Design, synthesis and biological evaluation of novel 4-aminopiperidine derivatives as SMO/ERK dual inhibitors.

The hedgehog (Hh) pathway is tightly related with the formation, metastasis and recurrence of various cancers, which makes it a perfect anticancer target. Smoothened (SMO) is one of its key members. Three drugs targeting the Hh pathway have been successfully used in clinic, and they are all known as SMO inhibitors. However, serious drug resistant problem has limited their clinical application. The interaction of oncogenic ERK pathway with the Hh pathway in multiple ways has been proved as one of the main factors that result in drug resistance. Dual inhibition of the Hh and ERK pathways has displayed synergistic suppression to cancer cells overexpressing both pathways. Herein, we designed and synthesized a series of novel 4-aminopiperidine derivatives as SMO/ERK dual inhibitors, and evaluated their biological activities. The results showed that compounds I-13 displayed strong inhibitory activities towards both SMO and ERK, and it also exhibited significant cytotoxicity against human cholangiocarcinoma RBE cells which overexpress both the Hh and ERK pathways. All the results indicate that compound I-13 is a promising anticancer candidate as a SMO/ERK dual inhibitor.

Synthesis, Biological Evaluation, and Structure-Activity Relationships of 4-Aminopiperidines as Novel Antifungal Agents Targeting Ergosterol Biosynthesis.

The aliphatic heterocycles piperidine and morpholine are core structures of well-known antifungals such as fenpropidin and fenpropimorph, commonly used as agrofungicides, and the related morpholine amorolfine is approved for the treatment of dermal mycoses in humans. Inspired by these lead structures, we describe here the synthesis and biological evaluation of 4-aminopiperidines as a novel chemotype of antifungals with remarkable antifungal activity. A library of more than 30 4-aminopiperidines was synthesized, starting from N-substituted 4-piperidone derivatives by reductive amination with appropriate amines using sodium triacetoxyborohydride. Antifungal activity was determined on the model strain Yarrowia lipolytica, and some compounds showed interesting growth-inhibiting activity. These compounds were tested on 20 clinically relevant fungal isolates (Aspergillus spp., Candida spp., Mucormycetes) by standardized microbroth dilution assays. Two of the six compounds, 1-benzyl-N-dodecylpiperidin-4-amine and N-dodecyl-1-phenethylpiperidin-4-amine, were identified as promising candidates for further development based on their in vitro antifungal activity against Candida spp. and Aspergillus spp. Antifungal activity was determined for 18 Aspergillus spp. and 19 Candida spp., and their impact on ergosterol and cholesterol biosynthesis was determined. Toxicity was determined on HL-60, HUVEC, and MCF10A cells, and in the alternative in vivo model Galleria mellonella. Analysis of sterol patterns after incubation gave valuable insights into the putative molecular mechanism of action, indicating inhibition of the enzymes sterol C14-reductase and sterol C8-isomerase in fungal ergosterol biosynthesis.

Identification of inhibitor against H. pylori HtrA protease using structure-based virtual screening and molecular dynamics simulations approaches.

The HtrA protease of Helicobacter pylori, which efficiently colonizes at the gastric epithelial of host cells, disrupts the mucosal integrity of E-cadherin and spreads inflammatory diseases including gastric cancer by cleaving the cell-cell adhesion of the host. The lack of knowledge on the molecular diversity, structural and functional behavior of HpHtrA necessitated the present study to explore its inhibition mechanism. At first, the similarity of HpHtrA with other gastro-intestinal pathogenic HtrA bacteria and its remote relationship with the Human HtrA homologs were ensured by the phylogenetic analysis and hence was identified as a novel therapeutic target for further design of inhibitors. The three dimensional structure of HpHtrA was modeled and simulated to achieve its stable conformation and was used as a receptor to screen for the possible lead compound through virtual screening (using ∼ 1.3 million compounds). Molecular dynamics simulations followed by the binding energy analysis revealed the affinity of the compound 300040 in forming a stable complex with HpHtrA and thereby revealed its potent role in inhibiting HpHtrA. It is also worthy to mention that, structurally, the ligand binding at the catalytic site of HpHtrA is mainly facilitated by the significant dynamics of L2 loop. Based on the present study, the hydroxyl-piperidine with 4-aminopiperidine scaffold is proposed to be one of the best possible lead compounds for the inhibition of H. pylori.

ZC88, a novel 4-amino piperidine analog, inhibits the growth of neuroblastoma cells through blocking hERG potassium channel.

Many studies have provided convincing evidence for hERG as an important diagnostic and prognostic factor in human cancers, as well as a useful target for antineoplastic therapy. Our previous study also revealed that knockdown of herg gene expression by shRNA interference inhibited the growth of neuroblastoma cells in vitro and in vivo. In the experiment, a novel 4-amino piperidine analog, ZC88, was examined for its effect on hERG potassium channels and its antitumor potency was observed in vitro and in vivo. The results showed that ZC88 could block hERG1 and hERG1b channels expressed in Xenopus oocytes in a concentration-dependent manner. ZC88 displayed significant antiproliferative activity in several tumor cell lines and the tumor cells with higher expression of hERG presented higher sensitivity to ZC88. The mitotic progression of tumor cells was markedly suppressed in the presence of ZC88 through arresting cells in G0/G1 phase. ZC88 significantly inhibited the tumor growth in nude mice at a dosage with slight influence on the cardiac QT interval. The antitumor effect of ZC88 was correlated at least partly with its blockage of hERG channels, which implicated a positive role of hERG potassium channel in tumor cell proliferation.