Insights into the mechanism of action of pterostilbene against influenza A virus-induced acute lung injury.

BACKGROUND: Severe respiratory system illness caused by influenza A virus infection is associated with excessive inflammation and abnormal apoptosis in alveolar epithelial cells (AEC). However, there are limited therapeutic options for influenza-associated lung inflammation and apoptosis. Pterostilbene (PTE, trans-3,5-dimethoxy-4-hydroxystilbene) is a dimethylated analog of resveratrol that has been reported to limit influenza A virus infection by promoting antiviral innate immunity, but has not been studied for its protective effects on virus-associated inflammation and injury in AEC. PURPOSE: Our study aimed to investigate the protective effects and underlying mechanisms of PTE in modulating inflammation and apoptosis in AEC, as well as its effects on macrophage polarization during influenza virus infection. STUDY DESIGN AND METHODS: A murine model of influenza A virus-mediated acute lung injury was established by intranasal inoculation with 5LD50 of mouse-adapted H1N1 viruses. Hematoxylin and eosin staining, immunofluorescence, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, western blotting, Luminex and flow cytometry were performed. RESULTS: PTE effectively mitigated lung histopathological changes and injury induced by H1N1 viruses in vivo. These beneficial effects of PTE were attributed to the suppression of inflammation and apoptosis in AEC, as well as the modulation of M1 macrophage polarization. Mechanistic investigations revealed that PTE activated the phosphorylated AMP-activated protein kinase alpha (P-AMPKα)/sirtui1 (Sirt1)/PPARγ coactivator 1-alpha (PGC1α) signal axis, leading to the inhibition of nuclear factor kappa-B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) signaling induced by H1N1 viruses, thereby attenuating inflammation and apoptosis in AEC. PTE also forced activation of the P-AMPKα/Sirt1/PGC1α signal axis in RAW264.7 cells, counteracting the activation of phosphorylated signal transducer and activator of transcription 1 (P-STAT1) induced by H1N1 viruses and the augment of P-STAT1 activation in RAW264.7 cells with interferon-gamma (IFN-γ) pretreatment before viral infection, thereby reducing H1N1 virus-mediated M1 macrophage polarization as well as the enhancement of macrophages into M1 phenotypes elicited by IFN-γ pretreatment. Additionally, the promotion of the transition of macrophages towards the M2 phenotype by PTE was also related to activation of the P-AMPKα/Sirt1/PGC1α signal axis. Moreover, co-culturing non-infected AEC with H1N1 virus-infected RAW264.7 cells in the presence of PTE inhibited apoptosis and tight junction disruption, which was attributed to the suppression of pro-inflammatory mediators and pro-apoptotic factors in an AMPKα-dependent manner. CONCLUSION: In conclusion, our findings suggest that PTE may serve as a promising novel therapeutic option for treating influenza-associated lung injury. Its ability to suppress inflammation and apoptosis in AEC, modulate macrophage polarization, and preserve alveolar epithelial cell integrity highlights its potential as a therapeutic agent in influenza diseases.

The Impact of Urbanization on Tree Growth and Xylem Anatomical Characteristics.

In the context of the intensification of global urbanization, how urbanization (urban heat island effect and air pollution) affects urban tree growth is not fully understood. In this paper, the radial growth and xylem anatomical characteristics of three different tree species (Quercus mongolica, Fraxinus mandshurica, and Pinus sylvestris var. mongolica) in urban and rural areas of Harbin were compared by means of tree-ring anatomy. The results showed that there were significant differences in the growth of both broadleaf trees and conifers between urban and rural areas. The vessel number, cumulative area of vessels, and theoretical hydraulic conductivity of all tree species in rural areas were higher than those in urban areas, indicating that urbanization may have the effect of slowing down growth. However, broadleaf trees in urban areas had higher vessel density and a greater percentage of a conductive area within xylem and theoretical xylem-specific hydraulic conductivity. The thickness of cell walls and cell wall reinforcement index of P. sylvestris var. mongolica were strongly reduced by air pollution, implying that it may be more sensitive to urbanization. Compared to Q. mongolica, F. mandshurica showed less sensitivity to urbanization. Warming and drying climate in Harbin may be an important factor affecting tree growth.

Bi2O2Se Nanowire/MoSe2 Mixed-Dimensional Polarization-Sensitive Photodiode with a Nanoscale Ultrafast-Response Channel.

