Search

The epitaxial growth of single-crystal thin films relies on the availability of a single-crystal substrate and a strong interaction between epilayer and substrate. Previous studies have reported the roles of the substrate (

Bruton's tyrosine kinase (BTK) inhibitors suppressing the aberrant activation of BTK have led to a paradigm shift in the therapy of B-cell malignancies. However, there is an urgent need to discover more selective covalent BTK inhibitors owing to the off-target adverse effects of the approved inhibitor, ibrutinib. Herein, we disclose the discovery and preliminary activity studies of novel BTK inhibitors carrying 1-amino-1

Grain size control has been a research field of great importance as it requires the exploration of material formation mechanism, a major decisive factor in obtaining material’s ideal size and structure. The purpose of this experiment was to analyse the effect of cerium ion doping concentration on the transformation of TiO2. Mixed-phase anatase and rutile were prepared for this experiment, providing means to examine the specific transformation relationships at different temperatures for a specific phase, and vice versa. The results of this experiment clearly also deduced the formation mechanism based on the third L. Pauling Principle and Ostward’s rule, and found grain effect of cerium doping on the transition of TiO2.

A variety of terminal alkenes were converted to the corresponding amides in yields of 25 to 86% in water via treatment with 1,3-dibromo-5,5-dimethylhydantoin, followed by reaction with molecular iodine and aq. NH3 (or amine) in one pot. This metal- and organic solvent-free protocol is not only suitable for styrene derivatives, but also, for the first time, works well on terminal aliphatic alkenes.

The field of small-molecule inhibitors of protein–protein interactions is rapidly advancing and the specific area of inhibitors of the p53/MDM2 interaction is a prime example. Several groups have published on this topic and multiple compounds are in various stages of clinical development. Building on the strength of the discovery of RG7112, a Nutlin imidazoline-based compound, and RG7388, a pyrrolidine-based compound, we have developed additional scaffolds that provide opportunities for future development. Here, we report the discovery and optimization of a highly potent and selective series of spiroindolinone small-molecule MDM2 inhibitors, culminating in RO8994.

The cyclin-dependent kinases (CDKs) and their cyclin partners are key regulators of the cell cycle. Since deregulation of CDKs is found with high frequency in many human cancer cells, pharmacological inhibition of CDKs with small molecules has the potential to provide an effective strategy for the treatment of cancer. The 2,4-diamino-5-ketopyrimidines 6 reported here represent a novel class of potent and ATP-competitive inhibitors that selectively target the cyclin-dependent kinase family. This diaminopyrimidine core with a substituted 4-piperidine moiety on the C2-amino position and 2-methoxybenzoyl at the C5 position has been identified as the critical structure responsible for the CDK inhibitory activity. Further optimization has led to a good number of analogues that show potent inhibitory activities against CDK1, CDK2, and CDK4 but are inactive against a large panel of serine/threonine and tyrosine kinases (K(i)10 microM). As one of these representative analogues, compound 39 (R547) has the best CDK inhibitory activities (K(i) = 0.001, 0.003, and 0.001 microM for CDK1, CDK2, and CDK4, respectively) and excellent in vitro cellular potency, inhibiting the growth of various human tumor cell lines including an HCT116 cell line (IC(50) = 0.08 microM). An X-ray crystal structure of 39 bound to CDK2 has been determined in this study, revealing a binding mode that is consistent with our SAR. Compound 39 demonstrates significant in vivo efficacy in the HCT116 human colorectal tumor xenograft model in nude mice with up to 95% tumor growth inhibition. On the basis of its superior overall profile, 39 was chosen for further evaluation and has progressed into Phase I clinical trial for the treatment of cancer.

The development of small-molecule MDM2 inhibitors to restore dysfunctional p53 activities represents a novel approach for cancer treatment. In a previous communication, the efforts leading to the identification of a non-imidazoline MDM2 inhibitor, RG7388, was disclosed and revealed the desirable in vitro and in vivo pharmacological properties that this class of pyrrolidine-based inhibitors possesses. Given this richness and the critical need for a wide variety of chemical structures to ensure success in the clinic, research was expanded to evaluate additional derivatives. Here we report two new potent, selective, and orally active p53-MDM2 antagonists, RO5353 and RO2468, as follow-ups with promising potential for clinical development.

