An Overview of Aplysinopsins: Synthesis and Biological Activities.

Marine products are among the most promising sources of biologically active molecules. Aplysinopsins, tryptophan-derived marine natural products, were isolated from different natural marine sources including sponges, stony corals (hard corals) especially genus scleractinian, as well as sea anemone, in addition to one nudibranch. Aplysinopsins were reported to be isolated from different marine organisms related to various geographic areas such as Pacific, Indonesia, Caribbean, and Mediterranean regions. This review gives an up-to-date overview of marine alkaloid aplysinopsins: their various sources, their synthesis, and the fact that many aplysinopsin derivatives are biologically active compounds.

Daniellia oliveri (Rolfe) Hutch and Dalziel: Antimicrobial Activities, Cytotoxicity Evaluation, and Phytochemical Identification by GC-MS.

During a previous study that identified plants used in traditional medicine in Togo to treat infectious diseases, Daniellia oliveri was specifically reported to treat intertrigo and candidiasis. Consequently, to explore the anti-infective potential of this plant, we investigated the antibacterial and the antifungal activity of the plant's parts, as well as the cytotoxic activities of raw extracts and subsequent fractions, and the chemical composition of the most active fractions. In order to evaluate the antimicrobial activity, MICs were determined using the broth dilution method. Then, the most active fractions were evaluated for cytotoxicity by using normal human cells (MRC-5 cells) via the MTT assay. Finally, the most active and not toxic fractions were phytochemically investigated by GC-MS. Interestingly, all the raw extracts and fractions were active against the bacteria tested, with MICs ranging from 16 µg/mL to 256 µg/mL, while no antifungal activity was observed at 256 µg/mL, the highest tested concentration. Moreover, no toxicity was observed with most of the active fractions. The subsequent chemical investigation of the most interesting fractions led to identifying terpenes, phytosterols, phenolic compounds, and fatty acids as the main compounds. In conclusion, this study demonstrated that D. oliveri possesses valuable antibacterial activities in accordance with traditional use.

Insight on Mercapto-Coumarins: Synthesis and Reactivity.

Mercapto (or sulfanyl)-coumarins are heterocycles of great interest in the development of valuable active structures in material and biological domains. They represent a highly exploitable class of compounds that open many possibilities for further chemical transformations. The present review aims to draw focus toward the synthetic applicability of various forms of mercapto-coumarins and their representations in pharmaceuticals and industries. This work covers the literature issued from 1970 to 2021.

A Comprehensive Overview of the Developments of Cdc25 Phosphatase Inhibitors.

Cdc25 phosphatases have been considered promising targets for anticancer development due to the correlation of their overexpression with a wide variety of cancers. In the last two decades, the interest in this subject has considerably increased and many publications have been launched concerning this issue. An overview is constructed based on data analysis of the results of the previous publications covering the years from 1992 to 2021. Thus, the main objective of the current review is to report the chemical structures of Cdc25s inhibitors and answer the question, how to design an inhibitor with better efficacy and lower toxicity?

Synthetic Analogs of Marine Alkaloid Aplysinopsin Suppress Anti-Apoptotic Protein BCL2 in Prostate Cancer.

Aplysinopsins are a class of indole alkaloids that possess various pharmacological activities. Although their action has been studied in regard to many diseases, their effect on prostate cancer has not yet been examined. Therefore, we synthesized a new series of aplysinopsin analogs and investigated their cytotoxic activity against prostate cancer. Five analogs showed high antitumor activity via suppressing the expression of the anti-apoptotic gene Bcl2, simulationously increasing the expression of the pro-apoptotic genes p53, Bax and Caspase 3. The inhibition of BCL2 led to the activation of BAX, which in turn activated Caspase 3, leading to apoptosis. This dual mechanism of action via apoptosis and cell cycle arrest induction is responsible for aplysinopsin analogs antitumor activity. Hence, our newly synthesized analogs are highly promising candidates for further preclinical studies against prostate cancer.

Synthetic Routes to Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Heterocycles Built on the α-Pyrone Moiety. Part II: Five-Membered Aromatic Rings with Multi Heteroatoms.

Coumarins are natural heterocycles that widely contribute to the design of various biologically active compounds. Fusing different aromatic heterocycles with coumarin at its 3,4-position is one of the interesting approaches to generating novel molecules with various biological activities. During our continuing interest in assembling information about fused five-membered aromatic heterocycles, and after having presented mono-hetero-atomic five-membered aromatic heterocycles in Part I. The current review Part II is intended to present an overview of the different synthetic routes to coumarin (benzopyrone)-fused five-membered aromatic heterocycles with multi-heteroatoms built on the pyrone ring, covering the literature from 1945 to 2021.

