IDO1 and TDO inhibitory evaluation of analogues of the marine pyrroloiminoquinone alkaloids: Wakayin and Tsitsikammamines.

Indoleamine 2,3-dioxygenase (IDO1) and tryptophane 2,3-dioxygenase (TDO) are two heme-containing enzymes which catalyze the conversion of tryptophan to N-formylkynurenine. Both enzymes are well establish therapeutic targets as important factors in the tumor immune evasion mechanism. A number of analogues of the marine pyrroloquinoline alkaloids tsitsikammamines or wakayin have been synthesized, two of them were synthesized using an original method to build the bispyrroloquinone framework. All the derivatives were evaluated in a cellular assay for their capacity to inhibit the enzymes. Six compounds have shown a significant potency on HEK 293-EBNA cell lines expressing hIDO1 or hTDO.

Design of granulatimide and isogranulatimide analogues as potential Chk1 inhibitors: Study of amino-platforms for their synthesis.

The two marine alkaloids granulatimide and isogranulatimide have been shown to inhibit the checkpoint kinase 1 (Chk1), a promising target for cancer treatment. A molecular docking study allowing the design of new potential Chk1 inhibitors based on the natural products skeleton and the synthetic work to an amino-target platform to prepare them are described.

Indoleamine 2,3-dioxygenase inhibitory activity of derivatives of marine alkaloid tsitsikammamine A.

Tsitsikammamines are marine alkaloids whose structure is based on the pyrroloiminoquinone scaffold. These and related compounds have attracted attention due to various interesting biological properties, including cytotoxicity, topoisomerase inhibition, antimicrobial, antifungal and antimalarial activity. Indoleamine 2,3-dioxygenase (IDO1) is a well-established therapeutic target as an important factor in the tumor immune evasion mechanism. In this preliminary communication, we report the inhibitory activity of tsitsikammamine derivatives against IDO1. Tsitsikammamine A analogue 11b displays submicromolar potency in an enzymatic assay. A number of derivatives are also active in a cellular assay while showing little or no activity towards tryptophan 2,3-dioxygenase (TDO), a functionally related enzyme. This IDO1 inhibitory activity is rationalized by molecular modeling studies. An interest is thus established in this class of compounds as a potential source of lead compounds for the development of new pharmaceutically useful IDO1 inhibitors.

Discovery of new diaryl ether inhibitors against Mycobacterium tuberculosis targeting the minor portal of InhA.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) affects 10 million people each year and the emergence of resistant TB augurs for a growing incidence. In the last 60 years, only three new drugs were approved for TB treatment, for which resistances are already emerging. Therefore, there is a crucial need for new chemotherapeutic agents capable of eradicating TB. Enzymes belonging to the type II fatty acid synthase system (FAS-II) are involved in the biosynthesis of mycolic acids, cell envelope components essential for mycobacterial survival. Among them, InhA is the primary target of isoniazid (INH), one of the most effective compounds to treat TB. INH acts as a prodrug requiring activation by the catalase-peroxidase KatG, whose mutations are the major cause for INH resistance. Herein, a new series of direct InhA inhibitors were designed based on a molecular hybridization approach. They exhibit potent inhibitory activities of InhA and, for some of them, good antitubercular activities. Moreover, they display a low toxicity on human cells. A study of the mechanism of action of the most effective molecules shows that they inhibit the biosynthesis of mycolic acids. The X-ray structures of two InhA/NAD+/inhibitor complexes have been obtained showing a binding mode of a part of the molecule in the minor portal, rarely seen in the InhA structures reported so far.

13C NMR discrimination of regioisomeric bispyrroloquinone/bispyrroloiminoquinone ring systems.

The structural assignment of bispyrroloquinone and bispyrroloiminoquinone regioisomers was achieved using (13)C NMR spectral data. In the case of bispyrroloiminoquinones, the carbonyl group in the regioisomer possessing a nitrogen atom in both alpha-positions was systematically less deshielded than the carbonyl group in the other regioisomer. In the case of bispyrroloquinones, the most deshielded carbonyl group in the regioisomer with a nitrogen atom in both alpha-positions was more deshielded than the same carbonyl group in the other regioisomer.

