantiomer based compounds do not protrude in the same area and as such are not thought to undergo any steric hindrance and in comparison to the S-enantiomer, possess greater inhibitory activity. Ó
Biochemical and Biophysical Research Communications, 2000
A novel molecular modeling study, involving inhibitors bound to the iron of cytochrome P450 heme, is described for nonsteroidal inhibitors of aromatase (AR). Study of compounds such as aminoglutethimide (AG) suggests that it utilizes hydrogen bonding group(s) at the active site which would usually H-bond to the steroid C(17) carbonyl group. Interaction between AG's carbonyl groups and the area of the active site corresponding to the substrate C(3)AO group is not possible due to steric interaction. Possible reasons for the difference in activity of enantiomers of alternative inhibitors is also suggested, as well as the mode of action of the new AR inhibitor, Arimidex-whose inhibitory activity previously has not been rationalized. The present study proposes that it is able to use hydrogen bonding groups at the active site corresponding to the steroid C(17)AO and C(3)AO area, contradicting a previous study where it is postulated that azole-type compounds only use polar groups at the active site corresponding to the steroid D ring. Using the hypotheses of the modeling study, we designed and synthesized a number of novel (enantiomerically pure) inhibitors, which upon biochemical evaluation were found to be good inhibitors; the N-nonyl derivative of the S-enantiomer was found to possess 39% inhibition at 100 M inhibitor concentration (using androstenedione as the substrate), under similar conditions, and AG possessed 20% inhibition.