Design, Synthesis, and Biological Activity of Sulfonamide Analogues of Antofine and Cryptopleurine as Potent and Orally Active Antitumor Agents

Due to their profound antiproliferative activity and unique mode of action, phenanthro­indolizidine and phenanthro­quinolizidine alkaloids, represented by antofine and cryptopleurine, have attracted attention recently as potential therapeutic agents. We have designed, synthesized, and evaluated the methanesulfonamide analogues of these natural alkaloids with the hope of improving their druglikeness. The analogues showed enhanced growth inhibition of human cancer cells compared with the parent natural products. In particular, a methanesulfonamide analogue of cryptopleurine (<b>5b</b>) exhibited improved bioavailability and significant antitumor activity, which suggests that <b>5b</b> is a promising new anticancer agent. Our studies suggest that the inhibition of cancer cell growth by <b>5b</b> is associated with the induction of G0/G1 cell cycle arrest via nicotinamide <i>N</i>-methyltransferase-dependent JNK activation in Caki-1 renal cancer cells. In addition, compound <b>5b</b> significantly inhibited the migration and invasion of Caki-1 cancer cells by modulating the p38 MAPK signaling pathway

Property-Based Optimization of Hydroxamate-Based γ‑Lactam HDAC Inhibitors to Improve Their Metabolic Stability and Pharmacokinetic Profiles

Hydroxamate-based HDAC inhibitors have promising anticancer activities but metabolic instability and poor pharmacokinetics leading to poor in vivo results. QSAR and PK studies of HDAC inhibitors showed that a γ-lactam core and a modified cap group, including halo, alkyl, and alkoxy groups with various carbon chain linkers, improved HDAC inhibition and metabolic stability. The biological properties of the γ-lactam HDAC inhibitors were evaluated; the compound designated <b>8f</b> had potent anticancer activity and high oral bioavailability

Property-Based Optimization of Hydroxamate-Based γ‑Lactam HDAC Inhibitors to Improve Their Metabolic Stability and Pharmacokinetic Profiles

Hydroxamate-based HDAC inhibitors have promising anticancer activities but metabolic instability and poor pharmacokinetics leading to poor in vivo results. QSAR and PK studies of HDAC inhibitors showed that a γ-lactam core and a modified cap group, including halo, alkyl, and alkoxy groups with various carbon chain linkers, improved HDAC inhibition and metabolic stability. The biological properties of the γ-lactam HDAC inhibitors were evaluated; the compound designated <b>8f</b> had potent anticancer activity and high oral bioavailability

Additional file 1: Table S1. of Biallelic modification of IL2RG leads to severe combined immunodeficiency in pigs

Oligos used to introduce sgRNA into px330. Each pair of forward and reverse primers were annealing and ligated into the PX330 vector. Table S2. Primers used to generate template DNA for in vitro transcription to produce sgRNA and mRNA form of Cas9. Table S3. Primers used to genotype IL2RG mutations introduced by CRISPR/Cas9 system. The extend primers were used to genotype IL2RG from fetus 3 and 6. Table S4. The mutation of fetus. Two fetus contained hemizygous mutation in IL2RG, other two fetus had biallelic mutation, and 2 fetus had presumable large deletion (>1.9kb). (DOCX 22 kb

Development of Novel 1,2,3,4-Tetrahydroquinoline Scaffolds as Potent NF-κB Inhibitors and Cytotoxic Agents

1,2,3,4-Tetrahydroquinolines have been identified as the most potent inhibitors of LPS-induced NF-κB transcriptional activity. To discover new molecules of this class with excellent activities, we designed and synthesized a series of novel derivatives of 1,2,3,4-tetrahydroquinolines (<b>4a</b>–<b>g</b>, <b>5a</b>–<b>h</b>, <b>6a</b>–<b>h</b>, and <b>7a</b>–<b>h</b>) and bioevaluated their <i>in vitro</i> activity against human cancer cell lines (NCI-H23, ACHN, MDA-MB-231, PC-3, NUGC-3, and HCT 15). Among all synthesized scaffolds, <b>6g</b> exhibited the most potent inhibition (53 times that of a reference compound) of LPS-induced NF-κB transcriptional activity and the most potent cytotoxicity against all evaluated human cancer cell lines