A novel photosensitizer based on hypocrellin B activated by cysteine over-expressed in cancer cells.

L-Cysteine (Cys)-activatable photosensitizer 3 was designed and synthesized based on hypocrellin B (1). Cys is a novel tumor-associated biomarker. 3 exhibited negligible photosensitizing ability without Cys. However, when 1 was released from 3 by reaction with Cys, the photosensitizing activity was restored. Furthermore, 3 showed selective and effective photo-cytotoxicity against only cancer cells such as HeLa and A549 cells that highly express Cys when irradiated with 660 nm light, which is inside the phototherapeutic window.

Design, Synthesis, and Biological Activity of Novel Quinone Derivatives as Potent STAT3 Inhibitors for Psoriasis Treatment.

Psoriasis, which severely affects the sufferer's life quality, is a chronic skin disease still lacking satisfactory medication. Recently, signal transducer and activator of transcription 3 (STAT3) was revealed playing an important role in the progression of psoriasis. In this paper, a total of 59 quinone derivatives with various scaffolds were designed, synthesized, and evaluated for antipsoriatic potential as STAT3 inhibitors. Among them, 15e was identified as the most potent antipsoriatic agent and could bind to STAT3; reduce both total and phosphorylated STAT3 levels, inhibit the nuclear translocation of STAT3; and, therefore, inhibit the transcription and expression of the propsoriatic factor IL-17A. In vivo experiments on mice showed that the topical application of 15e was effective in alleviating IMQ-induced psoriasis without noticeable side effects. In all, this research rendered 15e as a promising drug candidate for psoriasis.

A novel L-shaped ortho-quinone analog suppresses glioblastoma progression by targeting acceleration of AR degradation and regulating PI3K/AKT pathway.

Glioblastoma (GBM) is a primary intracranial malignant tumor with the highest mortality and morbidity among all malignant central nervous system tumors. Tanshinone IIA is a fat-soluble active ingredient obtained from Salvia miltiorrhiza, which has an inhibitory effect against various cancers. We designed and synthesized a novel L-shaped ortho-quinone analog TE5 with tanshinone IIA as the lead compound and tested its antitumor activity against GBM. The results indicated that TE5 effectively inhibited the proliferation, migration, and invasion of GBM cells, and demonstrated low toxicity in vitro. We found that TE5 may bind to androgen receptors and promote their degradation through the proteasome. Inhibition of the PI3K/AKT signaling pathway was also observed in TE5 treated GBM cells. Additionally, TE5 arrested the cell cycle at the G2/M phase and induced mitochondria-dependent apoptosis. In vivo experiments further confirmed the anti-tumor activity, safety, and effect on androgen receptor level of TE5 in animal models of GBM. Our results suggest that TE5 may be a potential therapeutic drug to treat GBM.

Exploration of novel isoxazole-fused quinone derivatives as anti-colorectal cancer agents through inhibiting STAT3 and elevating ROS level.

Colorectal cancer (CRC) is trending to be a major health problem throughout the world. Therapeutics with dual modes of action have shown latent capacity to create ideal anti-tumor activity. Signal transducer and activator of transcription 3 (STAT3) has been proved to be a potential target for the development of anti-colon cancer drug. In addition, modulation of tumor redox homeostasis through deploying exogenous reactive oxygen species (ROS)-enhancing agents has been widely applied as anti-tumor strategy. Thus, simultaneously targeting STAT3 and modulation ROS balance would offer a fresh avenue to combat CRC. In this work, we designed and synthesized a novel series of isoxazole-fused quinones, which were evaluated for their preliminary anti-proliferative activity against HCT116 cells. Among these quinones, compound 41 exerted excellent in vitro anti-tumor effect against HCT116 cell line with an IC50 value of 10.18 ± 0.4 nM. Compound 41 was proved to bind to STAT3 by using Bio-Layer Interferometry (BLI) assay, and can significantly inhibit phosphorylation of STAT3. It also elevated ROS of HCT116 cells by acting as a substrate of NQO1. Mitochondrial dysfunction, apoptosis, and cell cycle arrest, which was caused by compound 41, might be partially due to the inhibition of STAT3 phosphorylation and ROS production induced by 41. Moreover, it exhibited ideal anti-tumor activity in human colorectal cancer xenograft model and good safety profiles in vivo. Overall, this study provided a novel quinone derivative 41 with excellent anti-tumor activity by inhibiting STAT3 and elevating ROS level, and gave insights into designing novel anti-tumor therapeutics by simultaneously modulation of STAT3 and ROS.