Restoration of p53 activity by inhibition of the p53–MDM2 interaction has been considered an attractive approach for cancer treatment. However, the hydrophobic protein–protein interaction surface represents a significant challenge for the development of small-molecule inhibitors with desirable pharmacological profiles. RG7112 was the first small-molecule p53–MDM2 inhibitor in clinical development. Here, we report the discovery and characterization of a second generation clinical MDM2 inhibitor, RG7388, with superior potency and selectivity.

The p53 tumor suppressor is a potent transcription factor that plays a key role in the regulation of cellular responses to stress. It is controlled by its negative regulator MDM2, which binds directly to p53 and inhibits its transcriptional activity. MDM2 also targets p53 for degradation by the proteasome. Many tumors produce high levels of MDM2, thereby impairing p53 function. Restoration of p53 activity by inhibiting the p53-MDM2 interaction may represent a novel approach to cancer treatment. RG7112 (2g) is the first clinical small-molecule MDM2 inhibitor designed to occupy the p53-binding pocket of MDM2. In cancer cells expressing wild-type p53, RG7112 stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest, apoptosis, and inhibition or regression of human tumor xenografts.

The synthesis of (±)-10,10-dimethylhuperzine A is reported together with its kinetic (k on and k off ) and dissociation constants for the inhibition of fetal bovine serum acetylcholinesterase. While somewhat more potent than (±)-hyperzine A, the dimethyl analogue shows a slower off-rate from AChE, a result that may be of potential therapeutic value.

The synthesis of (±)-10,10-dimethylhuperzine A is reported together with its kinetic (k on and k off ) and dissociation constants for the inhibition of fetal bovine serum acetylcholinesterase. While somewhat more potent than (±)-hyperzine A, the dimethyl analogue shows a slower off-rate from AChE, a result that may be of potential therapeutic value.

A novel series of pyrazolobenzodiazepines 3 has been identified as potent inhibitors of cyclin-dependent kinase 2 (CDK2). Their synthesis and structure-activity relationships (SAR) are described. Representative compounds from this class reversibly inhibit CDK2 activity in vitro, and block cell cycle progression in human tumor cell lines. Further exploration has revealed that this class of compounds inhibits several kinases that play critical roles in cancer cell growth and division as well as tumor angiogenesis. Together, these properties suggest a compelling basis for their use as antitumor agents.

Huperzine A is a potent and selective reversible inhibitor of mammalian acetylcholinesterase (AChE), the enzyme that catalyzes the hydrolysis of acetylcholine in the brain (Wang et al., 1986). In vivo studies have shown that huperzine A has the potential to improve memory in humans (Zhang et al., 1991), while in vitro studies indicate that it is superior to physostigmine and tacrine for the treatment of Alzheimer’s disease (Wang et al., 1986). Due to the promise this drug holds for the palliative treatment of a disease that afflicts millions of individuals worldwide, several studies have explored the structure-activity relationships of this alkaloid (Ashani et al., 1992; Ashani et al., 1994; Saxena et al., 1994). Molecular modeling coupled with site-directed mutagenesis using mouse AChE mutants implicated Tyr337(Phe330) and mouse Trp86(84) in the binding of huperzine A to AChE (Ashani et al., 1994; Saxena et al., 1994). The X-ray crystal structure of the Torpedo AChE-huperzine A complex was recently resolved (Raves et al., 1997). In this structure, the interactions described were a major hydrogen bond between the carbonyl group of huperzine A and Tyr130 of AChE and a minor cation-π interaction between the primary nitrogen group of huperzine A and the aromatic rings of Trp84 and Phe330. However, the observed pharmacological data supports a major role for Y337(F330) in the binding and stereoselectivity of huperzine A for AChE. The superior inhibition properties of huperzine A have been attributed to the very slow dissociation (t05 = 35 min) of the AChE-huperzine A complex in solution (Ashani et al., 1992). In an effort to discover more potent analogues of huperzine A, we chose to investigate the synthesis and biological activity of its C-10 substituted analogues.