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Tyrosine kinases are a subgroup of a large class of protein kinases that transfer phosphate groups from ATP to various amino acid residues. By phosphorylating the tyrosine residues, the tyrosine kinases are responsible for the activation of various proteins through signal transduction cascades, which serves as a ubiquitous mechanism of cell signaling. The frequent success of many tyrosine kinase inhibitors (TKIs) in clinical success and diseasecausing mutations in protein kinases suggests that a large number of kinases may represent therapeutically relevant targets. To date, most of the clinical and preclinical TKIs are ATPcompetitive non-covalent inhibitors, which achieve their selectivity by recognizing the unique features of specific protein kinases. Of growing interest now in the scientific community is the development of irreversible inhibitors that form covalent bonds with cysteines or other nucleophilic residues in the ATP binding pocket. Irreversible TKIs have many potential advantages including prolonged pharmacodynamics, reasonable compound design suitability, high potency, and the ability to validate pharmacological specificity by mutations in reactive cysteine residues. Here, we review recent efforts to develop cysteine-targeting irreversible TKIs and to discuss their patterns of configuration that identify adenosine triphosphate binding pockets and their biological activities.

A set of ninety-eight B-RafV600E inhibitors was used for the development of a molecular docking based QSAR model using linear and non-linear regression models. The integration of docking scores and key interaction profiles significantly improved the accuracy of the QSAR models, providing reasonable statistical parameters (Rtrain2 = 0.935, Rtest2 = 0.728 and QCV2 = 0.905). The established MD-SVR (molecular docking based SMV regression) model as well as model screening of a natural product database was carried out and two natural products (quercetin and myricetin) with good prediction activities were biologically evaluated. Both compounds exhibited promising B-RafV600E inhibitory activities (ICQuercetin50 = 7.59 μM and ICMyricetin50 = 1.56 μM), suggesting a high reliability and good applicability of the established MD-SVR model in the future development of B-RafV600E inhibitors with high efficacy.

In this in vitro study, a series of novel pyrazole derivatives were designed, synthesized, and evaluated against five human cancer cell lines (PC3, A549, HL60, HCT116, and SW620) for their antiproliferative and p53-MDM2 binding inhibitory activities. Although biological evaluations showed that this series of compounds possessed weak p53-MDM2 inhibitory activities, most of them displayed moderate to potent antiproliferative activities against the tested cells lines. Compound 11c exhibited the best potency for MDM2 (FP-IC50 = 29.22 μm) and demonstrated antiproliferative activities in response to the five tested cell lines (IC50 = 4.09-16.82 μm). Compared with the positive control Nutlin-1, there was enhanced antiproliferative activity to p53-mutated or p53-deficient cell lines (SW620, HL60, and PC3).

A series of spiro-indolin-2-one derivatives were designed and synthesized as p53-MDM2 binding inhibitors. Though p53-MDM2 binding inhibitory and activities against p53 wild-type cell lines of most compounds were not that promising, some obtained structures showed moderate to strong inhibitory activities (IC50

p53 is a powerful tumor suppressor, and p53–MDM2 protein–protein interaction has been considered as an attractive cancer therapeutic target. More recently developed small molecules exert their effects by interrupting the p53–MDM2 binding and enhancing the anti-proliferative activities of p53. Small molecules such as Nutlin, MI-63, MI-219, and MI-319 that can activate p53 have shown their anti-tumor effects in different types of malignancies. Drug combinations between p53–MDM2 binding inhibitors with the other anti-proliferative small molecules may allow reduction in the amount of single component with a lower incidence of side effects or better therapeutic effects. In this current review, we present the recent achievements in combination applications between p53–MDM2 binding inhibitors with other small molecules in malignancies. In addition, we discuss how this combination holds promise as a therapeutic strategy for recent and future novel therapies in these diseases.

Hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that mediates the adaptation of tumor cells and tissues to the hypoxic microenvironment, has attracted considerable interest as a potential therapeutic target. Recently, HIF-1α has been recognized as the critical target of cardiac glycosides for cancer therapy, but the molecular mechanism of cardiac glycosides' inhibition of HIF-1α is still poorly understood. In the present study, we observed that neither HIF-1α mRNA levels nor HIF-1α protein degradation are affected by Ouabain. However, Ouabain was found to be associated with the regulation of HIF-1α translation. Basing on in silico, in vitro and ex vivo models of translation processing, further studies revealed that eIF4E plays a critical role in the inhibitory effect of Ouabain on HIF-1α protein synthesis, rather than mTORC1, eIF2α signaling or Na(+)/K(+)-ATPase inhibition. Mechanistically, Ouabain directly binds eIF4E, disrupts eIF4E/eIF4G association (200 μM, Inhibit rate =61 ± 3%) but not the eIF4E/mRNA complex formation (200 μM, Inhibit rate =18 ± 5%) both in vitro and in cells, thereby inhibiting the intracellular cap-dependent translation. The association between Ouabain and eIF4E not only raises the hope of using cardiac glycosides for cancer therapeutics more rational, but also offers a pharmacologic means for developing novel anti-cancer HIF-1α antagonists.

