Neuroprotective Effects of a Novel Demeclocycline Derivative Lacking Antibiotic Activity: From a Hit to a Promising Lead Compound.

The antibiotic tetracycline demeclocycline (DMC) was recently reported to rescue α-synuclein (α-Syn) fibril-induced pathology. However, the antimicrobial activity of DMC precludes its potential use in long-term neuroprotective treatments. Here, we synthesized a doubly reduced DMC (DDMC) derivative with residual antibiotic activity and improved neuroprotective effects. The molecule was obtained by removal the dimethylamino substituent at position 4 and the reduction of the hydroxyl group at position 12a on ring A of DMC. The modifications strongly diminished its antibiotic activity against Gram-positive and Gram-negative bacteria. Moreover, this compound preserved the low toxicity of DMC in dopaminergic cell lines while improving its ability to interfere with α-Syn amyloid-like aggregation, showing the highest effectiveness of all tetracyclines tested. Likewise, DDMC demonstrated the ability to reduce seeding induced by the exogenous addition of α-Syn preformed fibrils (α-SynPFF) in biophysical assays and in a SH-SY5Y-α-Syn-tRFP cell model. In addition, DDMC rendered α-SynPFF less inflammogenic. Our results suggest that DDMC may be a promising drug candidate for hit-to-lead development and preclinical studies in Parkinson's disease and other synucleinopathies.

Three novel non-nitrogenous cassane diterpenoids from Erythrophleum suaveolens (Guill. et Perr.) Brenan (Fabaceae).

During our research to contribute to the elucidation of the chemical composition of the root bark of E. suaveolens, six non-nitrogenous cassane diterpenoids (1-6) were isolated and identified. Of these secondary metabolites, three have never been previously described: Cassan-13,15-dien-3-oxo-17-oic acid (2), Cassan-15-en-[7,17]-γ-lactone (3) and 6α-hydroxy-cassamic acid (5). The other are known but, never isolated from the root barks of E. suaveolens (Fabaceae): Cassan-13,15-dien-17-oic acid (1), 6α-hydroxy-cassamic acid methyl esther (4) and cassamic acid (6). Their structures were established according to the spectroscopic data (NMR 1D and 2D, HR-ESI-MS and IR), in comparison with those of literature. The originality of this study lies in the fact that three new natural molecules were isolated and identified. In addition, all the isolated compounds (1-6) were reported for the first time from the root barks of E. suaveolens.

Streamlined targeting of Amaryllidaceae alkaloids from the bulbs of Crinum scillifolium using spectrometric and taxonomically-informed scoring metabolite annotations.

Four undescribed alkaloids have been isolated from the bulbs of the previously unstudied Crinum scillifolium. These compounds were targeted following a state-of-the-art molecular networking strategy comprising a dereplication against in silico databases and re-ranking of the candidate structures based on taxonomically informed scoring. The unreported structures span across a variety of Amaryllidaceae alkaloids appendages. Their structures were unambiguously elucidated by thorough interpretation of their HRESIMS and 1D and 2D NMR data, and comparison to literature data. DFT-NMR calculations were performed to support the determined relative configurations of scillitazettine and scilli-N-desmethylpretazettine and their absolute configurations were mitigated by comparison between experimental and theoretically calculated ECD spectra. The lack of a methyl group on the nitrogen atom in the structure of scilli-N-desmethylpretazettine series is highly unusual in the pretazettine/tazettine series but the most original structural feature in it lies in its 11α disposed hydrogen, which is new to pretazettines. The antiplasmodial as well as the cytotoxic activities against the human colon cancer cell line HCT116 were evaluated, revealing mild to null activities.

Five new cassane diterpenes from the seeds and bark of Erythrophleum suaveolens.

Five new cassane-type diterpenoid heterosides, i. e. two cassane-type amides (1-2), two erythrophlamine-type amine esters (3-4) and a non­nitrogenous erythrophlamine analogue (5) were isolated from the root barks (1-2) and the seeds (3-5) of Erythrophleum suaveolens. Their structures were unambiguously established by interpretation of their HRESIMS, 1D and 2D NMR data, and chemical degradation for sugar determination. Compounds 3-5 were evaluated for their cytotoxicity against a panel of three cell lines, revealing modest to strong activities.

Spectroscopic data of new cassane diterpenoids from the root bark of Erythrophleum suaveolens.

The data are related to the research article entitled ''New cassane diterpenoids from the root bark of Erythrophleum suaveolens'' (Jacques et al., 2019). The article provides method of purification and data to determine structure of two novel cassane diterpenoid amines: 3ß-hydroxy-3-methylbutanoyloxy-6α-hydroxy-nor-cassamine (1) and 3ß-hydroxy-3-methylbutanoyloxy-erythrosuamine (2). This data in brief provides IR, NMR and Q-TOF-MS spectra, along with fragmentation pathways that allowed to the identification of both new compounds.