In recent years, polarization-sensitive photodiodes based on one-dimensional/two-dimensional (1D/2D) van der Waals (vdWs) heterostructures have garnered significant attention due to the high specific surface area, strong orientation degree of 1D structures, and large photo-active area and mechanical flexibility of 2D structures. Therefore, they are applicable in wearable electronics, electrical-driven lasers, image sensing, optical communication, optical switches, etc. Herein, 1D Bi2O2Se nanowires have been successfully synthesized via chemical vapor deposition. Impressively, the strongest Raman vibration modes can be achieved along the short edge (y-axis) of Bi2O2Se nanowires with high crystalline quality, which originate from Se and Bi vacancies. Moreover, the Bi2O2Se/MoSe2 photodiode designed with type-II band alignment demonstrates a high rectification ratio of 103. Intuitively, the photocurrent peaks are mainly distributed in the overlapped region under the self-powered mode and reverse bias, within the wavelength range of 400-nm. The resulting device exhibits excellent optoelectrical performances, including high responsivities (R) and fast response speed of 656 mA/W and 350/380 µs (zero bias) and 17.17 A/W and 100/110 µs (-1 V) under 635 nm illumination, surpassing the majority of reported mixed-dimensional photodiodes. The most significant feature of our photodiode is its highest photocurrent anisotropic ratio of ∼2.2 (-0.8 V) along the long side (x-axis) of Bi2O2Se nanowires under 635 nm illumination. The above results reveal a robust and distinctive correlation between structural defects and polarized orientation for 1D Bi2O2Se nanowires. Furthermore, 1D Bi2O2Se nanowires appear to be a great potential candidate for high-performance rectifiers, polarization-sensitive photodiodes, and phototransistors based on mixed vdWs heterostructures.

Polarization-Resolved p-Se/n-WS2 Heterojunctions toward Application in Microcomputer System as Multivalued Signal Trigger.

Polarization-sensitive photodetectors based on van der Waals heterojunctions (vdWH) have excellent polarization-resolved optoelectronic properties that can enable the applications in polarized light identification and imaging. With the development of optical microcomputer control systems (OMCS), it is crucial and energy efficient to adopt the self-powered and polarization-resolved signal-generators to optimize the circuit design of OMCS. In this work, the selenium (Se) flakes with in-plane anisotropy and p-type character are grown and incorporated with n-type tungsten disulfide (WS2 ) to construct the type-II vdWH for polarization-sensitive and self-powered photodetectors. Under 405 nm monochrome laser with 1.33 mW cm-2 power density, the photovoltaic device exhibits superior photodetection performance with the photoelectric conversion efficiency (PCE) of 3.6%, the responsivity (R) of 196 mA W-1 and the external quantum efficiency (EQE) of about 60%. The strong in-plane anisotropy of Se crystal structure gives rise to the capability of polarized light detection with anisotropic photocurrent ratio of ≈2.2 under the 405 nm laser (13.71 mW cm-2 ). Benefiting from the well polarization-sensitive and photovoltaic properties, the p-Se/n-WS2 vdWH is successfully applied in the OMCS as multivalued signal trigger. This work develops the new anisotropic vdWH and demonstrates its feasibility for applications in logic circuits and control systems.

A 12-hour rapid titration method for cancer pain: a randomized, controlled, open-label study.

BACKGROUND: Opioid titration is the best way to achieve a balance of pain relief and tolerable side effects for moderate-to-severe cancer pain. Rapid dose titration helps to achieve early analgesia. We explored the efficacy and safety of a 12-hour rapid dose titration in treating cancer pain. METHODS: Opioid-naïve patients with moderate-to-severe cancer pain were randomly divided into oxycodone group and morphine group. The medicines were adjusted to oxycodone sustained-release tablets after 12 hours, and the dose of oxycodone sustained-release tablets was adjusted every 12 hours. The analgesic efficacy and adverse reactions during the treatment were observed until the 72nd hour. RESULTS: A total of 106 patients were included in the analysis, with 51 patients in the oxycodone group and 55 in the morphine group. The pain control rate of all patients reached 96.2% 24 hours after treatment, and it was not significantly different between two groups (P=0.619). The proportion of Numeric Rating Scale (NRS) score that decreased by ≥50% was significantly higher in the oxycodone group than in the morphine group (P=0.013). In the first 12 hours and 24 hours, significantly lower proportions of patients in the oxycodone group experienced multiple episodes of breakthrough pain (BTP) than in the morphine group (P=0.032, P=0.021, respectively). The quality of life of the patients in the oxycodone group was significantly higher than that in the morphine group at the 24th hour (P=0.047), as was the degree to which the quality of life had improved (P<0.001). Only grade 1 or 2 adverse reactions were observed during the study period, and no significant difference between two groups. CONCLUSIONS: The 12-hour rapid dose titration method can achieve early analgesia, with mild adverse reactions. In particular, the rapid titration method with background sustained-release oxycodone can reduce BTP episodes and achieve significant early pain relief.