It has been a long story of the development of anticancer metallopharmaceuticals since the identification of cisplatin. Advances in metallodrugs discovery during the past 40 years have made it an ever-growing area of research in medicinal inorganic chemistry. Meanwhile, the emerging of N-heterocyclic carbene (NHC) chemistry has stimulated the newly burgeoning interests in the biomedical applications of metal-NHC complexes. This review will detail what have been achieved hitherto in the research of metal-NHC complexes as potential anti-tumor agents coupled with gold, silver, copper, platinum and palladium. Their mechanism of action will also be discussed. All the results obtained indicate that this promising approach is worthy of more focuses and further studies.

A series of pyrimido[4,5-b]quinoline-2,4-dione derivatives was synthesized and evaluated for their cytotoxic activities in vitro against five human cancer cell lines. Selected compounds were tested for their MDM2 E3 ligase inhibitory activities and p53-MDM2 binding inhibitory activities. Among tested compounds, four sulfur-containing compounds (4-7) displayed enhanced cytotoxic activities and better MDM2 E3 ligase inhibitoty activities in comparison with that of HLI98c. Three compounds (4-6) showed better p53-MDM2 binding inhibitory potency with IC50 values ranging from 1.3 μM to 9.0 μM.

Background: Biaryl seven-membered lactones (BSLs), the target compounds are a class of bioactive compounds with anti-arrhythmic activity, which also serve as a starting material or structural units for chemical synthesis. Objective: To report a simple and efficient procedure for the synthesis of biaryl seven-membered lactones. Method: Under microwave, the umpolung reaction was promoted by N-heterocyclic carbenes under oxygen, with anhydrous potassium carbonate as base and with 1,4,7,10,13,16-Hexanoxacyclooctadecane (18-crown-6) as a phase-transfer catalyst. Results: The practical protocol was found to be compatible with different structurally diverse substrates and with moderate to excellent yields. Conclusion: This synthesis method has the advantage of high efficacy and novelty, short reaction time, operation simplicity, mild condition and high yields, providing a useful and atom-economic approach to the synthesis of BSLs.

A series of novel N1-amino-acid substituted 2,4,5-triphenyl imidazoline derivatives was designed and synthesized based on our previous studies. All synthesized target compounds were screened for their p53–MDM2 binding inhibitory activities and anti-proliferative activities against five cancer cell lines. Among them, twelve compounds displayed improved binding inhibitory activities and most compounds showed higher cell growth inhibition activities with IC50 values in the low micromolar range. Compound 6c exhibited marked p53–MDM2 binding inhibitory activity (IC50 = 0.59 μM) which was eightfold more potent than that of Nutlin-1 (IC50 = 4.78 μM). CoMFA analysis was performed based on obtained biological data and resulted in a statistically significant CoMFA model with high predict abilities (q2 = 0.645, r2 = 0.979).

A series of new 4β-anilino-4'-O-demethyl-4-desoxypodophyllotoxin derivatives were prepared and evaluated for their cytotoxicities against four human cancer cell lines including KB, KB/VCR, A549 and 95D. Most compounds showed better growth-inhibition activities against tested cell lines than that of etoposide (VP-16). Preliminary structure-activity relationships (SARs) were concluded and it indicated that the side chains substituted at 4β position of podophyllotoxin significantly influenced the cytotoxic activity, especially for the drug resistance profile. In vivo studies of compound 26c on highly metastatic human lung cancer xenograft in nude mice showed that it can significantly inhibit tumor growth with administrating by oral route.

