MedChemComm最新文献

Fv-antibodies targeting the proprotein convertase (PPC) region of the SARS-CoV-2 spike protein (SP) were screened from an Fv-antibody library to inhibit SARS-CoV-2 infection. Two selected Fv-antibodies were expressed as soluble recombinant proteins, and their binding affinities were assessed using a surface plasmon resonance biosensor. The binding regions of these Fv-antibodies corresponded to the cleavage sites of furin (S1/S2) and transmembrane serine protease 2 (TMPRSS2, S2′). The neutralizing activities of the two Fv-antibodies were demonstrated using a cell-based infection assay with pseudo-viruses carrying the SP of four different SARS-CoV-2 variants: wild-type (D614), delta (B.1.617.2), omicron (BA.2), and omicron (BA.4/5).

Small molecule drug conjugates are an emerging targeted therapy for cancer treatment. Building upon the overexpressed prostate-specific membrane antigen (PSMA) in prostate cancer, we herein report the design and synthesis of a novel PSMA–PI3K small molecule drug conjugate 1. Conjugate 1 demonstrates potent inhibition against PI3K with an IC₅₀ value of 0.40 nM and simultaneously targets PSMA, giving rise to selective growth inhibition activity for PSMA-positive cancer cells. Conjugate 1 also potently inhibits the phosphorylation of PI3K main downstream effectors and arrests the cell cycle in the G0/G1 phase in PSMA-positive 22Rv1 prostate cancer cells. Further in vivo evaluation shows that conjugate 1 has favorable efficacy and tolerability in a 22Rv1 xenograft model, demonstrating its potential application in targeted cancer therapy.

Conjugation of the naturally occurring product piplartine (PPT, 1), which is a potent cytotoxic compound and ROS inducer, with a diphenyl sulfonyl-substituted furoxan moiety (namely, 3,4-bis(phenylsulfonyl)-1,2,5-oxadiazole-2-oxide), an important type of NO donor, via an ether linker of different chain lengths is described, characterized and screened for the anticancer potential. The cytotoxicity of the new hybrids was evaluated on a panel of human cancer cell lines (MCF-7, PC3 and OVCAR-3) and two non-cancer human cells (MCF10A and PNT2). In general, the synthesized hybrids were more cytotoxic and selective compared to their furoxan precursors 4–6 and PPT in the above cancer cells. Particularly, PC3 cells are the most sensitive to hybrids 7 and 9 (IC₅₀ values of 240 nM and 50 nM, respectively), while a lower potency was found for the prostate normal cells (IC₅₀ = 17.8 μM and 14.1 μM, respectively), corresponding to selectivity indices of ca. 75 and 280, respectively. NO generation by the PPT–furoxan compounds in PC3 cells was confirmed using the Griess reaction. Furthermore, the cell growth inhibitory effect of 9 was significantly attenuated by the NO scavenger carboxy-PTIO. The intracellular ROS generation by 7 and 9 was also verified, and different assays showed that co-treatment with the antioxidant N-acetyl-L-cysteine (NAC) provided protection against PPT-induced ROS generation. Further mechanistic studies revealed that 7 and 9 had strong cytotoxicity to induce apoptosis in PC3 cells, being mediated, at least in part, by the NO-release and increase in ROS production. Notably, the ability of 9 to induce apoptosis was stronger than that of 7, which may be attributed to higher levels of NO released by 9. Compounds 7 and 9 modulated the expression profiles of critical regulators of cell cycle, such as CDKN1A (p21), c-MYC, and CCND1 (cyclin D1), as well as induced DNA damage. Overall, tethering the furoxan NO-releasing moiety to the cytotoxic natural product PPT had significant impact on the potential anticancer activity and selectivity of the novel hybrid drug candidates, especially 9, as a result of synergistic effects of both furoxan and PPT's ability to release NO, generate ROS, induce DNA damage, and trigger apoptosis.

We mapped the hydrophobic floor, an interesting subsite at the active site of DNA gyrase B (GyrB) from E. coli. We synthesized three new compounds with pendant groups targeting the hydrophobic floor and evaluated their inhibitory activities on DNA gyrase. A new benzothiazole derivative with a benzyl substituent at position 3 of the benzothiazole ring exhibited strong inhibitory activity against E. coli DNA gyrase (IC₅₀ = 19 ± 3 nM). An exhaustive conformational study using potential energy surfaces (PESs) allowed us to map the new subsite evaluating all critical points on the surface and conformational interconversion pathways. We analyzed the molecular interactions using QTAIM calculations. Our data provide insights into the mechanism of action of these new ligands at the molecular level. Theoretical and experimental data suggest that new ligand optimization strategies should focus on strengthening interactions at the hydrophobic floor while preserving the binding mode of the main scaffold.