Positioning of an unprecedented 1,5-oxaza spiroquinone scaffold into SMYD2 inhibitors in epigenetic space.

Lysine methyltransferases are important regulators of epigenetic signaling and are emerging as a novel drug target for drug discovery. This work demonstrates the positioning of novel 1,5-oxaza spiroquinone scaffold into selective SET and MYND domain-containing proteins 2 methyltransferases inhibitors. Selectivity of the scaffold was identified by epigenetic target screening followed by SAR study for the scaffold. The optimization was performed iteratively by two-step optimization consisting of iterative synthesis and computational studies (docking, metadynamics simulations). Computational binding studies guided the important interactions of the spiro[5.5]undeca scaffold in pocket 1 and Lysine channel and suggested extension of tail length for the improvement of potency (IC50: up to 399 nM). The effective performance of cell proliferation assay for chosen compounds (IC50: up to 11.9 nM) led to further evaluation in xenograft assay. The potent compound 24 demonstrated desirable in vivo efficacy with growth inhibition rate of 77.7% (4 fold decrease of tumor weight and 3 fold decrease of tumor volume). Moreover, mirosomal assay and pharmacokinetic profile suggested further developability of this scaffold through the identification of major metabolites (dealkylation at silyl group, reversible hydration product, the absence of toxic quinone fragments) and enough exposure of the testing compound 24 in plasma. Such spiro[5.5]undeca framework or ring system was neither been reported nor suggested as a modulator of methyltransferases. The chemo-centric target positioning and structural novelty can lead to potential pharmacological benefit.

[Development of New Synthetic Methods for Carbazole Compounds Aimed at Drug Discovery and Exploratory Research on Pharmaceutical Materials].

We are developing the synthesis of biologically interesting carbazole compounds, including natural products by tandem cyclic reactions. In this report, we describe the new synthesis of carbazole-1,4-quinones as follows; 1) the synthesis of carbazole-1,4-quinones using a tandem ring closing metathesis (RCM) -dehydrogenation reaction, 2) a novel one-pot synthesis of carbazole-1,4-quinone by consecutive Pd-catalyzed cyclocarbonylation, desilylation, and oxidation reactions. Two new synthetic strategies were applied to the synthesis of carbazole-1,4-quinone alkaloids and ellipticine quinones, and then the antiproliferative activity against HCT-116 and HL-60 cells of the synthesized compounds were evaluated.

A novel hypocrellin-based assembly for sonodynamic therapy against glioblastoma.

The non-invasive treatment of glioblastoma (GBM) is of great significance and can greatly reduce the complications of craniotomy. Sonodynamic therapy (SDT) is an emerging tumor therapeutic strategy that overcomes some fatal flaws of photodynamic therapy (PDT). Different from PDT, SDT has deep tissue penetration and can be applied in the non-invasive treatment of deep-seated tumors. However, effective sonosensitizers that can be used for SDT of GBM are still very rare. Herein, we have prepared a suitable assembly based on a hypocrellin derivative (CTHB) with good biocompatibility. Excitedly, the hypocrellin-based assembly (CTHB NPs) can effectively produce reactive oxygen species under ultrasound stimulation. The inherent fluorescence and photoacoustic imaging characteristics of the CTHB NPs are conducive to the precise positioning of the tumors. It has been proved both in subcutaneous and in intracranial tumor models that CTHB NPs can be used as an effective sonosensitizer to inhibit tumor growth under ultrasound irradiation. This hypocrellin-based assembly has a good clinical prospect in the non-invasive treatment of GBM.

Design, synthesis, and evaluation of proliferation inhibitory activity of novel L-shaped ortho-quinone analogs as anticancer agents.

In this study, we present the design and synthesis of novel fully synthetic L-shaped ortho-quinone analogs with tanshinone IIA as the lead compoud, which is a molecule with numerous pharmacological benefits and potential to treat life-threatening diseases, such as cancer and viral infections. 24 L-shaped ortho-quinone analogs were designed and synthesized via click chemistry and introduced 1,2,3-triazole at the C-2 terminal of the furan ring. The cytotoxicity of these analogs toward different cancer cell lines was investigated in vitro. The new TD compounds showed potent inhibitory activities toward prostate cancer (PC3), leukemia (K562), breast cancer (MDA-231), lung cancer (A549), and cervical cancer (Hela) cell lines. Among them, TD1, TD11, and TD17 showed excellent broad-spectrum cytotoxic effects on five cancer cell lines by inducing apoptosis and arresting the cell cycle phase. Besides, TD1, TD11, and TD17 could target-bind with NQO1 protein in the prostate cancer cells PC3 leukemia cells K562. The results showed that removing the methyl group at C-3 and introducing 1,2,3-triazoles at the C-2 terminal of the furan ring were effective strategies for improving the broad-spectrum anticancer activity of L-shaped ortho-quinone analogs.

