The
estrogen receptor α (ERα) is identified as an effective
target for the treatment of ERα+ breast cancer; thus, discovery
of novel selective estrogen receptor degraders (SERDs) are developed
as an effective method to overcome the resistance of breast cancer.
Herein, the hot-spot residues for protein–ligand interaction
between SERDs and ERα are analyzed by molecular dynamic simulation
technology, focusing on the hot-spot residues for four series of designed
and synthesized SERDs. SAR studies revealed that while the acrylic
acid moiety of AZD9496 is scaffold hopping into benzoic
acid, compound D24 exhibits potent binding affinity with
ERα, good degradation efficacy of ERα, and inhibitory
effect against the MCF-7 breast cancer cell line. Besides, D24 also displays good antitumor efficacy in the MCF-7 human breast
cancer xenograft model in vivo, favorable pharmacokinetic properties,
excellent druggability, and good safety property, making D24 as a promising drug candidate of SERD for further evaluation.
Fibroblast
growth factor receptor 4 (FGFR4) has been identified
as a potential target due to its transmission of the FGF19 signaling
pathway, which is critical to hepatocellular carcinoma (HCC). Therefore,
focusing on the specific Cys552 of FGFR4 subtype, we designed and
synthesized a novel family of 1,6-naphthyridin-2(1H)-one derivatives as potent and highly selective FGFR4 inhibitors.
Through detailed structural optimizations, the representative compound A34 exhibited improved FGFR4 inhibitory capability and selectivity
and excellent anti-proliferative activities against FGFR4-dependent
HCC cell lines. Additionally, A34 demonstrated remarkable
antitumor efficacy in a Hep-3B HCC xenograft model, with favorable
pharmacokinetic properties, and low risk of hERG toxicity. A34 also showed moderate inhibitory activities against the FGFR4 V550L
mutant in vitro, which indicates that it has the potential as a novel
anticancer agent for HCC.
Twelve guaianolide-type sesquiterpene oligomers with diverse structures were isolated from the whole plants of Ainsliaea fragrans, including a novel trimer (1) and two new dimers (2, 3). The chemical structures of the new compounds were elucidated through spectroscopic data interpretation and computational calculations. Ainsfragolide ( 1) is an unusual guaianolide sesquiterpene trimer generated with a novel C−C linkage at C 2' −C 15″ , which may be biosynthesized prospectively through a further Michael addition. Cytotoxicity results showed that ainsfragolide (1) was the most potent compound against five cancer cell lines with IC 50 values in the range of 0.4−8.3 μM.
A highly diastereoselective [4 + 1] annulation reaction of in situ generated p-quinone methides for the synthesis of 3-aryl-substituted indolines has been developed.
A one-pot
and step economic reaction involving Rh(III)-catalyzed
C–H thiolation and relay Cu(II)-catalyzed C–N amination
of acetanilide and 2-bromothiophenol is reported here, with several
valuable phenothiazine products obtained. This synthesis protocol
proceeds from easily starting materials, demonstrating high atom economy,
broad substrate scope, and good yield. Furthermore, the directing
group can be easily eliminated, and chlorpromazine is provided in
a large scale; thus this synthesis protocol could be utilized to construct
phenothiazine scaffolds.
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