Cancer patients undergoing chemotherapy are highly susceptible to infections owing to their compromised immune system, which also promotes cancer progression through inflammation. Thus, this study aimed to develop novel chemotherapeutic agents with both anticancer and antimicrobial properties. A series of diarylurea derivatives based on pyridazinone scaffolds were designed, synthesized, and characterized as surrogates for sorafenib. The synthesized compounds were tested for their antimicrobial activity and screened against 60 cancer cell lines at the National Cancer Institute (NCI). Compound 10h exhibited potent antibacterial activity against Staphylococcus aureus (MIC = 16 μg mL⁻¹), whereas compound 8g showed significant antifungal activity against Candida albicans (MIC = 16 μg mL⁻¹). Additionally, ten compounds were further evaluated for VEGFR-2 inhibition, with compound 17a showing the best inhibitory activity. Compounds 8f, 10l, and 17a demonstrated significant anticancer activity against melanoma, NSCLC, prostate cancer, and colon cancer, with growth inhibition percentages (GI%) ranging from 62.21% to 100.14%. Compounds 10l and 17a were selected for five-dose screening, displaying GI₅₀ values of 1.66–100 μM. Compound 10l induced G0–G1 phase cell cycle arrest in the A549/ATCC cell line, increasing the cell population from 85.41% to 90.86%. Gene expression analysis showed that compound 10l upregulated pro-apoptotic genes p53 and Bax and downregulated the anti-apoptotic gene Bcl-2. Molecular docking studies provided insights into the binding modes of the compounds to the VEGFR-2 enzyme. In conclusion, the pyridazinone-based diarylurea derivatives developed in this study show promise as dual-function antimicrobial and anticancer agents, warranting further investigation.

Accumulating evidence suggests that the root of drug chemoresistance in ovarian cancer is tightly associated with subpopulations of cancer stem cells (CSCs), whose activation is largely associated with signal transducer and activator of transcription 3 (STAT3) signaling. Recently, celastrol has shown a significant anti-cancer effect on ovarian cancer, but its clinical translation is very challenging due to its oral bioavailability and high organ toxicity. In this study, a celastrol derivative (Cel-N) was synthesized to augment the overall efficacy, and its underlying mechanisms were also explored. Different ovarian cancer cells, SKOV3 and A2780, were used to evaluate and compare the anticancer effects. Cel-N displayed potent activities against all the tested ovarian cancer cells, with the lowest IC₅₀ value of 0.14–0.25 μM. Further studies showed that Cel-N effectively suppressed the colony formation and sphere formation ability, decreased the percentage of CD44⁺CD24⁻ and ALDH⁺ cells, and induced ROS production. Furthermore, western blot analysis indicated that Cel-N significantly inhibited both Tyr705 and Ser727 phosphorylation and reduced the protein expression of STAT3. In addition, Cel-N could dramatically induce apoptosis and cell cycle arrest, and inhibit migration and invasion. Importantly, Cel-N showed a potent antitumor efficacy with no or limited systemic toxicity in mice xenograft models. The anticancer effect of Cel-N is stronger than celastrol. Cel-N attenuates cancer cell stemness, inhibits the STAT3 pathway, and exerts anti-ovarian cancer effects in cell and mouse models. Our data support that Cel-N is a potent drug candidate for ovarian cancer.