Identification of a Novel 1,4,8-Triazaphenanthrene Derivative as a Neuroprotectant for Dopamine Neurons Vulnerable in Parkinson's Disease.

Parkinson's disease (PD) is a chronic degenerative disorder characterized by typical motor symptoms caused by the death of dopamine (DA) neurons in the midbrain and ensuing shortage of DA in the striatum, at the level of nerve terminals. No curative treatment is presently available for PD in clinical practice. In our search for neuroprotectants in PD, we generated new 1,4,8-triazaphenanthrenes by combining 6-endo-dig-cycloisomerization of propargylquinoxalines and Suzuki or Sonogashira cross-coupling reactions. Neuroprotection assessment of newly synthesized 1,4,8-triazaphenanthrenes in a PD cellular model resulted in the discovery of a new hit compound PPQ (5m). Neuroprotection by 5m was concentration-dependent and the result of a combined effect on intracellular calcium release channels and astroglial cells. Of interest, 5m also counteracted DA cell loss in a mouse model of PD, making this molecule a promising candidate for PD treatment.

New 6-Aminoquinoxaline Derivatives with Neuroprotective Effect on Dopaminergic Neurons in Cellular and Animal Parkinson Disease Models.

Parkinson's disease (PD) is a neurodegenerative disorder of aging characterized by motor symptoms that result from the loss of midbrain dopamine neurons and the disruption of dopamine-mediated neurotransmission. There is currently no curative treatment for this disorder. To discover druggable neuroprotective compounds for dopamine neurons, we have designed and synthesized a second-generation of quinoxaline-derived molecules based on structure-activity relationship studies, which led previously to the discovery of our first neuroprotective brain penetrant hit compound MPAQ (5c). Neuroprotection assessment in PD cellular models of our newly synthesized quinoxaline-derived compounds has led to the selection of a better hit compound, PAQ (4c). Extensive in vitro characterization of 4c showed that its neuroprotective action is partially attributable to the activation of reticulum endoplasmic ryanodine receptor channels. Most interestingly, 4c was able to attenuate neurodegeneration in a mouse model of PD, making this compound an interesting drug candidate for the treatment of this disorder.

Bioactive phloroglucinols from Mallotus oppositifolius.

The two new acylphloroglucinol derivatives, methylene-bis-aspidinol AB (1) and mallopposinol (2), together with the nine known compounds, aspidinol B (3), methylene-bis-aspidinol (4), (+)-α-tocopherol (5), lupeol (6), stigmasterol (7), phytol (8), bergenin (9), squalene (11) and methyl gallate (10) were isolated from the leaves of Mallotus oppositifolius. Their structures were elucidated by spectral analysis including MS, 1D and 2D-NMR spectroscopy. In vitro trypanocidal and antileishmanial activities of compounds 1-9 were evaluated. Mallopposinol (2) and aspidinol B (3) displayed weak antileishmanial activities against Leishmania donovani promastigotes, with EC50 values of 21.3 and 38.8µM, respectively. Only the methylene-bis-aspidinol (4) exhibited trypanocidal activity against Trypanosoma brucei brucei trypomastigotes (LC100=0.8µM) similar to the reference drug pentamidine (LC100=0.4µM).

Neuroprotective effects of a brain permeant 6-aminoquinoxaline derivative in cell culture conditions that model the loss of dopaminergic neurons in Parkinson disease.

Parkinson disease is a neurodegenerative disorder of aging, characterized by disabling motor symptoms resulting from the loss of midbrain dopaminergic neurons and the decrease of dopamine in the striatum. Current therapies are directed at treating the symptoms but there is presently no cure for the disease. In order to discover neuroprotective compounds with a therapeutical potential, our research team has established original and highly regioselective methods for the synthesis of 2,3-disubstituted 6-aminoquinoxalines. To evaluate the neuroprotective activity of these molecules, we used midbrain cultures and various experimental conditions that promote dopaminergic cell loss. Among a series of 11 molecules, only compound MPAQ (2-methyl-3-phenyl-6-aminoquinoxaline) afforded substantial protection in a paradigm where dopaminergic neurons die spontaneously and progressively as they mature. Prediction of blood-brain barrier permeation by Quantitative Structure-Activity Relationship studies (QSARs) suggested that MPAQ was able to reach the brain parenchyma with sufficient efficacy. HPLC-MS/MS quantification in brain homogenates and MALDI-TOF mass spectrometry imaging on brain tissue sections performed in MPAQ-treated mice allowed us to confirm this prediction and to demonstrate, by MALDI-TOF mass spectrometry imaging, that MPAQ was localized in areas containing vulnerable neurons and/or their terminals. Of interest, MPAQ also rescued dopaminergic neurons, which (i) acquired dependency on the trophic peptide GDNF for their survival or (ii) underwent oxidative stress-mediated insults mediated by catalytically active iron. In summary, MPAQ possesses an interesting pharmacological profile as it penetrates the brain parenchyma and counteracts mechanisms possibly contributive to dopaminergic cell death in Parkinson disease.

