Design, Synthesis, and Antitumor Evaluation of 4‑Amino-(1<i>H</i>)‑pyrazole Derivatives as JAKs Inhibitors

Abnormalities in the JAK/STAT signaling pathway lead to many diseases such as immunodeficiency, inflammation, and cancer. Herein, we designed and synthesized a series of 4-amino-(1<i>H</i>)-pyrazole derivatives as potent JAKs inhibitors for cancer treatment. Results from <i>in vitro</i> protein kinase inhibition experiments indicated that compounds <b>3a</b>–<b>f</b> and <b>11b</b> are potent JAKs inhibitors. For example, the IC₅₀ values of compound <b>3f</b> against JAK1, JAK2, and JAK3 were 3.4, 2.2, and 3.5 nM, respectively. In cell culture experiments, compound <b>3f</b> showed potent antiproliferative activity against various cell lines (PC-3, HEL, K562, MCF-7, and MOLT4) at low micromolar levels, while compound <b>11b</b> showed selective cytotoxicity at submicromolar levels against HEL (IC₅₀: 0.35 μM) and K562 (IC₅₀: 0.37 μM) cell lines. It is worth noting that both <b>3f</b> and <b>11b</b> showed more potent antiproliferative activities than the approved JAKs inhibitor Ruxolitinib

Discovery of Novel Pazopanib-Based HDAC and VEGFR Dual Inhibitors Targeting Cancer Epigenetics and Angiogenesis Simultaneously

Herein a novel series of pazopanib hybrids as polypharmacological antitumor agents were developed based on the crosstalk between histone deacetylases (HDACs) and vascular endothelial growth factor (VEGF) pathway. Among them, one <i>ortho</i>-aminoanilide <b>6d</b> and one hydroxamic acid <b>13f</b> exhibited considerable total HDACs and VEGFR-2 inhibitory activities. The HDAC inhibitory activities endowed <b>6d</b> and <b>13f</b> with potent antiproliferative activities, which was not observed in the approved VEGFR inhibitor pazopanib. Compounds <b>6d</b> and <b>13f</b> possessed comparable HDAC isoform selectivity profiles to the clinical class I HDAC inhibitor MS-275 and the approved pan-HDAC inhibitor SAHA, respectively. <b>6d</b> and <b>13f</b> also exhibited uncompromised multiple tyrosine kinases inhibitory activities relative to pazopanib. The intracellular dual inhibition to HDAC and VEGFR of <b>6d</b> and <b>13f</b> was validated by Western blot analysis. In both HUVECs tube formation assay and rat thoracic aorta rings assay, <b>6d</b> and <b>13f</b> showed comparable antiangiogenic potencies to pazopanib. What’s more, <b>6d</b> possessed desirable pharmacokinetic profiles with the oral bioavailability of 72% in SD rats and considerable in vivo antitumor efficacy in a human colorectal adenocarcinoma (HT-29) xenograft model

Optimization of N‑Substituted Oseltamivir Derivatives as Potent Inhibitors of Group‑1 and -2 Influenza A Neuraminidases, Including a Drug-Resistant Variant

On the basis of our earlier discovery of N1-selective inhibitors, the 150-cavity of influenza virus neuraminidases (NAs) could be further exploited to yield more potent oseltamivir derivatives. Among the synthesized compounds, <b>15b</b> and <b>15c</b> were exceptionally active against both group-1 and -2 NAs. Especially for 09N1, N2, N6, and N9 subtypes, they showed 6.80–12.47 and 1.20–3.94 times greater activity than oseltamivir carboxylate (OSC). They also showed greater inhibitory activity than OSC toward H274Y and E119V variant. In cellular assays, they exhibited greater potency than OSC toward H5N1, H5N2, H5N6, and H5N8 viruses. <b>15b</b> demonstrated high metabolic stability, low cytotoxicity in vitro, and low acute toxicity in mice. Computational modeling and molecular dynamics studies provided insights into the role of R group of <b>15b</b> in improving potency toward group-1 and -2 NAs. We believe the successful exploitation of the 150-cavity of NAs represents an important breakthrough in the development of more potent anti-influenza agents