Anti-Leukemic Properties of Aplysinopsin Derivative EE-84 Alone and Combined to BH3 Mimetic A-1210477.

Aplysinopsins are a class of marine indole alkaloids that exhibit a wide range of biological activities. Although both the indole and N-benzyl moieties of aplysinopsins are known to possess antiproliferative activity against cancer cells, their mechanism of action remains unclear. Through in vitro and in vivo proliferation and viability screening of newly synthesized aplysinopsin analogs on myelogenous leukemia cell lines and zebrafish toxicity tests, as well as analysis of differential toxicity in noncancerous RPMI 1788 cells and PBMCs, we identified EE-84 as a promising novel drug candidate against chronic myeloid leukemia. This indole derivative demonstrated drug-likeness in agreement with Lipinski's rule of five. Furthermore, EE-84 induced a senescent-like phenotype in K562 cells in line with its cytostatic effect. EE-84-treated K562 cells underwent morphological changes in line with mitochondrial dysfunction concomitant with autophagy and ER stress induction. Finally, we demonstrated the synergistic cytotoxic effect of EE-84 with a BH3 mimetic, the Mcl-1 inhibitor A-1210477, against imatinib-sensitive and resistant K562 cells, highlighting the inhibition of antiapoptotic Bcl-2 proteins as a promising novel senolytic approach against chronic myeloid leukemia.

Selenofolate inhibits the proliferation of IGROV1 cancer cells independently from folate receptor alpha.

Cancer is one of the main causes of human mortality worldwide and novel chemotherapeutics are required due to the limitations of conventional cancer therapies. For example, using redox selenium compounds as novel chemotherapeutics seem to be very promising. The objective of this study was to explore if folate could be used as a carrier to deliver a newly synthesised selenium derivative selenofolate into cancer cells. Particularly, the cytotoxic effects of this selenofolate compound were investigated in a variety of cancer cell types including lung, liver, and cervical cancers and specifically IGROV1 cells. Our results showed that selenofolate inhibits the growth of cancer cells in-vitro. However, despite the expectations, folate receptor alpha (FRα) was not involved in the transportation of selenofolate compound into the cells i.e. growth inhibition was independent of FRα, suggesting that multiple transporters (e.g. reduced folate carrier-1) are possibly involved in the delivery and internalisation of folate in IGROV1 cells. Additionally, selenofolate did not exert cell death through apoptosis. Instead, anti-proliferative activity showed to be the main cause of growth inhibition of selenolofate in the IGROV1 cell line. In conclusion, selenofolate inhibits the growth of cancer cells and thus, may be explored further as a potential chemotherapeutic agent.

Synthetic Routes to Coumarin(Benzopyrone)-Fused Five-Membered Aromatic Heterocycles Built on the α-Pyrone Moiety. Part 1: Five-Membered Aromatic Rings with One Heteroatom.

This review gives an up-to-date overview of the different ways (routes) to the synthesis of coumarin (benzopyrone)-fused, five-membered aromatic heterocycles with one heteroatom, built on the pyrone moiety. Covering 1966 to 2020.

The HDAC6 inhibitor 7b induces BCR-ABL ubiquitination and downregulation and synergizes with imatinib to trigger apoptosis in chronic myeloid leukemia.

Despite the discovery of tyrosine kinase inhibitors (TKIs) for the treatment of breakpoint cluster region-Abelson (BCR-ABL)+ cancer types, patients with chronic myeloid leukemia (CML) treated with TKIs develop resistance and severe adverse effects. Combination treatment, especially with a histone deacetylase (HDAC) 6 inhibitor (HDAC6i), appears to be an attractive option to prevent TKI resistance, considering the potential capacity of an HDAC6i to diminish BCR-ABL expression. We first validated the in vivo anti-cancer potential of the compound 7b by significantly reducing the tumor burden of BALB/c mice xenografted with K-562 cells, without notable organ toxicity. Here, we hypothesize that the HDAC6i compound 7b can lead to BCR-ABL downregulation in CML cells and sensitize them to TKI treatment. The results showed that combination treatment with imatinib and 7b resulted in strong synergistic caspase-dependent apoptotic cell death and drastically reduced the proportion of leukemia stem cells, whereas this treatment only moderately affected healthy cells. Ultimately, the combination significantly decreased colony formation in a semisolid methylcellulose medium and tumor mass in xenografted zebrafish compared to each compound alone. Mechanistically, the combination induced BCR-ABL ubiquitination and downregulation followed by disturbance of key proteins in downstream pathways involved in CML proliferation and survival. Taken together, our results suggest that an HDAC6i potentiates the effect of imatinib and could overcome TKI resistance in CML cells.