Marine pyrrolocarbazoles and analogues: synthesis and kinase inhibition.

Granulatimide and isogranulatimide are alkaloids obtained from marine sources which have been shown to inhibit cell-cycle G2-checkpoint, targeting more particularly checkpoint 1 kinase (Chk1). At a structural level, they possess a characteristic pyrrolocarbazole framework also shared by the well-known rebeccamycin and staurosporine microbial metabolites which have been described to inhibit topoisomerase I and diverse kinases, respectively. This review reports precisely on the synthesis and kinase inhibitory activities of pyrrolocarbazole-based analogues of granulatimide.

Ascididemin and meridine stabilise G-quadruplexes and inhibit telomerase in vitro.

Ascididemin and Meridine are two marine compounds with pyridoacridine skeletons known to exhibit interesting antitumour activities. These molecules have been reported to behave like DNA intercalators. In this study, dialysis competition assay and mass spectrometry experiments were used to determine the affinity of ascididemin and meridine for DNA structures among duplexes, triplexes, quadruplexes and single-strands. Our data confirm that ascididemin and meridine interact with DNA but also recognize triplex and quadruplex structures. These molecules exhibit a significant preference for quadruplexes over duplexes or single-strands. Meridine is a stronger quadruplex ligand and therefore a stronger telomerase inhibitor than ascididemin (IC50=11 and >80 muM, respectively in a standard TRAP assay).

Synthesis and antitumor characterization of pyrazolic analogues of the marine pyrroloquinoline alkaloids: wakayin and tsitsikammamines.

A series of aza analogues of the marine alkaloids wakayin and tsitsikammamines A and B have been synthesized. The strategy used was based on [3 + 2] cycloaddition reactions involving 3-ethylamine-indole-4,7-dione and different diazo reagents. All the compounds were evaluated in vitro for antiproliferative activity against five distinct cancer cell lines and for their inhibitory effect on topoisomerase isoenzymes I and II. Some of the compounds inhibited the topoisomerase I and/or II catalyzed relaxation of supercoiled DNA at a concentration comparable to the drugs camptothecin and etoposide. Only a few of them exhibited cytotoxic activity with IC50 values in the micromolar range.

Hemisynthesis, Antitumoral Effect, and Molecular Docking Studies of Ferutinin and Its Analogues.

The natural product ferutinin was shown to act as an agonist to estrogen receptor ERα and agonist/antagonist to ERß featuring a weak antiproliferative activity toward breast cancer cells. To enhance this activity, ferutinin analogues were synthesized by esterification of jaeschkenadiol with different acids. These compounds were assayed for their in vitro antiproliferative activity against estrogen-dependent (MCF-7) and estrogen-independent (MDA-MB-231) breast cancer cell lines. Among the compounds, 3c' exhibited a potent inhibitory selective activity against MCF-7 with IC50 value of 1 µM. Docking simulation of 3c' in the ligand binding domain of the ERs indicated a potential antagonism interaction with both ER subtypes. Functional assay showed that 3c' binds as an antagonist to ERα protein while ferutinin acts as an agonist.

Synthesis and in vitro antiproliferative activity of amido and amino analogues of the marine alkaloid isogranulatimide.

