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International audience; Biosynthetic considerations inspired us to harness the templating properties offered by DNA to promote a [2+2] photoinduced cycloaddition. The method was developed based on the dimerization of (E)-aplysinopsin, which was previously shown to be unproductive in solution. In sharp contrast, exposure of this tryptophan-derived olefin to light in the presence of salmon testes DNA (st-DNA) reproducibly afforded the corresponding homo-dimerized spiro-fused cyclobutane in excellent yields. DNA provides unique templating interactions enabling a singular mimic of the solid-state aggregation necessary for the [2+2] photocycloaddition to occur. This method was ultimately used to promote the prerequisite dimerizations leading to both dictazole B and tubastrindole B, thus constituting the first example of a DNA-mediated transformation to be applied to the total synthesis of a natural product.

Marine natural products represent a rich source of bioactive secondary metabolites, one of which is the marine indole alkaloids aplysinopsins. Aplysinopsins were first described in 1977 from the extracts of Indo-Pacific sponge species. Since that initial description, they have been isolated from a wide range of marine sources: sponges, corals, mollusks, and sea anemones. Aplysinopsins are composed of an indole coupled with an imidazolidinone moiety. The structural variation of naturally occurring aplysinopsin analogs occurs in the bromination pattern on the indole moiety as well as the pattern of N-methylations on the imidazolidinone ring. There are multiple synthetic strategies used to access the aplysinopsin scaffold. The majority of them are convergent routes that begin with synthesis of the desired indole moiety followed by the imidazolidinone synthesis and, ultimately, coupling of the two systems via several different methodologies. Aplysinopsins possess a wide variety of biological activities, from antimicrobial and antimalarial to antitumor activity seen in mice. However, their neuromodulatory activities have generated the most recent interest in their bioactivity. Both natural and synthetic aplysinopsin analogs have been found to act on both the serotonin receptor and the monoamine oxidase system. This chapter will review recently published synthetic strategies used to construct aplysinopsin analogs. It will also highlight significant and promising biological activities displayed by aplysinopsins, with an emphasis of neuromodulatory activities.

Aplysinopsin monomers are considered as plausible biosynthetic precursors of the wider aplysinopsin family of marine alkaloids. The idea of harnessing their intrinsic reactivity to undertake the synthesis of dictazoles or cycloaplysinopsins logically emerged from this status. These biosynthetic considerations led us to the first total syntheses of dictazole B and other valuable cyclobutanes. When further exploiting pre-encoded reactivity, our first total synthesis of tubastrindole B originated from the ring-expansion cascade of its dictazole-type precursor. Moreover, the isolation of a transient biosynthetic intermediate combined with dimerization outcomes of a hydantoin-containing monomer allowed us to explain the formation of cycloaplysinopsins A and B. 1 Introduction 2 Easy Access to Dictazole Cyclobutanes 3 Synthesis of Cycloaplysinopsins by Ring Expansion 4 Conclusion and Future Prospects

A new two-step approach toward the synthesis of aplysinopsin analogues 5-(1-R-1H-indol-3-ylmethylene)-2-aryl-3,5-dihydroimidazol-4-ones consisting in obtaining and reaction of 4-(1-R-1H-indol-3-ylmethilene)-2-Ar-4H-oxazol-5-ones with amines was developed. The configuration of starting compounds and final products was determined by 13С and 1H-nmr spectroscopy.

Applying a biomimetic approach, the first total synthesis of (±)-tubastrindole B is reported herein. This work features a ring-expansion cascade of a dictazole-type precursor into cycloaplysinopsin-type congeners. Moreover, the isolation of a transient biogenetic intermediate represents a milestone in the biosynthetic understanding of this family of marine alkaloids.

Guided by biosynthetic considerations, the total synthesis of dictazole B is reported for the first time. Experimental evidence for an easy access to challenging cyclobutane alkaloids of marine origin, which are often postulated to be biosynthetic precursors of more complex structures, is provided.