Discovery of the First Human Arylsulfatase A Reversible Inhibitor Impairing Mouse Oocyte Fertilization.

Arylsulfatase A (ARSA) plays a crucial role in the reproduction of mammals due to its involvement in the specific gamete interaction preceding sperm and egg fusion leading to fertilization. Recently, it has been shown that zona pellucida (ZP) sperm binding and in vivo fertilization in mice are markedly hampered by using a specific anti-ARSA antibody. Herein, the design and discovery of the first ARSA small molecule inhibitor based on a coumarin-containing polycycle are presented. Through a structure-based approach applied on our in-house library, compound 1r was identified as an ARSA reversible inhibitor (ARSAi); then its activity was validated through both surface plasmon resonance and biochemical inhibition experiments, the first providing a KD value of 21 µM and the latter an IC50 value of 13.2 µM. Further investigations highlighted that compound 1r induced 20% sperm death at 25 µM and also impaired sperm motility; nevertheless both the effects were mediated by ROS production, since they were rescued by the cotreatment of 1r and N-acetyl cysteine (NAC). Interestingly, while 1r was not able to hamper the ZP/sperm binding, it markedly decreased the in vitro oocyte fertilization by mouse sperm up to 60%. Notably, this effect was not hampered by 1r/NAC coadministration, hence allowing the ruling out of an ROS-dependent mechanism. In conclusion, herein is reported the first ever hit of ARSAi as a chemical tool that will enable better exploration of ARSA's biological role in fertilization as well as provide a starting point for developing 1r structure optimization aimed at increasing enzyme inhibition potency but also providing a deeper understanding of the involvement of ARSA in the fertilization pathway mechanism.

Investigating the Potential of Conjugated Selenium Redox Folic Acid as a Treatment for Triple Negative Breast Cancer.

Previous studies have demonstrated that redox selenium compounds arrest cancer cell viability in vitro through their pro-oxidative activity by generating superoxide (O2•-). Currently, there are no efficacious treatment options for women with Triple Negative Breast Cancer (TNBC). However, the association between the over-expression of the Folate Receptor Alpha (FRA) in TNBC and other cancer cells, has led to the possibility that TNBCs might be treated by targeting the FRA with redox selenium covalent Folic Acid conjugates. The present study reports the synthesis of the redox active vitamer, Selenofolate, generating superoxide. Superoxide (O2•-) catalytic generation by Selenofolate was assessed by an in vitro chemiluminescence (CL) assay and by a Dihydroethidium (DHE) in vivo assay. Cytotoxicity of Selenofolate was assessed against the TNBC cell line MDA-MB-468 and an immortalized, mammary epithelial cell line, HME50-5E. Cytotoxicity of Selenofolate was compared to Folic Acid and sodium selenite, in a time and dose dependent manner. Selenofolate and selenite treatments resulted in greater inhibition of MDA-MB-468 cell proliferation than HME50-5E as evaluated by Trypan Blue exclusion, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) metabolic assay and Annexin V apoptosis assays. Folate receptor alpha (FRA) protein expression was assessed by Western blotting, with the experimental results showing that redox active Selenofolate and selenite, but not Folic Acid, was cytotoxic to MDA-MB-468 cells in vitro, suggesting a possible clinical option for treating TNBC and other cancers over-expressing FRA.

New approach in the characterization of bioactive compounds isolated from Calycotome spinosa (L.) Link leaves by the use of negative electrospray ionization LITMSn, LC-ESI-MS/MS, as well as NMR analysis.

