Akt acts as a pivotal regulator in the PI3K/Akt signaling pathway and represents a potential drug target for cancer therapy. To search for new inhibitors of Akt kinase, we performed a structure-based virtual screening using the DOCK 4.0 program and the X-ray crystal structure of human Akt kinase. From the virtual screening, 48 compounds were selected and subjected to the Akt kinase inhibition assay. Twenty-six of the test compounds showed more potent inhibitory effects on Akt kinase than the reference compound, H-89. These 26 compounds were further evaluated for their cytotoxicity against HCT-116 human colon cancer cells and HEK-293 normal human embryonic kidney cells. Twelve compounds were found to display more potent or comparable cytotoxic activity compared to compound H-89 against HCT-116 colon cancer cells. The best results were obtained with Compounds a46 and a48 having IC₅₀ values (for HCT-116) of 11.1 and 9.5 µM, respectively, and selectivity indices (IC₅₀ for HEK-293/IC₅₀ for HCT-116) of 12.5 and 16.1, respectively. Through structure-based virtual screening and biological evaluations, we have successfully identified several new Akt inhibitors that displayed cytotoxic activity against HCT-116 human colon cancer cells. Especially, Compounds a46 and a48 may serve as useful lead compounds for further development of new anticancer agents.

Background: SN38 (7-ethyl-10-hydroxycamptothecin) is a camptothecin derivative acts against various tumors. However, SN38 is hydrolyzed in the physiological environment (pH 7.4), and this instability interferes with its potential therapeutic effect. Our objective was to investigate SN38-loaded liposomes to overcome the poor solubility of SN38 and its biodistribution, which further diminish its toxicity. Materials and methods: The sub-100 nm targeted liposomes was employed to deliver SN-38 and evaluate the characterization, release behaviors, cytotoxicity, in vivo pharmacokinetics and biochemical assay. Results: The SN38-loaded targeted liposomes consisted of small (100.49 nm) spherical nanoparticles with negative charge (-37.93 mV) and high entrapment efficiency (92.47%). The release behavior of the SN38-loaded targeted liposomes was fitted with Higuchi kinetics (R₂=0.9860). Free SN38 presented initial burst release. The IC₅₀ for the SN38-loaded targeted liposomes (0.11 µM) was significantly lower than for the SN38 solution (0.37 µM) in the MCF7 cell line (P<0.01). Confocal laser scanning microscopy also confirmed highly efficient accumulation in the MCF7 cells. Pharmacokinetics demonstrated that the SN38-loaded targeted liposomes had a slightly increased half-life and mean residence time and decreased area under the concentration–time curve and maximum concentration. The results suggested that retention was achieved while the exposure of SN38 was significantly decreased. A noninvasive in vivo imaging system also showed that the targeted liposomes selectively targeted MCF7 tumors. In vivo toxicity data demonstrated that the decrease in platelets was significantly improved by SN38-loaded targeted liposomes, and diarrhea was not observed in BALB/c mice. Conclusion: In summary, SN38-loaded targeted liposomes could be a good candidate for application in human breast cancer.

During rheumatoid arthritis (RA) treatment, long-term injection of antitumor necrosis factor α antibodies (anti-TNFα Abs) may induce on-target toxicities, including severe infections (tuberculosis [TB] or septic arthritis) and malignancy. Here, we used an immunoglobulin G1 (IgG1) hinge as an Ab lock to cover the TNFα-binding site of Infliximab by linking it with matrix metalloproteinase (MMP) -2/9 substrate to generate pro-Infliximab that can be specifically activated in the RA region to enhance the selectivity and safety of treatment. The Ab lock significantly inhibits the TNFα binding and reduces the anti-idiotypic (anti-Id) Ab binding to pro-Infliximab by 395-fold, 108-fold compared with Infliximab, respectively, and MMP-2/9 can completely restore the TNFα neutralizing ability of pro-Infliximab to block TNFα downstream signaling. Pro-Infliximab was only selectively activated in the disease site (mouse paws) and presented similar pharmacokinetics (PKs) and bio-distribution to Infliximab. Furthermore, pro-Infliximab not only provided equivalent therapeutic efficacy to Infliximab but also maintained mouse immunity against Listeria infection in the RA mouse model, leading to a significantly higher survival rate (71%) than that of the Infliximab treatment group (0%). The high-selectivity pro-Infliximab maintains host immunity and keeps the original therapeutic efficiency, providing a novel strategy for RA therapy.

