Tetraketones: a new class of tyrosinase inhibitors

Twenty-eight tetraketones (1-28) with variable substituents at C-7 were synthesized and evaluated as tyrosinase inhibitors. Remarkably compounds 25 (IC(50)=2.06 microM), 11 (IC(50)=2.09 microM), 15 (IC(50)=2.61 microM), and 27 (IC(50)=3.19 microM) were found to be the most active compounds of the series, even better than both standards kojic acid (IC(50)=16.67 microM) and L-mimosine (IC(50)=3.68 microM). This study may lead to the discovery of therapeutically potent agents against clinically very important dermatological disorders including hyperpigmentation as well as skin melanoma.     

Synthetic tyrosyl gallate derivatives as potent melanin formation inhibitors

Three tyrosyl gallate derivatives (1-3) with variable hydroxyl substituent at the aromatic ring of tyrosol were synthesized and evaluated as potent inhibitors on tyrosinase activity and melanin formation in melan-a cells. Among three tyrosyl gallate derivatives, 4-hydroxyphenethyl 3,4,5-trihydroxybenote (1) (IC(50)=4.93 microM), 3-hydroxyphenethyl 3,4,5-trihydroxybenote (2) (IC(50)=15.21 microM), and 2-hydroxyphenethyl 3,4,5-trihydroxybenote (3) (IC(50)=14.50 microM) exhibited significant inhibitory effect on tyrosinase activity. Compound 1 was the most active compound, though it did not show the inhibitory effect on melanin formation in melan-a cells. However, compounds 2 (IC(50)=8.94 microM) and 3 (IC(50)=13.67 microM) significantly suppressed the cellular melanin formation without cytotoxicity. This study shows that the position of hydroxyl substituent at the aromatic ring of tyrosol plays an important role in the intracellular regulation of melanin formation in cell-based assay system.     

Synthesis and evaluation of 2',4',6'-trihydroxychalcones as a new class of tyrosinase inhibitors

In this study, we synthesized a series of hydroxychalcones and examined their tyrosinase inhibitory activity. The results showed that 2',4',6'-trihydroxychalcone (1), 2,2',3,4',6'-pentahydroxychalcone (4), 2',3,4,4',5,6'-hexahydroxychalcone (5), 2',4',6'-trihydroxy- 3,4-dimethoxychalcone (9) and 2,2',4,4',6'-pentahydroxychalcone (15) exhibited high inhibitory effects on tyrosinase with respect to l-tyrosine as a substrate. By the structure-activity relationship study, it was suggested that the 2',4',6'-trihydroxyl substructure in the chalcone skeleton were efficacious for the inhibition of tyrosinase activity. And also, the catechol structure on B-ring of chalcones was not advantageous for the inhibitory potency. Furthermore, 15 (IC(50)=1microM) was found to show the highest activity out of a set of 15 hydroxychalcones, even better than both 2,2',4,4'-tetrahydroxychalcone (13, IC(50)=5microM) and kojic acid (16, IC(50)=12microM), which were known as potent tyrosinase inhibitors. Kinetic study revealed that 15 acts as a competitive inhibitor of tyrosinase with K(i) value of 3.1microM.     

New tyrosinase inhibitors selected by atomic linear indices-based classification models

In the present report, the use of the atom-based linear indices for finding functions that discriminate between the tyrosinase inhibitor compounds and inactive ones is presented. In this sense, discriminant models were applied and globally good classifications of 93.51% and 92.46% were observed for non-stochastic and stochastic linear indices best models, respectively, in the training set. The external prediction sets had accuracies of 91.67% and 89.44%. In addition, these fitted models were used in the screening of new cycloartane compounds isolated from herbal plants. A good behavior is shown between the theoretical and experimental results. These results provide a tool that can be used in the identification of new tyrosinase inhibitor compounds.     

Pentacyclic triterpenes. Part 5: synthesis and SAR study of corosolic acid derivatives as inhibitors of glycogen phosphorylases

The synthesis and biological evaluation of corosolic acid derivatives and related compounds as inhibitors of rabbit muscle glycogen phosphorylase a is described. Within this series of compounds, 8 (IC(50)=7.31 microM), 12d (IC(50)=3.26 microM), and 12e (IC(50)=5.1 microM) exhibited more potent activities than the parent compound 1 (IC(50)=20 microM). SAR of these compounds is also discussed.     

Synthesis, biological evaluation, and molecular docking of N-{3-[3-(9-methyl-9H-carbazol-3-yl)-acryloyl]-phenyl}-benzamide/amide derivatives as xanthine oxidase and tyrosinase inhibitors

Claisen-Schmidt condensation of 3-formyl-9-methylcarbazole with various amides of 3-aminoacetophenone afforded N-{3-[3-(9-methyl-9H-carbazol-3-yl)-acryloyl]-phenyl}-benzamide/amide derivatives. All compounds were investigated for their in vitro xanthine oxidase (XO), tyrosinase and melanin production inhibitory activity. Most of the target compounds had more potent XO inhibitory activity than the standard drug (IC(50)=4.3-5.6μM). Interestingly, compound 7q bearing cyclopropyl ring was found to be the most potent inhibitor of XO (IC(50)=4.3μM). Molecular modelling study gave an insight into its binding modes with XO. Compounds 7a, 7d, 7e, 7g, and 7k were found to be potent inhibitors of tyrosinase (IC(50)=14.01-17.52μM). These results suggest the possible use of these compounds for the design and development of novel XO and tyrosinase inhibitors.     

