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Monoamine oxidases (MAOs) are well-known pharmacological targets in neurological and neurodegenerative diseases. However, recent studies have revealed a new role for MAOs in certain types of cancer such as glioblastoma and prostate cancer, in which they have been found overexpressed. This finding is opening new frontiers for MAO inhibitors as potential antiproliferative agents. In light of our previous studies demonstrating how a polyamine scaffold can act as MAO inhibitor, our aim was to search for novel analogs with greater inhibitory potency for human MAOs and possibly with antiproliferative activity. A small in-house library of polyamine analogs (2-7) was selected to investigate the effect of constrained linkers between the inner amine functions of a polyamine backbone on the inhibitory potency. Compounds 4 and 5, characterized by a dianiline (4) or dianilide (5) moiety, emerged as the most potent, reversible, and mainly competitive MAO inhibitors (Ki < 1 µM). Additionally, they exhibited a high antiproliferative activity in the LN-229 human glioblastoma cell line (GI50 < 1 µM). The scaffold of compound 5 could represent a potential starting point for future development of anticancer agents endowed with MAO inhibitory activity.

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Polyamine (PA) catabolism is often reduced in cancer cells. The activation of this metabolic pathway produces cytotoxic substances that might cause apoptosis in cancer cells. Chemical compounds able to restore the level of PA catabolism in tumors could become potential antineoplastic agents. The search for activators of PA catabolism among bicyclononan-9-ones is a promising strategy for drug development. The aim of the study was to evaluate the biological activity of new 3,7-diazabicyclo[3.3.1]nonan-9-one derivatives that have antiproliferative properties by accelerating PA catabolism. Eight bispidine derivatives were synthetized and demonstrated the ability to activate PA catabolism in regenerating rat liver homogenates. However, only three of them demonstrated a potent ability to decrease the viability of cancer cells in the MTT assay. Compounds 4c and 4e could induce apoptosis more effectively in cancer HepG2 cells rather than in normal WI-38 fibroblasts. The lead compound 4e could significantly enhance cancer cell death, but not the death of normal cells if PAs were added to the cell culture media. Thus, the bispidine derivative 4e 3-(3-methoxypropyl)-7-[3-(1H-piperazin-1-yl)ethyl]-3,7-diazabicyclo[3.3.1]nonane could become a potential anticancer drug substance whose mechanism relies on the induction of PA catabolism in cancer cells.

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Conformationally restrained polyamine analog PG11047 is a well-known drug candidate that modulates polyamine metabolism and inhibits cancer cell growth in a broad spectrum of cancers. Here, we report a structure-activity relationship study of the PG11047 analogs (HPGs) containing alkyl chains of varying length, while keeping the unsaturated spermine backbone unchanged. Synthesis of higher symmetrical homologues was achieved through a synthetic route with fewer steps than the previous route to PG11047. The amphiphilic HPG analogs underwent self-assembly and formed spherically shaped nanoparticles whose size increased with the hydrophobic alkyl group's increasing chain length. Assessment of the in vitro anticancer activity showed more than an eight-fold increase in the cancer cell inhibition activity of the analogs with longer alkyl chains compared to PG11047 in human colon cancer cell line HCT116, and a more than ten-fold increase in human lung cancer cell line A549. Evaluation of the inhibition of spermine oxidase (SMOX) showed no activity for PG11047, but activity was observed for its higher symmetrical homologues. Comparison with a reference SMOX inhibitor MDL72527 showed nine-fold better activity for the best performing HPG analog.