Efficacy and safety of apatinib as third- or further-line therapy for patients with advanced NSCLC: a retrospective study.

BACKGROUND: Apatinib, an oral small-molecule angiogenesis inhibitor, selectively inhibits vascular endothelial growth factor receptor 2 (VEGFR-2), which inhibits vascular endothelial growth factor (VEGF) stimulated endothelial cell migration and proliferation and decreases tumour growth and metastasis. Recently, the efficacy of multi-target angiogenic drugs has been demonstrated for many cancers, including non-small-cell lung cancer (NSCLC). The aim of this retrospective study was to evaluate the clinical efficacy of apatinib in patients with advanced NSCLC. PATIENTS AND METHODS: We conducted a retrospective analysis of 70 patients with advanced NSCLC who received second-line and later treatment from November 2015 to July 2017 with poor results. Out of the 70 patients, 36 patients received apatinib treatment after second-line or later treatment, whereas 34 patients in the control group did not receive further treatment. The patients were treated with oral apatinib 500 mg once a day every day for 4 weeks per cycle. Treatment was continued in responding and stable patients until disease progression or intolerable toxicity. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and side effects of the drug were recorded and reviewed. RESULTS: ORR, DCR, PFS, and OS were evaluated in 36 patients receiving apatinib and 34 patients in the control group. The ORR and DCR in patients receiving apatinib therapy were 22.2% and 77.8%, respectively. The median PFS and OS in the treatment group were 5.6 and 9.6 months, respectively. The median OS in the apatinib group was significantly longer than that in the control group (9.6 versus 3.8 months; p < 0.0001). In contrast, there were no differences in adverse reactions between the patients in the treatment and control groups. CONCLUSION: Apatinib showed favourable efficacy and safety and can thus be used as a treatment option for patients with advanced NSCLC.

Discovery of cytotoxic dolastatin 10 analogues with N-terminal modifications.

Auristatins, synthetic analogues of the antineoplastic natural product Dolastatin 10, are ultrapotent cytotoxic microtubule inhibitors that are clinically used as payloads in antibody-drug conjugates (ADCs). The design and synthesis of several new auristatin analogues with N-terminal modifications that include amino acids with α,α-disubstituted carbon atoms are described, including the discovery of our lead auristatin, PF-06380101. This modification of the peptide structure is unprecedented and led to analogues with excellent potencies in tumor cell proliferation assays and differential ADME properties when compared to other synthetic auristatin analogues that are used in the preparation of ADCs. In addition, auristatin cocrystal structures with tubulin are being presented that allow for the detailed examination of their binding modes. A surprising finding is that all analyzed analogues have a cis-configuration at the Val-Dil amide bond in their functionally relevant tubulin bound state, whereas in solution this bond is exclusively in the trans-configuration. This remarkable observation shines light onto the preferred binding mode of auristatins and serves as a valuable tool for structure-based drug design.

The concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung cancer.

It has been demonstrated that erlotinib is effective in treating patients with brain metastasis from non-small-cell lung cancer. However, the number of studies determining the erlotinib concentration in these patients is limited. The purpose of this study was to measure the concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung carcinoma. Six patients were treated with the standard recommended daily dose of erlotinib (150 mg) for 4 weeks. All the patients had previously received chemotherapy, but no brain radiotherapy. At the end of the treatment period, blood plasma and cerebrospinal fluid samples were collected and the erlotinib concentration was determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The average erlotinib concentration in the blood plasma and the cerebrospinal fluid was 717.7±459.7 and 23.7±13.4 ng/ml, respectively. The blood-brain barrier permeation rate of erlotinib was found to be 4.4±3.2%. In patients with partial response (PR), stable disease (SD) and progressive disease (PD), the average concentrations of erlotinib in the cerebrospinal fluid were 35.5±19.0, 19.1±8.7 and 16.4±5.9 ng/ml, respectively. In addition, the efficacy rate of erlotinib for metastatic brain lesions was 33.3%, increasing to 50% in patients with EGFR mutations. However, erlotinib appeared to be ineffective in cases with wild-type EGFR. In conclusion, a relatively high concentration of erlotinib was detected in the cerebrospinal fluid of patients with brain metastases from non-small-cell lung cancer. Thus, erlotinib may be considered as a treatment option for this patient population.