Two novel compounds were isolated for the first time from Calycotome spinosa (L.) Link, an alkaloid 5-Hydroxy-1H-indole (4) and a cyclitol D-pinitol (5), together with the three well-known flavonoids; Chrysin-7-O-(ß-D-glucopyranoside) (1), Chrysin-7-O-ß-D-(6″-acetyl)glycopyranoside (2) and Apigenin-7-O-ß-D-glycopyranoside (3). The chemical structures of the isolated compounds were elucidated by spectroscopic data and mass spectrometric analyses; including a fresh approach 1D-NMR, 2D-NMR with LC-ESI-MS/MS. In this study, the new compound (4) that has been obtained from the leaves MeOH extract presented the best radical scavenging activity (DPPH) (IC50 < 10 µg/mL) compared to the standard butylated hydroxytoluene (BHT, IC50 = 34.73 ± 0.23 µg/mL) and showed the highest total antioxidant capacity (TAC = 985.54 ± 0.13 mg AAE/g extract) in contrast to ascorbic acid (TAC = 905.95 ± 0.07 mg AAE/g extract). Furthermore, the strongest reducing power (EC50 = 344.82 ± 0.02 µg/mL), as well as the remarkable scavenging potential by ABTS assay (IC50 = 7.8 ± 0.43 µg/mL), were exhibited by the same composite (4). Followed by the methanol crude extract and the compound (3) that also showed a potent antioxidant (DPPH; IC50 = 41.04 ± 0.15 and 47.36 ± 0.21 µg/mL, TAC; 671.02 ± 0.21 and 608.67 ± 0.34 mg AAE/g extract, FRAP; EC50 = 763.73 ± 0.32 and 814.61 ± 0.31 µg/mL, ABTS; IC50 = 19.18 ± 0.06 and 63.72 ± 0.64 µg/mL, respectively), but less than the previous samples. On the opposite side, compound (5) had the lowest activity, in which its values were less interesting to determine. Moreover, compound (4) has equally exerted an attractive antibacterial activity against Staphylococcus aureus (ATTC-25923), Pseudomonas aeruginosa (ATTC- 27853) and Salmonella abony (NCTC 6017), as measured by the disc diffusion assay, with inhibition zones of 16 ± 0.5, 9.83 ± 0.29 and 8 ± 0.28 mm, in that order. To the best of our knowledge, 5-Hydroxy-1H-indole was isolated from plants for the second time in our current work. Thus, the obtained results from this investigation propose that the leaves of C. spinosa are a rich natural source for value molecules as potential antioxidants and antimicrobial agents for best human health.

Secondary metabolites and biological activity of Pentas species: A minireview.

The genus Pentas belongs to the Rubiaceae family, which contains approximately 40 species. Several Pentas species were reported to be used as a folk treatment by African indigenous people in treating some diseases such as malaria, tapeworms, dysentery, gonorrhea, syphilis and snake poisoning. This article covers the period from 1962 to 2017 and presents an overview of the biological activity of different Pentas species and describes their phytochemical traits. As a conclusion, the main secondary metabolites from Pentas species are quinones, highly oxygenated chromene-based structures, and iridoids. Pentas species are widely used in folk medicine but they have to be more investigated for their medicinal properties.

A cascade synthesis, in vitro cholinesterases inhibitory activity and docking studies of novel Tacrine-pyranopyrazole derivatives.

In this work, we describe the preparation of some new Tacrine analogues modified with a pyranopyrazole moiety. A one-pot multicomponent reaction of 3-methyl-1H-pyrazol-5(4H)-one, aryl(or hetero)aldehydes, malononitrile and cyclohexanone involving a Friedländer condensation led to the title compounds. The synthesized heterocyclic analogues of this molecule were evaluated in vitro for their AChE and BChE inhibitory activities in search for potent cholinesterase enzyme inhibitors. Most of the synthesized compounds displayed remarkable AChE inhibitory activities with IC50 values ranging from 0.044 to 5.80 µM, wherein compounds 5e and 5j were found to be most active inhibitors against AChE with IC50 values of 0.058 and 0.044 µM respectively. Molecular modeling simulation on AChE and BChE receptors, showed good correlation between IC50 values and binding interaction template of the most active inhibitors docked into the active site of their relevant enzymes.

Antibacterial activity and cytotoxicity of Pterocarpus erinaceus Poir extracts, fractions and isolated compounds.