Chemical investigation of nonindigenous Tubastraea coccinea and T. tagusensis by Raman spectroscopy resulted in the identification of carotenoids and indolic alkaloids. Comparison of Raman data obtained for the in situ and crude extracts has shown the potential of the technique for characterizing samples which are metabolic fingerprints, by means of band analysis. Raman bands at ca. 1520, 1160, and 1005 cm(-1) assigned to ν1(C═C), ν2(C-C), and ρ3(C-CH3) modes were attributed to astaxanthin, and the band at 1665 cm(-1) could be assigned to the ν(C-N), ν(C-O), and ν(C-C) coupled mode of the iminoimidazolinone from aplysinopsin. The antioxidant activity of the crude extracts has also been demonstrated, suggesting a possible role of these classes of compounds in the studied corals.

The detailed chemical inspection of the Mediterranean coral Astroides calycularis led to the isolation and structure characterization of two families of alkaloids. Derivatives of orthidine were for the first time isolated from this species. The second family of alkaloids includes the aplysinopsins among which a new derivative is described. The structure was identified on the basis of extensive NMR data interpretation. These results are of chemotaxonomic relevance in order to link this species to the Atlantic Tubastrea aurea.

A new two-step approach toward the synthesis of aplysinopsin analogues 5-(1-R-1H-indol-3-ylmethylene)-2-aryl-3,5-dihydroimidazol-4-ones consisting in obtaining and reaction of 4-(1-R-1H-indol-3-ylmethilene)-2-Ar-4H-oxazol-5-ones with amines was developed. The configuration of starting compounds and final products was determined by 13С and 1H-nmr spectroscopy.

A series of substituted (Z)-5-(N-benzylindol-3-ylmethylene)imidazolidine-2,4-dione (3) analogs structurally related to aplysinopsin, and that incorporate a variety of substituents in both the indole and N-benzyl moieties have been synthesized under microwave irradiation and conventional heating methods These analogs were evaluated for their anti-proliferative activity against MCF-7 and MDA-231 breast cancer cell lines, and A549 and H460 lung cancer cell lines. Two analogs, 3f and 3j had IC(50) values of 4.4 and 5.2microM, respectively, compared to 5-fluorouracil (IC(50)=15.2microM) against MCF-7 cells.

Tubastarea sp., a stony coral (Dendrophylliidae) from the Great Hanish in the Archipelago of the Hanish Islands, Yemen, contains, in addition to the known aplysinopsin (1) and 6-bromo-3'-deimino-3'-oxoaplysinopsin (2), the new bis(indole) alkaloid (3). The structures of compounds (1-3) were elucidated by interpretation of spectral data. Compound 3 inhibits the growth of Plasmodium falciparum (chloroquine-resistant strain) with an IC(50) 1.2 microg mL(-1).

Three aplysinopsin analogs were synthesized by reacting 5-bromo-5-fluoro- and 6-bromoindole-3-carboxaldehyde with either creatinine or 2-imino-1,3-dimethyl-imidazolidin-4-one or 2-imino-1-methyl-3-ethylimidazolidin-4-one Single crystal structures on 5-bromo-4′-de-N-methylaplysinopsin DMF solvate [from creatinine, space group P21/n, lattice parameters a = 13.117(3) A, b = 8.6663(15) A, c = 14.743(3) A, β = 99.538(10)° at 173 K], 5-fluoroaplysinopsin DMF solvate [from 2-imino-1,3-dimethyl-imidazolidin-4-one, space group P21/c, lattice parameters a = 11.114(3) A, b = 19.118(2) A, c = 8.503(2) A, β = 112.290(7)°], and 6-bromoindole-3-carboxaldehyde (space group P21/n, lattice parameters a = 7.657(2) A, b = 7.933(2) A, c = 13.521(3) A, β = 99.046(13)°) have been determined. Characterizations include spectrometric identifications employing IR, UV, HRMS, and 1H and 13C NMR. 5-Bromo-4′-de-N-methylaplysinopsin and 5-fluoroaplysinopsin exist in the E configuration. Single crystal X-ray structural analyses were carried out on 5-bromo-4′-de-N-methylaplysinopsin, 5-fluoroaplysinopsin, and 6-bromoindole-3-carboxaldehyde.