New cytotoxic benzosuberene analogs. Synthesis, molecular modeling and biological evaluation.

In this Letter we describe the synthesis and biological evaluation of new benzosuberene analogs with structural modifications on the B-ring. The focus was initially to probe the chemical space around the B-ring C-8 position. This position was readily available for derivatization chemistry using our recently developed new synthesis for this compound class. Furthermore, we describe two new B-ring analogs, one containing a diene and the other a cyclic ether group. Both new analogs show excellent potencies in tumor cell proliferation assays. In addition, we describe molecular modeling studies that provide a binding rationale for reference compound 8 in the colchicine binding site using the known colchicine crystal structure. We also examine whether the cell based potency data obtained with selected new analogs are supported by modeling results.

Identification of 2-oxatriazines as highly potent pan-PI3K/mTOR dual inhibitors.

We recently described several highly potent, triazine (1) and triazolopyrimidine (2) scaffold-based, dual PI3K/mTOR-inhibitors (e.g., 1, PKI-587) that were efficacious in both in vitro and in vivo models. In order to further optimize these compounds we devised a novel series, the 2-oxatriazines, which also exhibited excellent potency and good metabolic stability. Some 2-oxatriazines showed promising in vivo biomarker suppression and induced apoptosis in the MDA-MB-361 breast cancer xenograft model.

Epidemiological survey of Angiostrongylus cantonensis in the west-central region of Guangdong Province, China.

The study was to understand the Angiostrongylus cantonensis infectious situation of rodent definitive host, snail intermediate host, and local residents in the west-central region of Guangdong Province in China. The snails Achatina fulica and Pomacea canaliculata collected from the survey place were digested with artificial gastric juice, and the third-stage larvae of A. cantonensis in the snails were examined under microscope. The heart and lung of rats captured from the survey place were taken to check the adult of A. cantonensis. The questionnaire surveys related to the infection of A. cantonensis were taken in local residents randomly selected, and the IgG antibody against A. cantonensis was tested in those residents with enzyme-linked immunosorbent assay (ELISA). A total of 1,391 rats including eight kinds of rats, such as Rattus norvegicus, Rattus flavipectus, Bandicota indica, Rattus sladeni, Mus musculus, Rattus rattoides, Suncus Murinus, and Rattus confucianus, were examined and 132 of them were infected by A. cantonensis, with an average infection rate of 9.49% and a mean intensity of A. cantonensis in infected rats was 9.39. A total of 3,184 snails A. fulica and 3,723 snails P. canaliculata were detected. The average infection rates of them were 25.03% (797/3,184) and 6.50% (242/3,723), respectively. There were 180 positive samples of IgG antibody against A. cantonensis in 1,800 serum samples of the residents, with a positive rate of 10.00%. The west-central region of Guangdong Province is the natural focus of A. cantonensis. In comparison with the investigation results in other regions of China, the infection rate of rat definitive host is at the middle level; in the intermediate host, the infection rate of snail A. fulica is above the middle level, and the infection rate of snail Pomacea canaliculata is below the middle level. Some local residents had already been infected by A. cantonensis or at the risk of being infected.

Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor.