Marine organisms have proven to be a promising source of new compounds with activity against tumor cell lines. Granulatimide and isogranulatimide are marine alkaloids that have been shown to inhibit checkpoint kinase 1 (Chk1), a key protein in the DNA damage response and an emerging target for anticancer therapeutics. Here, we describe the synthesis and preliminary evaluation of amido and amino analogues of isogranulatimide. The new derivatives were prepared in three steps from 2-imidazol-1-yl-1H-indol-5-ylamine. Two of the compounds synthesized exhibited more potent in vitro antiproliferative activity (single-digit micromolar concentration range), by at least one log of magnitude, than the natural product isogranulatimide when evaluated in six human tumor cell lines: non-small-cell lung cancer (A549), colon cancer (LoVo), breast cancer (MCF7), oligodendroglioma (Hs683), glioblastoma (U373), and melanoma (SKMEL28). The mechanism of action of these derivatives remains to be elucidated, given that they did not significantly inhibit Chk1, however these compounds are easily synthesized and exhibit potent anticancer activity and are thus worthy of further study.

Synthesis and in vitro antitumor activity of phenanthrolin-7-one derivatives, analogues of the marine pyridoacridine alkaloids ascididemin and meridine: structure-activity relationship.

A series of substituted pyrido[4,3,2-de][1,7] or [1,10]-phenanthrolin-7-ones, analogues of the marine pyridoacridines meridine and ascididemin, have been synthesized on the basis of Diels-Alder reactions involving different quinoline-5,8-diones and N,N-aldehyde-dimethylhydrazones. All the compounds were evaluated for in vitro cytotoxic activity against 12 distinct human cancer cell lines. They all exhibit cytotoxic activity with IC(50) values at least of micromolar order.

Synthesis and in vitro antitumor activity of novel ring D analogues of the marine pyridoacridine ascididemin: structure-activity relationship.

Marine compounds with pyridoacridine skeletons are known to exhibit interesting antitumor activities. Ascididemin has already been reported as displaying significant antitumor activities in vitro and has also been found to have a relatively high global toxicity in vivo. We synthesized a series of 16 analogues (among which 11 compounds were different from previously described ones) with the aim of developing new anticancer agents with significantly improved efficacy/tolerability ratios. These compounds were obtained either by total synthesis from 5,8-quinolinedione and substituted 2-aminoacetophenones or by the direct substitution of ascididemin. The different compounds and ascididemin used as the control compound were tested at six different concentrations on 12 different human cancer cell lines of various histopathological types (glioblastomas and breast, colon, lung, prostate, and bladder cancers). The IC(50) value (i.e., the drug concentration inhibiting the mean growth value of the 12 cell lines by 50%) of these compounds ranged over five log concentrations, i.e., between 10 000 and 0.1 nM. For several new chemical entities, the antitumor activity (determined in vitro) and tolerability (determined in vivo) were superior to those of the parent alkaloids, i.e., ascididemin and 2-bromoleptoclinidone.

Marine natural products and other derivatives as potent indoleamine 2,3-dioxygenase inhibitors.

Cancer cells are able to elaborate enzymatic mechanisms allowing tumors to resist or escape imune rejection. Among the enzymes involved, indoleamine 2,3-dioxygenase (IDO), an intracellular enzyme that initiates the first and rate-limiting step of tryptophan breakdown along the kynurenine pathway, has emerged as a promising molecular target for the development of new immunotherapeutic anticancer agents. This review summarizes the synthesis and IDO activities of the different classes of marine and other inhibitors reported so far.

Synthesis and biological evaluation of analogs of the marine alkaloids granulatimide and isogranulatimide.

A series of pyrrolic analogs and two series of regioisomeric pyrazolic analogs of the marine alkaloids granulatimide and isogranulatimide were prepared. The synthesis of the two first ones was based on the condensation reaction of diversely 5-substituted 3-bromoindoles with pyrrole or pyrazole followed by addition of the intermediates on maleimide or dibromomaleimide, respectively, the so-obtained acyclic adducts being finally photocyclized to the desired analogs. Compounds of the last series were obtained by reacting different 5-substituted-indole-3-glyoxylates with N-Boc-pyrazole-3-acetamide and subsequent photochemical cyclization of the adducts. All the compounds were evaluated for their in vitro growth inhibitory properties toward eight cancer cell lines. Several compounds were also assayed for their ability to abrogate the G2-cell cycle checkpoint or to inhibit a panel of Ser/Thr kinases. Lastly, computer-assisted phase-contrast microscopy (quantitative videomicroscopy) revealed that the three most potent compounds (4a, 9a, 9e), with IC(50) growth inhibitory concentrations ranging between 10 and 20 µM, displayed cytostatic, not cytotoxic, anticancer effects.