Species belonging to the Michelia genus are arboreous plants, growing in the temperate zones of oriental India, southern China, Malaysia, and Indonesia. Various chemical constituents isolated from different species of the genus Michelia include aporphines, oxoaporphines, steroids, benzenoids, and terpenoids. The important biological activities of constituents isolated from Michelia are anticancer, antiplasmodial and antibacterial activities [1]. Lesser-known species, such as Michelia crassipes Y. W. Law, are used as ornamental plants and to obtain essences. [1]. M. crassipes Y. W. Law, a small evergreen shrub tree in Magnoliaceae, is a great ornamental plant with fragrant and dark purple flowers. It became a useful cross-breeding germplasm resource. Field observation in Changsha (China) indicated that its flowers started blooming in late March and continued into early May for about 50 days [2]. In the course of screening for biologically and chemically novel agents from Formosan Magnoliaceous plants [3-7], M. crassipes was chosen for further phytochemical investigation. The compounds derived from the stems include one oxoaporphine, liriodenine (1) [8]; four benzenoids, vanillic acid (2) [9], vanillin (3) [10], p-hydroxybenzoic acid (4) [10], and p-hydroxybenzaldehyde (5) [11]; two amides, N-trans-feruloyltyramine (6) [12] and N-cis-feruloyltyramine (7) [13]; one cyclitol, (-)-liriodendritol (8) [14]. The newly identified novel coronavirus (SARS-CoV-2) has posed a serious threat to human health. COVID-19 is a pandemic disease worldwide and is resulted in millions of deaths and caused rampant economic damage worldwide [15, 16]. Therefore, it is very important to develop the drug against COVID-19. We chose the 3C-like protease (3CL protease) of SARS-CoV-2 which is crucial in viral replication, as our strategy to develop the compound [17, 18]. The inhibitory of efficient potential compounds were screened by protease activity assay. The 100 μM compounds 1-8 or PBS were incubated with 40 nM 3CL protease of COVID-19 for 30 min at RT, followed by the addition of the 10-μM SARS-CoV2 substrate for 60 min at 37°C. The fluorescence intensity was determined to monitor the protease activity. As shown in Table 1, the Protease activity of 3CL protease of COVID-19 could efficiently inhibit via all of our compounds. The results show the inhibitory ability of vanillin acid (2), p-hydroxybenzaldehyde (5), and (-)-liriodendritol (8), which have the potential to be developed to the anti-COVID-19 drugs. These results indicated that the 2, 5, and 8 of M. crassipes could specifically and efficiently inhibit the protease activity of 3CL protease of COVID-19. The stems of M. crassipes Y. W. Law were collected from New Taipei City, Taiwan, May 2016. Plant material was identified by Prof.

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer with a worse prognosis than other types. There are currently no specific approved treatments for TNBC. Albumin is a promising biomimetic material that may be fabricated into nanoparticles to possibly exert passive effects on targeted tumors. Irinotecan has been extensively used in clinical settings, although a high dosage is required due to its low efficiency of conversion into the active metabolite SN-38, also known as 7-ethyl-10-hydroxy-camptothecin. The aim of this work was to optimize SN-38-loaded bovine serum albumin nanoparticles (sBSANPs) and evaluate their potency against TNBC. The sBSANPs were characterized by a small size of about 134–264 nm, a negative charge of −37 to −40 mV, an entrapment efficiency of 59–71%, and a particle yield of 65–86%. The cytotoxicity assays using sBSANPs showed a higher potency specifically against both MDA-MB-468 and MDA-MB-231 cells (ER−, PR−, HER2−) compared to MCF-7 (ER+, PR+, HER2−), and exhibited an extremely low IC₅₀ at the nanomolar levels (2.01–6.82 nM). The release profiles indicated that SN-38 presented an initial burst release within 12 h, and sBSANPs had a slow release pattern. Flow cytometry results showed that the fluorescence intensity of sBSANPs was significantly higher than that of the control group. The confocal images also confirmed that sBSANPs were taken up by MDA-MB-468 cells. Moreover, we found that a larger BSANP size resulted in an increased hemolytic effect. In vivo animal studies demonstrated that loading of SN-38 into bovine serum albumin nanoparticles could minimize the initial concentration without extending the elimination half-life, but significantly minimized the Cmax (p < 0.001) as compared with irinotecan treatment.