PURPOSE: The aim of this study was to show preclinical efficacy and clinical development potential of PKI-587, a dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitor. EXPERIMENTAL DESIGN: In vitro class 1 PI3K enzyme and human tumor cell growth inhibition assays and in vivo five tumor xenograft models were used to show efficacy. RESULTS: In vitro, PKI-587 potently inhibited class I PI3Ks (IC(50) vs. PI3K-α = 0.4 nmol/L), PI3K-α mutants, and mTOR. PKI-587 inhibited growth of 50 diverse human tumor cell lines at IC(50) values of less than 100 nmol/L. PKI-587 suppressed phosphorylation of PI3K/mTOR effectors (e.g., Akt), and induced apoptosis in human tumor cell lines with elevated PI3K/mTOR signaling. MDA-MB-361 [breast; HER2(+), PIK3CA mutant (E545K)] was particularly sensitive to this effect, with cleaved PARP, an apoptosis marker, induced by 30 nmol/L PKI-587 at 4 hours. In vivo, PKI-587 inhibited tumor growth in breast (MDA-MB-361, BT474), colon (HCT116), lung (H1975), and glioma (U87MG) xenograft models. In MDA-MB-361 tumors, PKI-587 (25 mg/kg, single dose i.v.) suppressed Akt phosphorylation [at threonine(T)308 and serine(S)473] for up to 36 hours, with cleaved PARP (cPARP) evident up to 18 hours. PKI-587 at 25 mg/kg (once weekly) shrank large (∼1,000 mm(3)) MDA-MB-361 tumors and suppressed tumor regrowth. Tumor regression correlated with suppression of phosphorylated Akt in the MDA-MB-361 model. PKI-587 also caused regression in other tumor models, and efficacy was enhanced when given in combination with PD0325901 (MEK 1/2 inhibitor), irinotecan (topoisomerase I inhibitor), or HKI-272 (neratinib, HER2 inhibitor). CONCLUSION: Significant antitumor efficacy and a favorable pharmacokinetic/safety profile justified phase 1 clinical evaluation of PKI-587.

Application of quantitative NMR in pharmacological evaluation of biologically generated metabolites: implications in drug discovery.

It is important to gain an understanding of the pharmacological activities of metabolite(s) of compounds in development, especially if they are found in systemic circulation in humans. Pharmacological evaluation of metabolites is normally conducted with synthetic standards, which become available during various stages of drug development. However, the synthesis of metabolite standards may be protracted, taking anywhere from several weeks to months to be completed. This often slows down early pharmacological evaluation of metabolites. Once a metabolite(s) is found to possess comparable (or greater) pharmacological activity than the parent compound, additional studies are performed to better understand the implications of circulating pharmacologically active metabolite(s). To conduct some of these studies as early as possible without slowing the progression of a compound in development is important, especially if critical go or no-go decisions impinge on the outcomes from these studies. Early pharmacological evaluation of significant metabolites is hereby proposed to be conducted in the drug discovery stage so that all pertinent studies and information can be gathered in a timely manner for decision-making. It is suggested that these major metabolites be isolated, either from biological or chemical sources, and quantified appropriately. For biologically generated metabolites, NMR is proposed as the tool of choice to quantitate these metabolites before their evaluation in pharmacological assays. For metabolites that have the same UV characteristics as the parent compound, quantitation can be conducted using UV spectroscopy instead of NMR. In this article, we propose a strategy that could be used to determine the pharmacological activities of metabolites isolated in submilligram quantities.

PKI-179: an orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor.

A series of mono-morpholino 1,3,5-triazine derivatives (8a-8q) bearing a 3-oxa-8-azabicyclo[3.2.1]octane were prepared and evaluated for PI3-kinase/mTOR activity. Replacement of one of the bis-morpholines in lead compound 1 (PKI-587) with 3-oxa-8-azabicyclo[3.2.1]octane and reduction of the molecular weight yielded 8m (PKI-179), an orally efficacious dual PI3-kinase/mTOR inhibitor. The in vitro activity, in vivo efficacy, and PK properties of 8m are discussed.

Antitumor efficacy profile of PKI-402, a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor.

PKI-402 is a selective, reversible, ATP-competitive, equipotent inhibitor of class I phosphatidylinositol 3-kinases (PI3K), including PI3K-alpha mutants, and mammalian target of rapamycin (mTOR; IC(50) versus PI3K-alpha = 2 nmol/L). PKI-402 inhibited growth of human tumor cell lines derived from breast, brain (glioma), pancreas, and non-small cell lung cancer tissue and suppressed phosphorylation of PI3K and mTOR effector proteins (e.g., Akt at T308) at concentrations that matched those that inhibited cell growth. In MDA-MB-361 [breast: Her2(+) and PIK3CA mutant (E545K)], 30 nmol/L PKI-402 induced cleaved poly(ADP-ribose) polymerase (PARP), a marker for apoptosis. In vivo, PKI-402 inhibited tumor growth in MDA-MB-361, glioma (U87MG), and lung (A549) xenograft models. In MDA-MB-361, PKI-402 at 100 mg/kg (daily for 5 days, one round) reduced initial tumor volume of 260 mm(3) to 129 mm(3) and prevented tumor regrowth for 70 days. In MDA-MB-361 tumors, PKI-402 (100 mg/kg, single dose) suppressed Akt phosphorylation (at T308) and induced cleaved PARP. Suppression of phosphorylated Akt (p-Akt) was complete at 8 hours and still evident at 24 hours. Cleaved PARP was evident at 8 and 24 hours. In normal tissue (heart and lung), PKI-402 (100 mg/kg) had minimal effect on p-Akt, with no detectable cleaved PARP. Preferential accumulation of PKI-402 in tumor tissue was observed. Complete, sustained suppression of Akt phosphorylation may cause tumor regression in MDA-MB-361 and other xenograft models. We are testing whether dual PI3K/mTOR inhibitors can durably suppress p-Akt, induce cleaved PARP, and cause tumor regression in a diverse set of human tumor xenograft models. Mol Cancer Ther; 9(4); 976-84. (c)2010 AACR.