ETHNOPHARMACOLOGICAL RELEVANCE: Pterocarpus erinaceus has been chosen based on ethnobotanical surveys carried out in the Tchamba district of the Republic of Togo. AIM OF THE STUDY: Investigation of the antibacterial as well as cytotoxic activities of whole extracts, fractions and compounds isolated from the leaves, trunk bark and roots of Pterocarpus erinaceus. MATERIALS AND METHODS: Bio-guided fractionation of the raw extracts of plant parts and subsequent isolation of compounds from active fractions using normal phase open column chromatography. The broth microdilution method was used to evaluate the antibacterial activity, based on the determination of Minimal Inhibitory Concentrations (MICs) against several bacterial species representative of the most commonly encountered infectious diseases worldwide. The cytotoxicity of the raw extract and the most active fractions on a human non-cancerous cell (namely MRC-5) was estimated with a MTT assay. The chemical structure of the compounds isolated was elucidated using a combination of advanced Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS). RESULTS: All extracts and fractions tested have shown good activities against Gram-positive bacteria (including Methicillin-Resistant Staphylococcus aureus, MRSA) and against Pseudomonas aeruginosa with MIC values ranging from 32µg/mL to 256µg/mL. In contrast, extracts were not toxic to MRC-5 cells. Four compounds have been isolated: Compound 1 (friedeline); Compound 2 (2,3 dihydroxypropyloctacosanoate); Compound 3 (a mixture of ß-sitosterol, stigmasterol and campesterol); Compound 4 (ß-sitosteryl-ß-D-glucopyranoside) and shown to be active against some of the bacteria tested. They were active with MIC equal to 4µg/mL against strains of S. aureus (including MRSA). To the best of our knowledge, all of them except friedeline have never been reported in this plant species. CONCLUSION: P. erinaceus is confirmed as a plant harboring promising antibacterial activity with activities against serious human pathogens at very low concentrations. Some of the compounds isolated are also active at concentrations as low as 4µg/mL and therefore, may provide new leads for the development of antibacterial agents.

Novel coumarin- and quinolinone-based polycycles as cell division cycle 25-A and -C phosphatases inhibitors induce proliferation arrest and apoptosis in cancer cells.

Cell division cycle phosphatases CDC25 A, B and C are involved in modulating cell cycle processes and are found overexpressed in a large panel of cancer typology. Here, we describe the development of two novel quinone-polycycle series of CDC25A and C inhibitors on the one hand 1a-k, coumarin-based, and on the other 2a-g, quinolinone-based, which inhibit either enzymes up to a sub-micro molar level and at single-digit micro molar concentrations, respectively. When tested in six different cancer cell lines, compound 2c displayed the highest efficacy to arrest cell viability, showing in almost all cell lines sub-micro molar IC50 values, a profile even better than the reference compound NCS95397. To investigate the putative binding mode of the inhibitors and to develop quantitative structure-activity relationships, molecular docking and 3-D QSAR studies were also carried out. Four selected inhibitors, 1a, 1d, 2a and 2c have been also tested in A431 cancer cells; among them, compound 2c was the most potent one leading to cell proliferation arrest and decreased CDC25C protein levels together with its splicing variant. Compound 2c displayed increased phosphorylation levels of histone H3, induction of PARP and caspase 3 cleavage, highlighting its contribution to cell death through pro-apoptotic effects.

Natural and Synthetic Coumarins with Effects on Inflammation.

In this review, we will present the different aspects of coumarins and derivatives, from natural origins or synthetically prepared, and their action on inflammation. Coumarins and also furo- and pyranocoumarins are found in many different plants. These compounds are very often investigated for antioxidant properties. Other biological properties are also possible and anti-inflammation activity is one of these. As coumarins are also available quite easily via synthesis, natural ones can be prepared this way but derivatives with special substituents are also feasible. A review on the same topic appeared in 2004 and our contribution will take into account everything published since then.

2-(Thienothiazolylimino)-1,3-thiazolidin-4-ones inhibit cell division cycle 25 A phosphatase.

Cell division cycle dual phosphatases (CDC25) are essential enzymes that regulate cell progression in cell cycle. Three isoforms exist as CDC25A, B and C. Over-expression of each CDC25 enzyme is found in cancers of diverse origins. Thiazolidinone derivatives have been reported to display anti-proliferative activities, bactericidal activities and to reduce inflammation process. New 2-(thienothiazolylimino)-1,3-thiazolidin-4-ones were synthesized and evaluated as inhibitors of CDC25 phosphatase. Among the molecules tested, compound 6 inhibited CDC25A with an IC50 estimated at 6.2±1.0µM. The binding of thiazolidinone derivative 6 onto CDC25A protein was reversible. In cellulo, compound 6 treatment led to MCF7 and MDA-MB-231 cell growth arrest. To our knowledge, it is the first time that such 4-thiazolidinone derivatives are characterized as CDC25 potential inhibitor.