Expanding the structure-activity relationship of cytotoxic diphenyl macrocycles.

Twenty-four biaryl tetrapeptide macrocycles were synthesized as an extension of our previous work. Two groups of compounds were constructed for establishing a structure-activity relationship: one having an aromatic substituent at α-position of one exo-peptide and the other group with a variation in the size of the lipophilic chain. Compound 13t had the best cytotoxicity from all the compounds tested (in a panel of six human cancer cell lines) and low toxicity on one healthy cell line. The study identified the lipophilic chain as the main structural moiety for improving the biological activity, being the seven-carbon chain the optimal length. On the other hand, the aromatic rings at α-position did not enhance the cytotoxicity.

Synthesis of nuevamine and a cyano-chilenine analog via divergent C(sp3)-H bond functionalization of isoindolinone derivatives.

Divergent C(sp3)-H bond functionalizations of isoindolinone derivatives were developed to synthesize nuevamine, a cyano-chilenine derivative, and two related analogs. A copper-catalyzed C-H cross-dehydrogenative coupling (via cation formation) allowed the formation of a new C-C bond leading to the direct assembly of the isoindolo[1,2-a]isoquinolinone tetracyclic system of the nuevamine. The syntheses of the cyano-chilenine derivatives were carried out by installing two nitrile groups under basic conditions (via anion formation). Then, the isoindolobenzazepinic system of the chilenine skeleton was constructed by a Houben-Hoesch cyclization process. The present methodology has the advantage of not requiring the use of pre-functionalized substrates.

Multicomponent synthesis and preliminary anti-inflammatory activity of lipophilic diphenylamines.

Non-Steroidal Anti-inflammatory Drugs (NSAIDs) are some of the most prescribed medications for pain but the incidence of adverse effects -especially during chronic treatment- points out the requirement of new analgesics. In this study, we showed an efficient two-steps synthesis of diphenylamine-containing dipeptides consisting of a multicomponent process followed by a Buchwald-Hartwig cross-coupling reaction. We prepared 16 diphenylamine derivatives and evaluated their in vivo anti-inflammatory activity through an ear edema model using 12-O-tetradecanoylpholbol-13-acetate. Furthermore, the toxicity of the more potent compounds in the Artemia salina model and their cell viability using murine RAW 264.7 cells is reported. The fluorinated compound 10k becomes a reliable candidate since it reduced the TPA-induced edema to 92%, lacked cytotoxicity against murine macrophages, and had minimal toxicity in Artemia salina.

Multicomponent synthesis and anti-proliferative screening of biaryl triazole-containing cyclophanes.

We report a practical two-step approach involving a Ugi 4-CR/ azide-alkyne cycloaddition for the synthesis of biaryl-containing cyclophanes. The series represents an extension of our previously reported macrocycles as an effort to enhance the anti-proliferative activity of this scaffold. In this variant, we incorporate a biphenyl moiety in the framework, thus enhancing the macrocycle size, lipophilicity, and structural diversity. Macrocycles were tested against different cell lines, being more cytotoxic against prostate (PC-3 and DU-145) and breast (MCF-7) tumor cells. Gratifyingly, the most active compound showed a significative enhancement of PC-3 growth inhibition with respect to our previous series, reaffirming the potential anti-proliferative activity of this kind of cyclophanes.

Pairing multicomponent stators with aromatic rotators for new emissive molecular rotors.

We demonstrate here that the Ugi-Sonogashira protocol can be successfully used to obtain five new molecular rotors 10a-e with strong emission. They have been synthesized by combining multicomponent Ugi stators and several aromatic rotary components: phenylene, p-xylene, naphthalene and anthracene. The synthesized conjugated rotors are highly fluorescent (Φf = 0.39 to Φf = 0.10), and changes in their emission were observed upon variations of the surrounding media. Particularly, we found that they are sensitive to aggregation (THF/water) or high viscosity (methanol/glycerol) conditions. This work paves the way to develop new emissive rotors with exciting photophysical properties.

