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For a development of broad spectrum antidepressant 3-aminoazetidine derivatives, two series of compounds were explored by bioisosteric modification of 3-α-oxyazetidine. We synthesized 166 novel 3-aminoazetidine derivatives in series A and B, starting from Boc-protected 3-azetidinone (3) and Boc-protected 3-azetidinal (9) respectively, through parallel syntheses. The inhibitory reuptake activities against serotonin (5-HT), norepinephrine (NE), and dopamine (DA) neurotransmitters were measured by the Neurotransmitter Transporter Uptake Assay Kit using the human embryonic kidney 293 (HEK293) cells stably transfected with the respective three kinds of human transporters (hSERT, hNET, and hDAT). Our study aimed to identify compounds having relative inhibitory activities against hSERT > hNET > hDAT. Lead optimization including microsomal stability, CYP, hERG assay, Ames test, BBB, and PK study resulted in the identification of compound 10dl as a candidate for further studies. KEYWORDS: Depression, triple reuptake inhibitor, 3-aminoazetidines, bioisosterism D epression is one of the leading diseases worldwide. Epidemiological studies demonstrate that depressive disorders are highly prevalent; it is estimated that, in general, the lifetime prevalence of major depression was 20% in women and 10% in men. The incidence of depression has risen every year since the early 20th century. There are probably many reasons for this rise, though most studies point to significant socioeconomic changes and complicated circumstances experienced by the younger generation. Pathophysiologically, the cause of depression is commonly associated with a deficiency of monoamine neurotransmitters (serotonin (5-HT), norepinephrine (NE), and dopamine (DA)) in the brain, and a number of antidepressants aim to increase the levels of these neurotransmitters in the synapses.1−4 Since the launch of the first selective serotonin reuptake inhibitors (SSRIs) in the 1980s, second generation antidepressants such as dual 5-HT and NE reuptake inhibitors (SNRIs) or NE and DA reuptake inhibitors (NDRIs) with enhanced properties have been substituted to tricyclic derivatives or monoamine oxidase inhibitors. 5,6 However, a very large percentage of patients treated with SSRIs or SNRIs show partial responses and remission rate around 30%.7 Additionally, the associated side effects such as insomnia, sexual dysfunction, and elevated blood pressure hamper their efficacy. 8,9 In modern therapies for depression, one important strategy to improve the efficacy and/or reduce the delay in the onset of their action is the addition of a DA component to SSRIs or SNRIs. Recent study results support the effect of DA in depression.10 NDRI bupropion enhanced the antidepressant actions of SSRIs and SNRIs in humans, 5,11 and suppression of DA reuptake enhances sexual function and may improve cognitive performance.1,12 An important recent development has been achieved with the discovery of triple reuptake inhibitors (TRIs), broad spectrum antidepressants that are capable of...

Novel 1,4-substituted piperazine derivatives 5, Series A and B were designed by fragment analysis and molecular modification of 4 selected piperazine-containing compounds which possess antidepressant activity. We synthesized new 39 analogues of Series A and 10 compounds of Series B, respectively. The antidepressant screening against DA, NE, and serotonin neurotransmitter uptake inhibition was carried out using the Neurotransmitter Transporter Uptake Assay Kit. The compounds in Series B showed relatively higher reuptake inhibitory activity for SERT, NET, and DAT than those in Series A. The length of spacer between the central piperazine core and the terminal phenyl ring substituted at the piperazine ring in Series B seems to exert an important role in the activity.

Novel azetidines based on the 3-aryl-3-oxypropylamine scaffold were designed, synthesized, and evaluated as TRIs. Reduction of 1 followed by Swern oxidation and then Grignard reaction gave 3. The alkylation of 3 provided the corresponding azetidine derivatives 6, of which the two most promising, 6bd and 6be, were selected from 86 prepared analogues based on their biological profiles. Compound 6be showed activity in vivo in FST at 10 mg/kg IV or 20-40 mg/kg PO.

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Focal adhesion kinase (FAK) is overexpressed in highly invasive and metastatic cancers. To identify novel FAK inhibitors, we designed and synthesized various thieno­[3,2-d]­pyrimidine derivatives. An intensive structure–activity relationship (SAR) study led to the identification of 26 as a lead. Moreover, 26, a multitargeted kinase inhibitor, possesses excellent potencies against FLT3 mutants as well as FAK. Gratifyingly, 26 remarkably inhibits recalcitrant FLT3 mutants, including F691L, that cause drug resistance. Importantly, 26 is superior to PF-562271 in terms of apoptosis induction, anchorage-independent growth inhibition, and tumor burden reduction in the MDA-MB-231 xenograft mouse model. Also, 26 causes regression of tumor growth in the MV4–11 xenograft mouse model, indicating that it could be effective against acute myeloid leukemia (AML). Finally, in an orthotopic mouse model using MDA-MB-231, 26 remarkably prevents metastasis of orthotopic tumors to lymph nodes. Taken together, the results indicate that 26 possesses potential therapeutic value against highly invasive cancers and relapsed AML.

Glioblastoma is the most common and aggressive primary malignant brain tumor. Temozolomide (TMZ), a chemotherapeutic agent combined with radiation therapy, is used as a standard treatment. The infiltrative nature of glioblastoma, however, interrupts effective treatment with TMZ and increases the tendency to relapse. Voltage-gated chloride channels have been identified as crucial regulators of glioma cell migration and invasion by mediating cell shape and volume change. Accordingly, chloride current inhibition by 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB), a chloride channel blocker, suppresses cell movement by diminishing the osmotic cell volume regulation. In this study, we developed a novel compound, TMZ conjugated with NPPB (TMZ-NPPB), as a potential anticancer drug. TMZ-NPPB blocked chloride currents in U373MG, a severely invasive human glioma cell line, and suppressed migration and invasion of U373MG cells. Moreover, TMZ-NPPB exhibited DNA modification activity similar to that of TMZ, and surprisingly showed remarkably enhanced cytotoxicity relative to TMZ by inducing apoptotic cell death via DNA damage. These findings indicate that TMZ-NPPB has a dual function in blocking both proliferation and migration of human glioma cells, thereby suggesting its potential to overcome challenges in current glioblastoma therapy.

Transient receptor potential cation channel subfamily M member 7 (TRPM7) composed of an ion channel and a kinase domain regulates triple‐negative breast cancer (TNBC) cell migration, invasion, and metastasis, but it does not modulate TNBC proliferation. However, previous studies have shown that the combination treatment of nonselective TRPM7 channel inhibitors (2‐aminoethoxydiphenyl borate and Gd3+) with tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) increases antiproliferative effects and apoptosis in prostate cancer cells and hepatic stellate cells. We, therefore, investigated the potential role of TRPM7 in proliferation and apoptosis of TNBC cells (MDA‐MB‐231 and MDA‐MB‐468 cells) with TRAIL. We demonstrated that suppression of TRPM7 via TRPM7 knockdown or pharmacological inhibition synergistically increases TRAIL‐induced antiproliferative effects and apoptosis in TNBC cells. Furthermore, we showed that the synergistic interaction might be associated with TRPM7 channel activities using combination treatments of TRAIL and TRPM7 inhibitors (NS8593 as a TRPM7 channel inhibitor and TG100‐115 as a TRPM7 kinase inhibitor). We reveal that downregulation of cellular FLICE‐inhibitory protein via inhibition of Ca2+ influx might be involved in the synergistic interaction. Our study would provide both a new role of TRPM7 in TNBC cell apoptosis and a potential combinatorial therapeutic strategy using TRPM7 inhibitors with TRAIL in the treatment of TNBC.