Pharmacologically active small organic molecules derived from natural resources are prominent drug candidates due to their inherent structural diversity. Herein, we explored one such bioactive molecule, niloticin, which is a tirucallane-type triterpenoid isolated from the stem barks of Aphanamixis polystachya (Wall.) Parker. After initial screening with other isolated compounds from the same plant, niloticin demonstrated selective cytotoxicity against cervical cancer cells (HeLa) with an IC₅₀ value of 11.64 μM. Whereas the compound exhibited minimal cytotoxicity in normal epithelial cell line MCF-10A, with an IC₅₀ value of 83.31 μM. Subsequently, in silico molecular docking studies of niloticin based on key apoptotic proteins such as p53, Fas, FasL, and TNF β revealed striking binding affinity, reflecting docking scores of −7.2, −7.1, −6.8, and −7.2. Thus, the binding stability was evaluated through molecular dynamic simulation. In a downstream process, the apoptotic capability of niloticin was effectively validated through in vitro fluorimetric assays, encompassing nuclear fragmentation. Additionally, an insightful approach involving surface-enhanced Raman spectroscopy (SERS) re-establishes the occurrence of DNA cleavage during cellular apoptosis. Furthermore, niloticin was observed to induce apoptosis through both intrinsic and extrinsic pathways. This was evidenced by the upregulation of upstream regulatory molecules such as CD40 and TNF, which facilitate the activation of caspase 8. Concurrently, niloticin-induced p53 activation augmented the expression of proapoptotic proteins Bax and Bcl-2 and downregulation of IAPs, leading to the release of cytochrome C and subsequent activation of caspase 9. Therefore, the reflection of mitochondrial-mediated apoptosis is in good agreement with molecular docking studies. Furthermore, the anti-metastatic potential was evidenced by wound area closure and Ki67 expression patterns. This pivotal in vitro assessment confirms the possibility of niloticin being a potent anti-cancer drug candidate, and to the best of our knowledge, this is the first comprehensive anticancer assessment of niloticin in HeLa cells.

A series of 14 conjugates of 2α,3β,23-triacetyl-madecassic acid and silybin were designed and synthesized. The madecassic acid unit was linked to silybin either directly at position C-7 or C-3; or through an amino acid linker (glycine, β-alanine, or 11-aminoundecanoic acid) at position C-3. The conjugates were tested in vitro for their cytotoxic effect on HepG2 cells using the MTT assay. The results confirmed that the conjugated compounds demonstrated a stronger cytotoxic effect compared to the parent compounds. Of these compounds, the most promising conjugate, compound 8, was evaluated for cytotoxic activity in the additional Hep3B, Huh7, and Huh7R human hepatocellular carcinoma cell lines and also for cell cycle changes and induction of apoptosis in HepG2 cells. This compound caused a rapid and significant induction of caspase 3 activity and induced cell cycle arrest in the S phase – effects distinct from the activity of madecassic acid. This is the first study on the synthesis and cytotoxicity of madecassic acid–silybin conjugates, and of their testing against liver cancer cell lines and provides evidence for a distinct biological profile versus madecassic acid alone.

Rho-associated coiled-coil containing kinase (ROCK) plays an important role in inflammation. Herein, a series of compounds were designed and synthesized as ROCK inhibitors based on the structure-based drug design (SBDD) strategy and were evaluated for cytotoxicity, antioxidant activity and anti-inflammatory activity. Among them, compound DC24 was identified as the optimal hit in enzymatic screening with an IC₅₀ value of 0.124 μM against ROCK2 and 50-fold selectivity over ROCK1. DC24 has a novel lipid amide scaffold with a bis(4-fluorophenyl)methyl substituent, and DC24 is the first ROCK2 inhibitor interacting with the hinge region of ROCK2 via the 1,2-dithiolan-3-yl motif, which has been confirmed by the binding model of DC24 with ROCK2. In a complete Freund's adjuvant (CFA) induced acute inflammation model, DC24 at a dose of 5 mg kg⁻¹ exhibited an anti-inflammatory effect better than that of belumosudil. Furthermore, DC24 exhibits good safety in vivo.

The natural marine betaine norzooanemonin (1,3-dimethylimidazolim-4-carboxylate) and its methyl and ethyl esters were used as ligand precursors to prepare a systematic series (12 members) of neutral monocarbene gold(I/III) and cationic dicarbene gold(I/III) complexes. The complexes were evaluated as inhibitors of bacterial thioredoxin reductase and for their antiproliferative and antimicrobial activities. While gold complexes with the parent norzooanemonin scaffold resulted in overall poor performance, the more lipophilic esters proved to be highly bioactive agents, related to their higher cellular uptake. The monocarbene gold(I/III) complexes showed significant potency as inhibitors of bacterial thioredoxin reductase. In most assays, the efficacy of both gold(I) and gold(III) analogues was found to be comparable. The cytotoxicity of dicarbene gold(I/III) complexes against cancer cells was strong, in some cases exceeding that of the standard reference auranofin.