(.+-.)-Tubastrindole B (Ia) and a precursor of (.+-.)-tubastrindole E (Ib) are prepared by a ring-expansion cascade of a dictazole-type precursor.

Reported here are two novel quasi-racemic (bis)indole alkaloids, cycloaplysinopsin A ( 5 ) and cycloaplysinopsin B ( 6 ), isolated from tropical Indo-Pacific (Comoros, Philippines) scleractinian corals of the family Dendrophylliidae. Although their structures suggest a Diels–Alder cycloaddition origin from aplysinopsin-type precursors, neither experiments, nor theory allowed us to clearly distinguish an enzymatic process with scarce enantioselection from the intrusion of an adventitious catalyst in the coral extracts, where the chiral environment caused a slight asymmetric induction.

3-Substituted 5-[(Z)-heteroarylmethylidene]imidazolidine-2,4-dione and 5-[(Z)-heteroarylmethylidene]- 2-thiooxoimidazolidin-4-one derivatives were prepared stereoselectively by coupling of 5-(dimethylamino)methylidene substituted hydantoin and thiohydantoin derivatives with carbocyclic and heterocyclic C-nucleophiles.Configuration around the exocyclic C=C double bond was determined by NMR, using NOESY and 2D HMBC techniques.

This chapter, covering the chemistry literature up until June 2013 and comprising 142 references, records the chemical structures of 130 bi-, bis-, and trisindole alkaloids isolated from a plethora of marine phyla including bacteria, algae, bryozoans, sponges, mollusks, hard corals, and ascidians. While the vast majority of bisindoles have been isolated from marine sponges, biindoles are more commonly found in red algae species than sponges. Trisindoles are far less common than bisindoles in the marine environment and have been limited to two species of sponge and a single species of marine microbe. Antimicrobial activity and cytotoxicity dominate the bioactivities explored for selected members of this family of alkaloids. Synthetic approaches to 28 natural products are presented in 33 schemes, and in the absence of any in vivo biosynthetic studies, the putative biosyntheses of eight bisindole metabolites are presented.

Some new aplysinopsin analogues were prepared by a simple coupling of N , N -(dimethylamino)methylidene substituted hydantoin, thiohydantoin, and thiazolone derivatives, with indole derivatives. Configuration around the exocyclic CC double bond was determined on the basis of long-range heteronuclear coupling constants using 2D HMBC correlation technique.

Some new six-membered aplysinopsin analogues were prepared from 5-dimethylaminomethylidene-2,4,6(1H,3H,5H)-pyrimidinetriones and indole derivatives. Also 2-[[(2,4,6-trioxohexahydropyrimidin-5-ylidene)methyl]amino]-3-dimethylaminopropenoates were synthesized and employed in the synthesis of fused 2H-pyran-2-ones.

Simple and stereoselective syntheses of aplysinopsins and their analogs from either methyl 2-[(2,2-disubstituted ethenyl)amino]-3-(dimethylamino)prop-2-enoates 11 or 5-[(dimethylamino)methylidene]imidazolidine-2,4-diones 20 are described. The structures of products are established by 1H- and 13C-NMR, and NOESY spectroscopy, and X-ray crystal-structure analysis.

Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine organisms and have been shown to possess a range of biological activities. In vitro receptor binding assays showed that of the 12 serotonin receptor subtypes, analogues showed a high affinity for the 5-HT2B and 5-HT2C receptor subtypes, with selectivity for 5-HT2B over 5-HT2C. While no conclusions could be drawn about the number and position of N-methylations, bromination at C-4 and C-5 of the indole ring resulted in greater binding affinities, with Ki's as low as 35 nM. This data, combined with previous knowledge of the CNS activity of aplysinopsin analogs, suggested that these compounds may have potential as leads for antidepressant drugs. Compounds 3c, 3u, and 3x were evaluated in the chick anxiety-depression model to assess their in vivo efficacy. Compound 3c showed a modest antidepressant effect at a dose of 30 nM/kg in the animal model.

Three novel bis(indole) alkaloids with an unprecedented skeleton have been isolated from a stony coral, Tubastraea sp. These indoles could biogenetically be derived from two molecules of aplysinopsin via a Diels–Alder reaction.

Aza Wittig-type reactions of iminophosphoranes 21, derived from ethyl α-azido-β-(3-indolyl)propenoates and triphenylphosphine, with methyl isocyanate, carbon dioxide or carbon disulfide provide the corresponding heterocumulenes 22, 25 and 28 which undergo cyclization by the action of nitrogenous reagents completing the assemblage of the framework of aplysinopsin. Further deprotection leads to naturally occurring aplysinopsin analogues.

Some new aplysinopsin analogues were prepared by a simple coupling of N , N -(dimethylamino)methylidene substituted hydantoin, thiohydantoin, and thiazolone derivatives, with indole derivatives. Configuration around the exocyclic CC double bond was determined on the basis of long-range heteronuclear coupling constants using 2D HMBC correlation technique.

The first preparation of 2-dimethylaminoimidazole 1a , a structural feature of several marine products was undertaken and its reactivity investigated. The synthesis of natural alkaloids 5 and 12b was achieved by direct coupling of the easily accessible oxidized 2-dimethylaminoimidazoles 7 and 8 with indole-3-carboxaldehyde and indole respectively, demonstrating the usefulness of this approach for other structurally related natural products.

Five novel bis(indole) alkaloids, which were composed of two molecules of aplysinopsin have been isolated from a stony coral, Tubastraea aurea. Their structures were elucidated on the basis of spectroscopic methods.

Various aplysinopsin and β -carboline thiohydantoin analogues were prepared starting from ethyl 3-formyl-1H-indole-2-carboxylate by condensation with the active methylene group of 2-thiohydantoin, rhodanine, or thiobarbituric acid derivatives

CDRI Compound 92/138, a synthetic analogue of aplysinopsin, was evaluated in experimental filarial infections, Litomosoides carinii in cotton rats (Sigmodon hispidus) and Acanthocheilonema viteae in Mastomys coucha. The compound killed 63.8 and 90% of adult L. carinii and A. viteae at doses of 30 and 50 mg/kg (i.p.) respectively given for 5 days. By the oral route, at 100 mg/kg for 5 days the compound caused 50.9 and 57% mortality of adult L. carinii and A. viteae, respectively. At 200 mg/kg administered orally on days 0, 10 and 25 post-infection, it reduced establishment of adult A. viteae by 68.5%. We also found 43.7 and 37.8% effect in vivo respectively on L3 and L4 stages of A. viteae at a single dose of 250 mg/kg, p.o. The compound was active in vitro at 100 micrograms/ml concentration and caused a significant decline in MTT reduction and 14C-glucose uptake by adult filariids. Thus synthetic marine aplysinopsin could provide a new pharmacophore for the development of antifilarial agents.

A novel domino synthesis of 1,3,5-trisubstituted hydantoin derivatives has been developed in low melting l-(+)-tartaric acid-DMU melt mixtures. The functionalized hydantoins are obtained in good yields from ?,?- unsaturated ketoacids and urea under environmentally benign and simple reaction conditions. � The Royal Society of Chemistry 2013.

Five novel bis(indole) alkaloids, which were composed of two molecules of aplysinopsin have been isolated from a stony coral, Tubastraea aurea. Their structures were elucidated on the basis of spectroscopic methods.