Synthesis and biological evaluation of novel penindolone derivatives as potential antiproliferative agents against SCLC in vitro.

Small cell lung cancer (SCLC) keeps on the leading cause of cancer mortality world widely, while there is lack of efficient therapeutic drugs especially for the resistant ones. In this work, a compound named penindolone (PND) with new skeleton was found to show weak inhibitory effect (IC50 = 42.5 µM) on H69AR cells (SCLC, adriamycin-resistant) proliferation by screening our in-house compound library. With the aim of improving its low potency, a series of PND derivatives were synthesized and biologically evaluated by the Sulforhodamine B (SRB) assay. Among all tested derivatives, compound 5h possessed higher antiproliferation potency (IC50 = 1.6 µM). Furthermore, preliminary mechanism investigation revealed that 5h was able to induce apoptosis and arrest the cell cycle at G0/G1 phase. These findings suggest that this novel skeleton has expanded the anti-SCLC compound reservoir and provided a new drug lead.

Design, synthesis, and biological evaluation of novel penindolone derivatives as potential inhibitors of hemagglutinin-mediated membrane fusion.

Development and design of anti-influenza drugs with novel mechanisms is of great significance to combat the ongoing threat of influenza A virus (IAV). Hemagglutinin (HA) is regarded as a potential target for the therapy of IAV. Our previous research led to the discovery of penindolone (PND), a new diclavatol indole adduct, as an HA targeting leading compound exhibited anti-IAV activity. To enhance the bioactivity and understand the structure-activity relationships (SARs), 65 PND derivatives were designed and synthesized, and the anti-IAV activities as well as the HA targeting effects were systematically investigated in this study. Among them, compound 5g possessed high affinity to HA and was more effective than PND in terms of inhibiting HA-mediated membrane fusion. Compound 5g may act on the trypsin cleavage site of HA to exhibit a strong inhibition on membrane fusion. In addition, oral administration of 5g can significantly reduce the pulmonary virus titer, attenuate the weight loss, and improve the survival of IAV-infected mice, superior to the effects of PND. These findings suggest that the HA inhibitor 5g has potential to be developed into a novel broad-spectrum anti-IAV agent in the future.

A bioluminescent probe for in vivo imaging of pyroglutamate aminopeptidase in a mouse model of inflammation.

Pyroglutamate aminopeptidase (PGP) specifically cleaves the peptide bond of pyroglutamic acid linked to the N-terminal end of a polypeptide or protein. Previous studies showed that PGP was associated with several physiological processes and diseases especially those involving inflammation. Utilizing a 'caging' strategy, we designed and synthesized a bioluminescence probe (PBL) with a limit-of-detection of 3.7 * 10-4 mU/mL. In vivo imaging in a mouse model of inflammatory liver disease revealed that the probe has excellent sensitivity and selectivity and provides a powerful tool for studying the physiological and pathological processes involving PGP.