Five innovative ternary copper(II) complexes [Cu(OH-PIP)(Phe)Cl](1), [Cu(OH-PIP)(Gly)(H 2 O)]NO 3 • 2H 2 O (2), [Cu(OH-PIP)(Ala)(Cl)]•H 2 O (3), [Cu(OH-PIP)(Met)]PF 6 •2H 2 O (4), and [Cu(OH-PIP)(Gln)(H 2 O)](Cl)• 3H 2 O (5) have been synthesized and characterized by infrared spectroscopy, elemental analysis, and single crystal X-ray diffraction analysis. X-ray crystallography indicates that all Cu atoms are five-coordinated in a square-pyramidal configuration. The complexes have been screened for cytotoxicity against human breast cancer cell lines MCF-7, MDA-MB-231, and CAL-51.The best anticancer activity is obtained with triple-negative breast cancer CAL-51 and MDA-MB-231 cell lines, with IC 50 values in the range of 0.082−0.69 μM. Importantly, the copper compounds were more effective than carboplatin at triggering cell death. Mechanistically, the complexes inhibit proteasomal chymotrypsin-like activity, and docking studies reveal their 20S proteasome binding sites. As a consequence, they cause the accumulation of ubiquitinated proteins, inhibit cell proliferation, and induce apoptosis. In addition, these copper complexes decrease the stemness of triple-negative breast cancer cells and have synergistic effects with CBP on TNBC cells, indicating their great potential as a novel therapy for triple-negative breast cancer.

Enantiopure α-aryl propionic acids are useful building blocks for pharmaceutical research and can be accessed enzymatically using arylmalonate decarboxylases (AMDases) from the corresponding malonic acids. However, the intrinsic instability of malonic acids is a major drawback to this approach in which spontaneous decarboxylation can occur, subsequently eroding enantioselectivity and giving rise to racemic products. This was particularly evident for a panel of N-heterocyclic propionic acids that we wished to access using the approach. Herein, we describe a process to overcome the spontaneous decarboxylation problem in which hydrogenolysis of the corresponding dibenzyl malonates was performed in a biphasic toluene–basic aqueous buffer mixture and telescoped into the subsequent AMDase step. This procedure enabled compounds to be accessed in high enantioselectivities and was successfully demonstrated on 120 g with high yield (76%) and ee (98%).

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MicroRNAs (miRNAs) have been reported to be associated with the modulation of tumor development, including alterations associated with the development of human laryngeal squamous cell carcinoma (LSCC). The present study was designed to investigate whether miRNA‑195 was associated with the pathophysiologic process of human LSCC and to identify its potential roles and underlying molecular mechanisms. To determine whether miRNA‑195 serves a role in LSCC, reverse transcription‑quantitative polymerase chain reaction was used to detect miRNA‑195 expression in LSCC tissues. The tumor‑suppressive effect of miRNA‑195 was determined by in vitro assays. Gain‑of‑function studies using miRNA‑195 mimics were performed to investigate cell viability, migration and invasion, and apoptosis in the AMC‑HN‑8 cell line. Western blotting was performed to reveal the molecular mechanisms of miRNA‑195 and its downstream signaling pathways in the LSCC AMC‑HN‑8 cell line. The present study demonstrated that miRNA‑195 is downregulated in primary LSCC tumors. Upregulating miRNA‑195 in vitro suppressed cell viability, migration and invasion in AMC‑HN‑8 cells. Overexpression of miRNA‑195 alone in AMC‑HN‑8 cells was sufficient to induce cell apoptosis, as identified by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Compared with the high expression of miRNA‑195 in AMC‑HN‑8 cells, the expression levels of vascular endothelial growth factor receptor‑II protein and downstream signaling pathway proteins, which were associated with cell viability, migration, invasion and apoptosis, were markedly decreased compared with control or miRNA‑195 negative control treatment group. Together, these data suggest the therapeutic potential of miRNA‑195 in modulating cell growth, migration and apoptosis during the pathophysiological progression of LSCC and that miRNA‑195 may serve as a potential therapeutic target in human LSCC.

In order to improve the antitumor potency and therapeutic margins of natural product sophoridine, its novel nitrogen mustard carbamate derivatives were designed and synthesized. In screening their in vitro activity, we found all the tested compounds were more potent against the highly aggressive triple‐negative breast cancer cell line MDA‐MB‐231. Cellular functional assays showed that representative compounds could induce G1‐phase arrest and trigger apoptosis, evidenced by the alteration of Bax, Bcl‐2, caspase‐3 and PARP levels. Furthermore, these compounds significantly enhanced the autophagic flux with increased expression of LC3‐II and Beclin‐1, as well as decreased level of p62, which may attribute to simultaneously inhibition of the phosphorylation of p70S6K, 4E‐BP1 and AKT, the key substrates of the mTOR signaling pathway. In vivo, two compounds revealed potent antitumor activity in mice bearing MDA‐MB‐231. Altogether, our work describes novel leads to yield more potent chemotherapeutics against triple‐negative breast cancers, possibly mesenchymal stem‐like subtype.

To elevate the potency of sophoridine, phosphoramidate mustard motif was incorporated to D‐ring opened sophoridine scaffold. A series of acyclic aryloxy phosphoramidate mustard functionalized sophoridine derivatives were synthesized and screened for cytostatic activity in a range of different tumor cell lines (S180, H22, K562, MCF‐7, SMMC‐7721, and LoVo). All these compounds were shown to be more sensitive to S180 and H22 cells with IC50 values ranging from 2.10 to 7.21 μM. In addition, all targeted derivatives distinctly are more cytotoxic to cancer cells than normal cell L929. Compounds 8b, 8c, 8d, and 8e displayed moderate tumor suppression without apparent organ toxicity in vivo against mice bearing H22 liver tumors. Their potential binding modes with DNA topoisomerase I complex have also been investigated.

Novel mustard functionalized sophoridine derivatives were synthesized and evaluated for their cytotoxicity against of a panel of various cancer cell lines. They were shown to be more sensitive to S180 and H22 tumor cells with IC50 values ranging from 1.01–3.65 μM, and distinctly were more cytotoxic to cancer cells than normal cell L929. In addition, compounds 7a, 7c, and 7e displayed moderate tumor suppression without apparent organ toxicity in vivo against mice bearing H22 liver tumors. Furthermore, they arrested tumor cells in the G1 phase and induced cellular apoptosis. Their potential binding modes with DNA-Top I complex have also been investigated.

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