Resveratrol analogues as selective cyclooxygenase-2 inhibitors: synthesis and structure-activity relationship

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is found in grapes and various medical plants. Among cytotoxic, antifungal, antibacterial cardioprotective activity resveratrol also demonstrates non-selective cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) inhibition. In order to find more selective COX-2 inhibitors a series of methoxylated and hydroxylated resveratrol derivatives were synthesized and evaluated for their ability to inhibit both enzymes using in vitro inhibition assays for COX-1 and COX-2 by measuring PGE(2) production. Hydroxylated but not methoxylated resveratrol derivatives showed a high rate of inhibition. The most potent resveratrol compounds were 3,3',4',5-tetra-trans-hydroxystilbene (COX-1: IC(50)=4.713, COX-2: IC(50)=0.0113 microM, selectivity index=417.08) and 3,3',4,4',5,5'-hexa-hydroxy-trans-stilbene (COX-1: IC(50)=0.748, COX-2: IC(50)=0.00104 microM, selectivity index=719.23). Their selectivity index was in part higher than celecoxib, a selective COX-2 inhibitor already established on the market (COX-1: IC(50)=19.026, COX-2: IC(50)=0.03482 microM, selectivity index=546.41). Effect of structural parameters on COX-2 inhibition was evaluated by quantitative structure-activity relationship (QSAR) analysis and a high correlation was found with the topological surface area TPSA (r=0.93). Docking studies on both COX-1 and COX-2 protein structures also revealed that hydroxylated but not methoxylated resveratrol analogues are able to bind to the previously identified binding sites of the enzymes. Hydroxylated resveratrol analogues therefore represent a novel class of highly selective COX-2 inhibitors and promising candidates for in vivo studies.     

Two- and three-dimensional quantitative structure-activity relationships for a series of purine nucleoside phosphorylase inhibitors

Comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis, and hologram quantitative structure-activity relationship (HQSAR) studies were conducted on a series of 52 training set inhibitors of calf spleen purine nucleoside phosphorylase (PNP). Significant cross-validated correlation coefficients (CoMFA, q(2)=0.68; CoMSIA, q(2)=0.66; and HQSAR, q(2)=0.70) were obtained, indicating the potential of the models for untested compounds. The models were then used to predict the inhibitory potency of 16 test set compounds that were not included in the training set, and the predicted values were in good agreement with the experimental results. The final QSAR models along with the information gathered from 3D contour and 2D contribution maps should be useful for the design of novel inhibitors of PNP having improved potency.     

Modeling the molecular basis for α4β1 integrin antagonism

We report a 3D QSAR study of almost 300 structurally diverse small molecule antagonists of the integrin α4β1 whose biological activity spans six orders of magnitude. The alignment of the molecules was based on the conformation of a structurally related ligand bound to the αIIBβ3 and αvβ3 integrins in X-ray crystallographic studies. The molecular field method, CoMSIA, was used to generate the 3D QSAR models. The resulting models showed that the lipophilic properties were the most important, with hydrogen bond donor and steric properties less relevant. The models were highly significant (r(2)=0.89, q2(LOO)=0.67, r(2) (test set)=0.76), and could make robust predictions of the data (SEE=0.46, SEP=0.78, SEP (test set)=0.66). We predicted the antagonist activities of a further ten compounds with useful accuracy. The model appears capable of predicting α4β1 integrin antagonist activity to within a factor of five for compounds within its domain of applicability. The implications for design of improved integrin antagonists will be discussed.     

Cantharimides: a new class of modified cantharidin analogues inhibiting protein phosphatases 1 and 2A.

Cantharidin and its analogues have been of considerable interest as potent inhibitors of the serine/threonine protein phosphatases 1 and 2A (PP1 and PP2A). However, limited modifications to the parent compounds is tolerated. As part of an on-going study we have developed a new series of cantharidin analogues, the cantharimides. Inhibition studies indicate that cantharimides possessing a D- or L-histidine, are more potent inhibitors of PP1 and PP2A (PP1 IC(50)=3.22+/-0.7 microM; PP2A IC(50)=0.81+/-0.1 microM and PP1 IC(50)=2.82+/-0.6 microM; PP2A IC(50)=1.35+/-0.3 microM, respectively) than norcantharidin (PP1 IC(50)=5.31+/-0.76 microM; PP2A IC(50)=2.9+/-1.04 microM) and essentially equipotent with cantharidin (PP1 IC(50)=3.6+/-0.42 microM; PP2A IC(50)=0.36+/-0.08 microM). Cantharimides with non-polar or acidic amino acid residues are only poor inhibitors of PP1 and PP2A.