Diversity-Oriented Synthesis of Highly Fluorescent Fused Isoquinolines for Specific Subcellular Localization.

A multicomponent diversity-oriented synthesis of new highly emissive tetracyclic isoquinolines that target specific organelles is described. The title compounds were prepared via a three-step protocol starting with an Ugi four-component reaction, followed by either an intramolecular alkyne hydroarylation and subsequent alkene isomerization or through a Pomeranz-Fritsch-type cyclization with a final intramolecular Heck reaction. Subcellular localization studies of these compounds using green channel confocal microscopy revealed remarkable and distinctive distribution patterns in live cells, showing an unprecedented high selectivity and imaging contrast. The differentiated organelle visualization-including localizers for mitochondria, lysosomes, Golgi apparatus, endoplasmic reticulum, and plasma membrane-was achieved by varying the nature of the tetracyclic system and substituent pattern, changing the original four-component set in the starting Ugi reaction.

Photocatalytic xanthate-based radical addition/cyclization reaction sequence toward 2-biphenyl isocyanides: synthesis of 6-alkylated phenanthridines.

A photocatalytic xanthate-based radical addition/cyclization reaction cascade toward 2-biphenylisocyanides is described as a practical and modular approach to 6-alkylated phenanthridines. The use of xanthates as radical precursors allowed the synthesis of diversely 6-substituted phenanthridines. Electrophilic radicals derived from nitriles, aromatic and aliphatic ketones, malonates, and amide derivatives, as well as radicals derived from phthalimidomethyl and benzylic derivatives were successfully introduced. The reaction proceeds under mild conditions without a stoichiometric amount of oxidant. Thirty novel phenanthridine scaffolds were synthesized with yields ranging from 24 to 76%.

Synthesis of diphenylamine macrocycles and their anti-inflammatory effects.

A collection of fourteen diphenylamine macrocyclic derivatives containing a peptide chain with different substituents was synthesized using a protocol of two Ugi four component reactions (Ugi-4CR) and a Buchwald-Hartwig macrocyclization. Their anti-inflammatory effects were assayed with an ear edema model using 12-O-tetradecanoylphorbol-13-acetate, while the activity of myeloperoxidase was determined to evaluate the index of leukocyte infiltration. Compound 5e had an ID50 of 0.18 µM per ear with a potency higher than that of the reference drugs indomethacin and celecoxib (0.24 and 0.91 µM per ear, respectively). Moreover, the cytotoxicity of the macrocycles was determined in two healthy cell lines, showing a low percentage of toxicity.

Synthesis of Structurally Diverse Emissive Molecular Rotors with Four-Component Ugi Stators.

The use of the multicomponent Ugi reaction to rapidly prepare a library of dumbbell-like molecular rotors is highlighted here. The synthetic strategy consisted of the atom-economic access to 15 bulky and structurally diverse iodinated stators, which were cross-coupled to the 1,4-diethynylphenylene rotator. From those experiments, up to six rotors 1a-c and 1l-n were obtained, with yields ranging from 35 to 69% per coupled C-C bond. In addition to the framework diversity, five of these compounds showed aggregate-enhanced emission properties thanks to their conjugated 1,4-bis(phenylethynyl)benzene cores, a property that rises by increasing the water fraction (fw) in their THF solutions. The results highlight the significance of the diversity-oriented synthesis of rapid access to new molecular fluorescent rotors.

A unified synthesis of topologically diverse Aspidosperma alkaloids through divergent iminium-trapping.