Synthesis and antitumor evaluation of analogues of the marine pyrroloiminoquinone tsitsikammamines.

Two series of analogues of the marine pyrroloiminoquinone alkaloids tsitsikammamine have been synthesized on the basis of a Michael addition between 2'-amino-1-(4-methoxyphenyl)-ethanol and two indolediones. All the compounds were evaluated in vitro for antiproliferative activity against distinct cancer cell lines.

Analogues of marine pyrroloiminoquinone alkaloids: synthesis and antitumor properties.

Marine organisms provide a valuable source for natural products. In recent years, iminoquinone alkaloids including makaluvamines, isobatzellines, tsitsikammamines and wakayin, have emerged as an essential class of marine metabolites due to their prominent biological activities and unusual ring structures. This review focuses on synthesis and antitumor evaluation of analogues of these products.

Aza-analogues of the marine pyrroloquinoline alkaloids wakayin and tsitsikammamines: synthesis and topoisomerase inhibition.

Two aza-analogues of the marine pyrroloquinoline alkaloids wakayin and tsitsikammamines A and B have been synthesized. The strategy used was based on a 1,3-dipolar cycloaddition reaction between indole 4,7-dione and a diazo-aminopropane derivative. One of the two analogues partially inhibits human topoisomerase I, whereas synthetic intermediates inhibit the enzyme DNA cleavage activity at a concentration comparable to that of the control drug camptothecin.

Marine pyridoacridine alkaloids and synthetic analogues as antitumor agents.

Pyrido[4,3,2-mn]acridines are of major interest as metabolites in sponges and ascidians. During the last few years, numerous additional compounds of this family were isolated, some of them being polycyclic structures already reported with different substituents (shermilamine or kuanoniamine-derivatives), others, such as neoamphimedine, arnoamines and styelsamines having original structures. The synthesis of these compounds and analogues have been performed in order to allow their biological evaluation. In most of the cases, the cytotoxicity of analogues was improved compared to the natural product, specially in ascididemin or meridine series. The pyridoacridines have not a sole mode of action, but it seems that the reductive DNA cleavage mediated by reactive oxygen species is a potential general mode of action.

Synthesis and cytotoxic evaluation of analogues of the marine pyridoacridine amphimedine.

4-Substituted-7H-pyrido-[4,3,2-de][1,8] or [1,9]-phenanthroline-7-ones and 9-methyl-1,4-diazanaphtacene-3,10-dione, analogues of the marine pyridoacridine amphimedine were synthesised from isoquinoline-5,8-dione. The first compounds were obtained starting from a Diels-Alder reaction whereas the synthesis of the last compound was initiated by a reaction of condensation with 2-aminoacetophenone. The different tetra- and pentacyclic compounds were evaluated for in vitro cytotoxic activities against six distinct human cancer cell lines. All the compounds exhibit cytotoxic activity with IC(50) values (i.e., the drug concentration inhibiting the mean growth value of the six cell lines by 50%)<10(-7)M for two of them.

Synthesis and in vitro antitumor activity of an isomer of the marine pyridoacridine alkaloid ascididemin and related compounds.

The isomer (9H-quino[4,3,2-de][1,7]phenanthroline-9-one) (2) of the marine alkaloid ascididemin (9H-quino[4,3,2-de][1,10]phenanthroline-9-one) (1) has been synthesized in six steps from 1,4-dimethoxyacridine (10) with an overall yield of 12%. Different related compounds were prepared and tested in vitro at six different concentrations on 12 different human cancer cell lines of various histopathological types (glioblastomas and breast, colon, lung, prostate and bladder cancers). Almost all the compounds present cytotoxic activity of micromolar order.