Synthesis and SAR of novel 4-morpholinopyrrolopyrimidine derivatives as potent phosphatidylinositol 3-kinase inhibitors.

Significant evidence suggests that deregulation of the PI3K/Akt pathway is important in tumor progression. Mechanisms include loss of function of the tumor suppressor PTEN and high frequency of mutation of the PI3K p110alpha isoform in human malignancies. This connection between PI3K and tumor genesis makes PI3K a promising target for cancer treatment. A series of 4-morpholinopyrrolopyrimidine derivatives were synthesized and evaluated as inhibitors of PI3Kalpha and mTOR, leading to the discovery of PI3Kalpha selective inhibitors (e.g., 9) and dual PI3Kalpha/mTOR kinase inhibitors (e.g., 46 and 48). PI3Kalpha/mTOR dual inhibitors demonstrated inhibition of tumor cell growth in vitro and in vivo and caused suppression of the pathway specific biomarkers [e.g., the phosphorylation of Akt at Thr308 (T308) and Ser473 (S473)] in the human breast cancer cell line MDA361. In addition, compound 46 demonstrated good in vivo efficacy in the MDA361 human breast tumor xenograft model.

Stereoselective synthesis of an active metabolite of the potent PI3 kinase inhibitor PKI-179.

The synthesis and stereochemical determination of 1-(4-(4-((1R,5R,6R)-6-hydroxy-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea (2), an active metabolite of the potent PI3 kinase inhibitor PKI-179 (1), is described. Stereospecific hydroboration of the double bond of 2,5-dihydro-1H-pyrrole 8 gave the 2,3-trans alcohol 9 exclusively. The configuration of the 3-hydroxyl group in 9 was inverted by an oxidation and stereoselective reduction sequence to give the corresponding 2,3-cis isomer 23. Both exo (21) and endo (27) isomers of the metabolite 2 were prepared via a practical synthetic route from 9 and 23, respectively, and the stereochemistry of 2 was determined to be endo. The endo isomer (27) was separated into two enantiomers 28 and 29 by chiral HPLC. Compound 2 was found to be enantiomerically pure and identical to the enantiomer 28. The absolute stereochemistry of the enantiomer 28 was determined by Mosher's method, thus establishing the stereochemistry of the active metabolite 2.

Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor.

The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 26 (PKI-587). Compound 26 has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously. The structure-activity relationships and the in vitro and in vivo activity of analogues in this series are described.

Novel imidazolopyrimidines as dual PI3-Kinase/mTOR inhibitors.

This article describes the syntheses and SAR of a series of imidazolopyrimidine derivatives, which are evaluated as inhibitors of PI3-Kinase (PI3K) and mTOR. These compounds were found to be ATP competitive with good tumor cell growth inhibition, and suppression of pathway specific biomakers such as phosphorylation of Akt at T308.

Lead optimization of N-3-substituted 7-morpholinotriazolopyrimidines as dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors: discovery of PKI-402.

Herein we describe the identification and lead optimization of triazolopyrimidines as a novel class of potent dual PI3K/mTOR inhibitors, resulting in the discovery of 3 (PKI-402). Compound 3 exhibits good physical properties and PK parameters, low nanomolar potency against PI3Kalpha and mTOR, and excellent inhibition of cell proliferation in several human cancer cell lines. Furthermore, in vitro and in vivo biomarker studies demonstrated the ability of 3 to shut down the PI3K/Akt pathway and induce apoptosis in cancer cells. In addition, 3 showed excellent in vivo efficacy in various human cancer xenografts, validating suppression of PI3K/mTOR signaling as a potential anticancer therapy.