Aspidospermidine, vincadifformine, 1,2-dehydroaspidospermidine, goniomitine, and quebrachamine, five Aspidosperma alkaloids distributed within three structurally diverse topologies, were synthesized from a single molecular scaffold, namely indole-valerolactam 6. This common intermediate can be divergently manipulated, through the incorporation of conformational and electronic constraints that influence the chemo-selectivity of the iminium ion derived therefrom, between three different reaction paths: N(1) vs. C(3) cyclization (indole numbering) vs. over-reduction. Moreover, a catalytic carbene insertion for direct C(3)-H indole functionalization is reported for the first time in an approach to goniomitine (4), and a following tandem ester reduction/iminium generation/cyclization secured its tetracyclic system. The development of a highly diastereoselective one-pot hemi-reduction/cyclization/deprotection process to obtain a cis-pyridocarbazole directly allowed the synthesis of pentacyclic Aspidosperma alkaloids 1, 2, and 3.

Synthesis of 6-methyl-3,4-dihydropyrazinones using an Ugi 4-CR/allenamide cycloisomerization protocol.

A synthetic approach to the 6-methyl-3,4-dihydropyrazinone core from Ugi adducts is described. This methodology relies on the regioselective C-N bond formation between an allenamide moiety at C-ß and an amide anion formed under base-mediated conditions. This protocol allows easy access to tricyclic systems such as pyrazino[2,1-a]isoindole and pyrazino[2,1-a]isoquinoline nuclei.

Diversity-oriented synthesis and cytotoxic activity evaluation of biaryl-containing macrocycles.

Synthesis of biaryl-containing macrocycles has been carried out through a four-step approach comprising two Ugi four component reactions and a Suzuki-Miyaura macrocyclization. This protocol allowed the synthesis of 12- and 14-membered macrocycles. Cytotoxic activity evaluation showed that some of the molecules were effective against leukemia, glioblastoma and lung cancer cell lines (IC50 = 4.0, 5.9 and 7.6, respectively).

meso-Dihydroguaiaretic acid derivatives with antibacterial and antimycobacterial activity.

Thirty-three meso-dihydroguaiaretic acid (meso-DGA) derivatives bearing esters, ethers, and amino-ethers were synthesized. All derivatives were tested against twelve drug-resistant clinical isolates of Gram-positive and Gram-negative bacteria, including sensitive (H37Rv) and multidrug-resistant Mycobacterium tuberculosis strains. Among the tested compounds, four esters (7, 11, 13, and 17), one ether (23), and three amino-ethers (30, 31, and 33) exhibited moderate activity against methicillin-resistant Staphylococcus aureus, whereas 30 and 31 showed better results than levofloxacin against vancomycin-resistant Enterococcus faecium. Additionally, nineteen meso-DGA derivatives displayed moderate to potent activity against M. tuberculosis H37Rv with minimum inhibitory concentration (MIC) values ranging from 3.125 to 50µg/mL. Seven meso-DGA derivatives bearing amino-ethers (26-31 and 33) exhibited the lowest MICs against M. tuberculosis H37Rv and G122 strains, with 31 being as potent as ethambutol (MICs of 3.125 and 6.25µg/mL). The presence of positively charged group precursors possessing steric and hydrophobic features (e.g. N-ethylpiperidine moieties in meso-31) resulted essential to significantly increase the antimycobacterial properties of parent meso-DGA as supported by the R-group pharmacophoric and field-based QSAR analyses. To investigate the safety profile of the antimycobacterial compounds, cytotoxicity on Vero cells was determined. The amino-ether 31 exhibited a selectivity index value of 23, which indicate it was more toxic to M. tuberculosis than to mammalian cells. Therefore, 31 can be considered as a promising antitubercular agent for further studies.

Multicomponent access to indolo[3,3a-c]isoquinolin-3,6-diones: formal synthesis of (±)-plicamine.

The complete tetracyclic core structure of plicamine, a novel Amaryllidaceae-type alkaloid, was expeditously prepared by a Ugi four-component condensation reaction, followed by a one-pot sequential phenolic oxidation and intramolecular coupling process. The employment of this strategy resulted in a rapid, formal synthesis of (±)-plicamine.

Practical synthesis and cytotoxic evaluation of the pyrazino[1,2-b]-isoquinoline ring system.