Etoposide (VP-16), a topoisomerase II (Topo II) inhibitor, has been widely used to treat malignancies. Its clinical application, however, has been hindered by the rise of acquired multidrug resistance (MDR). Here, we report that 4β-{[4-(pyrrolidin-1-ylmethyl)phenyl]amino}-4'-O-Demethyl-4-Epipodophyllotoxin (5k), a novel β-O-demethyl-epipodophyllotoxin analogue, possesses higher antitumor activity than its parent compound (VP-16) in a panel of various human tumor cell lines. More importantly, it was also effective against MDR cells both in vitro and in vivo. Using a KB/VCR MDR tumor xenograft model that overexpresses P-gp, 5k (2.5 mg/kg) exhibited a 2.4-fold higher growth inhibition rate versus VP-16 (5 mg/kg). In contrast, 5k and VP-16 displayed similar antitumor activities in a KB tumor xenograft model. Molecular and cellular mechanism studies revealed that 5k targeted Topo II by trapping DNA-Topo II cleavage complexes that could directly cause DNA damage. There were two distinct cellular responses to DNA damage elicited by the treatment with 5k: at low concentrations (20-80 nM), mitotic entry was arrested through the suppression of the activity of Cyclin B1/Cdc 2 complexes via the ATM/ATR signaling pathway; at high concentrations (1.25-5.00 μM), 5k-induced apoptotic signaling was mediated by the mitochondrial death pathways. Collectively, these data demonstrate the potential value of 5k as an antitumor drug candidate that should be further developed.

A new series of indanone and aurone derivatives have been synthesized and tested for in vitro AChE inhibitory activity by modified Ellman method. Most of them exhibit AChE inhibitory activities superior to rivastigmine. Further, the most potent compound 1g was selected to evaluate the effect on the acquisition and memory impairment by mice step-down passive avoidance test.

A simple and efficient method for the synthesis of spiro[4H-pyran-oxindole] derivatives by means of threecomponent reactions between isatins, malononitrile or ethyl cyano-acetate, and 1,3-dicarbonyl compounds in the presence of catalytic amount of magnesium perchlorate in 50% aqueous ethanol medium has been described.

A series of 3,4,5-trisubstituted aminothiophenes were designed, synthesized, and evaluated for their p53-MDM2 binding inhibitory potency and anti-proliferation activities against A549 and PC3 tumor cell lines. Fourteen compounds had appreciably improved MDM2 binding affinities than lead compound MCL0527 (3) and a few compounds showed comparable activities to that of Nutlin-3. Meanwhile, most of the 3,4,5-trisubstituted aminothiophenes displayed better or equivalent anti-proliferation activities against wild-type p53 cell line A549 compared to that of Nutlin-3. Over ten compounds exhibited desirable selective profiles of p53 status. Particularly, compounds 9, 16 and 18 displayed 22-, 6- and 22-fold selectivity of p53 status, respectively, much better than that of Nutlin-3 (fourfold).

Five series of novel 3,4,5-trisubstituted aminothiophene derivatives and analogs were designed and synthesized based on our previous studies. All target compounds were evaluated for their p53–MDM2 binding inhibitory activities and anti-proliferation activities against A549 and PC3 tumor cell lines. Twelve compounds displayed comparable p53–MDM2 binding inhibitory activities to that of Nutlin-3. Among them, compound 7a exhibited marked binding affinity (IC50 = 0.086 μM). In addition, most target compounds showed potent anti-proliferation activities with IC50 values at low micromolar level. A good selective profile for wild-type p53 expression cell line was also observed. Molecular docking analysis was performed as well to predict possible binding modes of target compounds with MDM2.

The title podophyllotoxin analogues are evaluated for their cytotoxicities against four human cancer cell lines including KB, KB/VCR, A549, and 95D.

Three series of novel imidazoline derivatives were designed, synthesized, and evaluated for their p53–MDM2 binding inhibitory activities, and anti-proliferation activities against PC3, A549, KB, and HCT116 cancer cell lines. Five of the tested compounds showed enhanced p53–MDM2 binding inhibitory potency and anti-proliferation activities in comparison with that of Nutlin-1. Flow cytometric analysis indicated that compound 7c, one of the most potent p53–MDM2 binding inhibitors with a Ki value of 0.6 μM, showed its ability to arrest cell cycle progression.

A new series of 4 beta-anilino-podophyllotoxin analogs have been designed, synthesized and evaluated their bioactivities as novel DNA-topoisomerase II poisons as well as P-glycoprotein (P-gp)-dependent multidrug resistance (MDR) inhibitors. The new compounds show improved potency and efficacy with respect to the parent molecule etoposide (VP-16), one of the semisynthetic derivatives of podophyllotoxin. The treatment of 5k-n in KB/VCR cells caused G(2)/M phase arrest and finally induced apoptosis. Furthermore, molecular docking is applied to testify that 5k-n could not be the substrates of P-gp, which is consistent with the result of MDR1 and P-glycoprotein express tests. The most potent compound 5n is chosen for in vivo studies, the administration of 5n was effective in treatment of cancer with a lower dose than VP-16 in drug-sensitive xenograft model and drug-resistant xenograft model. Compound 5n is a potential drug candidate for anticancer chemotherapy.