Tryptamine-derived alkaloids from Annonaceae exerting neurotrophin-like properties on primary dopaminergic neurons.

N-fatty acyl tryptamines constitute a scarce group of natural compounds mainly encountered in Annonaceous plants. No biological activity was reported so far for these rare molecules. This study investigated the neurotrophic properties of these natural tryptaminic derivatives on dopaminergic (DA) neurons in primary mesencephalic cultures. A structure-activity relationships study led us to precise the role of a nitrogen atom into the aliphatic chain conferring to the compounds a combined neuroprotective and neuritogenic activity in the nanomolar range. The potent antioxidant activity of these natural products seems to be involved in part of their mechanism of action. This study provides the first description of natural neurotrophin mimetics present in Annonaceae extracts, and led to the biological characterization of compounds, which present a potential interest in neurodegenerative diseases such as Parkinson's disease.

Coumarins from Galipea panamensis and Their Activity against Leishmania panamensis.

Two new coumarin compounds (1 and 2), phebalosin (3), its derived artifact murralongin (4), and murrangatin acetonide (5) were isolated from the leaves of Galipea panamensis. The structures of 1 and 2 were assigned as 7-{[(2R*)-3,3-dimethyloxiran-2-yl]methoxy}-8-[(2R*,3R*)-3-isopropenyloxiran-2-yl]-2H-chromen-2-one and 7-methoxy-8-(4-methyl-3-furyl)-2H-chromen-2-one, respectively, on the basis of their spectroscopic data (primarily NMR and MS). Compounds 1-3 were tested against axenic amastigote forms of Leishmania panamensis and displayed 50% effective concentrations (EC(50)) of 9.9, 10.5, and 14.1 microg/mL, respectively. These three compounds also displayed cytotoxicity (IC(50)) at concentrations of 9.7, 33.0, and 20.7 microg/mL, respectively, on human promonocytic U-937 cells.

Chemicals possessing a neurotrophin-like activity on dopaminergic neurons in primary culture.

BACKGROUND: Neurotrophic factors have been shown to possess strong neuroprotective and neurorestaurative properties in Parkinson's disease patients. However the issues to control their delivery into the interest areas of the brain and their surgical administration linked to their unability to cross the blood brain barrier are many drawbacks responsible of undesirable side effects limiting their clinical use. A strategy implying the use of neurotrophic small molecules could provide an interesting alternative avoiding neurotrophin administration and side effects. In an attempt to develop drugs mimicking neurotrophic factors, we have designed and synthesized low molecular weight molecules that exhibit neuroprotective and neuritogenic potential for dopaminergic neurons. PRINCIPAL FINDINGS: A cell-based screening of an in-house quinoline-derived compound collection led to the characterization of compounds exhibiting both activities in the nanomolar range on mesencephalic dopaminergic neurons in spontaneous or 1-methyl-4-phenylpyridinium (MPP(+))-induced neurodegeneration. This study provides evidence that rescued neurons possess a functional dopamine transporter and underlines the involvement of the extracellular signal-regulated kinase 1/2 signaling pathway in these processes. CONCLUSION: Cell-based screening led to the discovery of a potent neurotrophic compound possessing expected physico-chemical properties for blood brain barrier penetration as a serious candidate for therapeutic use in Parkinson disease.

Quinoline compounds decrease in vitro spontaneous proliferation of peripheral blood mononuclear cells (PBMC) from human T-cell lymphotropic virus (HTLV) type-1-infected patients.

In vitro spontaneous proliferation is the immunological hallmark of peripheral blood mononuclear cells (PBMC) from HTLV-1-infected individuals. Quinoline compounds down regulate in vitro cell proliferation of HTLV-1 transformed cell lines. In the present study we assessed the capacity of quinolines to inhibit spontaneous cell proliferation of PBMC from HTLV-1-infected individuals. Twenty-two quinolines were evaluated. Toxicity was first assessed on PBMC from healthy donors by using both the Trypan blue technique and Tetrazolium Salt (XTT) method and then the antiproliferative effect was measured by a classic lymphoproliferative assay on PBMC from three HTLV-1-infected individuals, in the presence of decreasing concentrations of quinolines (from 100microM to 0.8microM), after 5 days of culture. We found that 14 out of 22 compounds were non-toxic to PBMC from uninfected individuals at 100, 50 and 10microM. Four compounds presented a capacity to inhibit more than 80% of the spontaneous proliferation: 7 at 25microM and 10, 20 and 23 at 100microM. Our results indicate that some quinolines block spontaneous proliferation of PBMC from HTLV-1-infected individuals.