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Polyamine levels are elevated in breast tumors compared to those of adjacent normal tissues. The female sex hormone, estrogen is implicated in the origin and progression of breast cancer. Estrogens stimulate and antiestrogens suppress the expression of polyamine biosynthetic enzyme, ornithine decarboxylate (ODC). Using several bis(ethyl)spermine analogues, we found that these analogues inhibited the proliferation of estrogen receptor-positive and estrogen receptor negative breast cancer cells in culture. There was structure-activity relationship in the efficacy of these compounds in suppressing cell growth. The activity of ODC was inhibited by these compounds, whereas the activity of the catabolizing enzyme, spermidine/spermine N¹-acetyl transferase (SSAT) was increased by 6-fold by bis(ethyl)norspermine in MCF-7 cells. In a transgenic mouse model of breast cancer, bis(ethyl)norspermine reduced the formation and growth of spontaneous mammary tumor. Recent studies indicate that induction of polyamine catabolic enzymes SSAT and spermine oxidase (SMO) play key roles in the anti-proliferative and apoptotic effects of polyamine analogues and their combinations with chemotherapeutic agents such as 5-fluorouracil (5-FU) and paclitaxel. Thus, polyamine catabolic enzymes might be important therapeutic targets and markers of sensitivity in utilizing polyamine analogues in combination with other therapeutic agents.

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Polyamines play critical roles as regulators of cell growth and differentiation. In contrast with other protozoa, the human parasite Trypanosoma cruzi, the etiological agent of Chagas disease, is auxotrophic for polyamines. Therefore, their intracellular availability depends exclusively on polyamine transport and inhibition of these uptake processes can alter the viability of the parasite. The polyamine analogues used in this work were successfully tested as antiproliferative agents in cancer cells, bacteria, fungi and also showed a potent antiplasmodial effect. We evaluated the activity of these compounds on polyamine transport in T. cruzi and assessed the effects on parasite viability. Three polyamine derivatives, AMXT1501, Ant4 and Ant44, inhibited the putrescine transport in epimastigotes (the insect stage of T. cruzi) with calculated IC50 values of 2.43, 5.02 and 3.98 µM, respectively. In addition, only Ant4 and Ant44 inhibited spermidine transport with IC50 of 8.78 µM and 13.34 µM, respectively. The Ant4 analogue showed a high trypanocidal effect on trypomastigotes (the bloodstream stage of T. cruzi) with an IC50 of 460 nM, (SI = 12.7) while in epimastigotes the IC50 was significantly higher (16.97 µM). In addition, we studied the effect of the combination of benznidazole, a drug used in treating Chagas disease, with Ant4 on the viability of epimastigotes. The combined treatment produced a significant increase on the inhibition of parasites growth compared with individual treatments. In summary, these results suggest that Ant4, a putrescine conjugate, is a promising compound for the treatment of Chagas disease because it showed a potent trypanocidal effect via its inhibition of polyamine import.

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Rapid tumor cell growth depends on intracellular polyamine levels higher than those of normal cells. Intracellular polyamine depletion inhibits tumor cell proliferation and induces tumor cell apoptosis. Therefore, polyamine metabolism has recently been identified as an important target for anti-tumor therapy. This article briefly summarizes recent polyamine metabolism targeting, polyamine depletion within the tumor cells through a variety of methods, and the antitumor effects of the treatment.

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The ability of symmetrically substituted long chain polymethylene tetramines, methoctramine (1) and its analogs 2-4 to kill cancer cells was studied. We found that an elevated cytotoxicity was correlated with a 12 methylene chain length separating the inner amine functions (6-12-6 carbon backbone), together with the introduction of diphenylethyl moieties on the terminal nitrogen atoms (compound 4) of a tetramine backbone. Compound 4 triggered dissipation of mitochondrial transmembrane potential and increased intracellular peroxide levels, leading to a caspase-independent HeLa cell death associated with a rapid activation of autophagy. The antioxidant N-acetylcysteine inhibited cell death and activation of autophagy, indicating a link between oxidative stress and autophagy. Autophagy was rapidly triggered even by tetramines 2 and 3, indicating that is related to their polyamine structure. Autophagy did not protect HeLa cells against cytotoxicity elicited by compound 4. The present study shows that, by modifications of the methoctramine structure, it is possible to design polyamine derivatives highly cytotoxic against tumor cells and that the appropriate design of molecules bearing polyamine-like structures leads to powerful inducers of autophagy.

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