A practical three-step protocol for the synthesis of pyrazino[1,2-b]isoquinolines is reported. This approach includes a one-pot parallel cyclization/cyclization parallel process followed by a non-common 6-endo Heck cyclization that transformed previously constructed Ugi adducts into diversely decorated tricyclic systems. Compounds bearing a t-butyl or 2,6-dimethylphenyl substituent showed significant cytotoxic activity. The most active analogue (6p) showed significant activity against HCT-15 and K562 (IC50 = 41.8 ± 3.3 and 57.7 ± 2.1 µM, respectively) with no cytotoxicity against human gingival fibroblasts.

Multicomponent/Palladium-Catalyzed Cascade Entry to Benzopyrrolizidine Derivatives: Synthesis and Antioxidant Evaluation.

A versatile and efficient protocol for the synthesis of highly substituted benzopyrrolizidines (tetrahydro-3H-pyrrolo[2,1-a]isoindol-3-ones) is reported. The strategy consisted of an Ugi four-component reaction/elimination methodology to afford dehydroalanines containing trans-cinnamic acid derivatives and different substituted 2-bromobenzylamines, followed by a palladium-catalyzed 5-exo-trig/5-exo-trig cascade carbocyclization process. Gratifyingly, benzopyrrolizidines were obtained in moderate to good yields (42-77%) with a Z geometry due to the structural requirements for syn-ß-hydride elimination. The prepared heterocyclic scaffolds are decorated with several substituents and incorporate a benzopyrrolizidine-fused system, along with an embedded cinnamic acid derivative, two privileged medicinal chemistry scaffolds. Additionally, since some of the compounds are derived from the well-known antioxidants ferulic and sinapinic acids, they were tested for their in vitro antioxidant capacity. The data suggested that compounds having a p-hydroxyl group showed moderate 2,2-diphenyl-1-picrylhydrazyl-radical-scavenging activity and were effective antioxidants in preventing lipoperoxidation in a thiobarbituric acid reactive substances assay.

Synthesis of novel tryptamine-based macrocycles using an Ugi 4-CR/microwave assisted click-cycloaddition reaction protocol.

A practical synthesis of novel tryptamine-based macrocycles using an Ugi 4-CR/click-cycloaddition sequential reaction protocol is described. The main features of the macrocyclic scaffolds are a peptoid moiety, a 1,3-substituted indole nucleus, and a triazole ring.

A Copper-Mediated Radical α-Heteroarylation of Nitriles with Azobis(alkylcarbonitriles).

A new practical method has been developed for the α-heteroarylation of aliphatic nitriles with heteroarenes and azobis(alkylcarbonitriles) using Cu(OAc)2 as an oxidizing agent. This method allows the easy construction of nitrile-, aryl-, and dialkyl-bearing quaternary carbon centers from readily available building blocks, without requiring prefunctionalization steps. This reaction is based on adding cyanodialkyl radicals onto heteroarenes, including benzofurans, furans, pyrroles, and indoles. The resulting α-heteroaryl nitriles are useful synthetic intermediates and pharmacophores in biologically active molecules.

Microwave-assisted C-3 selective oxidative radical alkylation of flavones.

Flavones were directly alkylated at the C-3 position in moderate yields using a xanthate-based oxidative radical addition procedure. This methodology is a suitable synthetic tool for the direct substitution of the vinylic and unactivated C-H bond of the C ring of the flavone by an alkyl functionality under neutral conditions.

Visible-Light Mediated Radical Alkylation of Flavones: A Modular Access to Nonsymmetrical 3,3″-Biflavones.

The first synthetic strategy for nonsymmetrical 3,3″-biflavones is described. To this end, a novel visible-light iridium-catalyzed radical C-3 alkylation of flavones with o-methoxy phenacyl bromides was developed. Selective demethylation of the alkylated flavones and acylation through a Baker-Venkataraman rearrangement with diverse acyl chlorides afforded a library of 20 structurally novel biflavones. This modular strategy rapidly expands the structural complexity and diversity of these privileged scaffolds.