Insights into carbon nanotube-assisted electro-oxidation of polycyclic aromatic hydrocarbons for mediated bioelectrocatalysis.

A series of polycyclic aromatics, naphthalene, phenanthrene, perylene, pyrene, 1-pyrenebutyric acid N-hydroxysuccinimide ester (pyrene NHS) and coronene, were immobilized via π stacking on carbon nanotube (CNT) electrodes and electro-oxidized in aqueous solutions. The obtained quinones were characterized and evaluated for the mediated electron transfer with FAD dependent glucose dehydrogenase during catalytic glucose oxidation.

Recent advances of quinones as a privileged structure in drug discovery.

Privileged structures are conductive to discover novel bioactive substances because they can bind to multiple targets with high affinity. Quinones are considered to be a privileged structure and useful template for the design of new compounds with potential pharmacological activity. This article presents the recent developments (2014-2021 update) of quinones in the fields of antitumor, antibacterial, antifungal, antiviral, anti-Alzheimer's disease (AD) and antimalarial, mainly focusing on biological activities, structural modification and mechanism of action.

Ruthenium(II)- and Palladium(II)-catalyzed position-divergent CH oxygenations of arylated quinones: Identification of hydroxylated quinonoid compounds with potent trypanocidal activity.

A diversity-oriented synthesis of hydroxylated aryl-quinones via CH oxygenation reactions and their evaluation against Trypanosoma cruzi, the etiological agent of Chagas disease, was accomplished. With the use of ruthenium(II)- or palladium(II)-based catalysts, complementary regioselectivities were observed in the hydroxylation reactions and we have identified 9 compounds more potent than benznidazole (Bz) among these novel arylated and hydroxylated quinones. For instance, 5-hydroxy-2-[4-(trifluoromethyl)phenyl]-1,4-naphthoquinone (4h) with an IC50/24 h value of 22.8 µM is 4.5-fold more active than the state-of-the-art drug Bz. This article provides the first example of the application of CH activation for the position-selective hydroxylation of arylated quinones and the identification of these compounds as trypanocidal drug candidates.

Design and synthesis of C-aryl angular luotonins via a one-pot aza-Nazarov-Friedlander sequence and their Topo-I inhibition studies along with C-aryl vasicinones and luotonins.

A facile one-pot synthesis of C-ring substituted angular luotonins has been realized via a methanesulfonic acid mediated aza-Nazarov-Friedlander condensation sequence on quinazolinonyl enones. Topoisomerase I (topo-I) inhibition studies revealed that the angular luotonin library (7a-7l) and their regioisomeric analogs (linear luotonins, 8a-8l) are weak negative modulators, compared to camptothecin. These results would fare well for the design of topo-I-inert luotonins for non-oncological applications such as anti-fungal and insecticide lead developments. Surprisingly, the tricyclic vasicinones (9h, 9i, and 9j) showed better topo-I inhibition compared to pentacyclic C-aryl luotonins providing a novel pharmacophore for further explorations.

Total Synthesis of Anti-Cancer Meroterpenoids Dysideanone†B and Dysiherbol†A and Structural Reassignment of Dysiherbol†A.

The first total synthesis of marine anti-cancer meroterpenoids dysideanone B and dysiherbol A have been accomplished in a divergent way. The synthetic route features: 1) a site and stereoselective α-position alkylation of a Wieland-Miescher ketone derivative with a bulky benzyl bromide to join the terpene and aromatic moieties together and set the stage for subsequent cyclization reactions; 2) an intramolecular radical cyclization to construct the 6/6/6/6-tetracycle of dysideanone B and an intramolecular Heck reaction to forge the 6/6/5/6-fused core structure of dysiherbol A. A late-stage introduction of the ethoxy group in dysideanone B reveals that this group might come from the solvent ethanol. The structure of dysiherbol A has been revised based on our chemical total synthesis.

New benzimidazolequinones as trypanosomicidal agents.

Herein, the design and synthesis of new 2-phenyl(pyridinyl)benzimidazolequinones and their 5-phenoxy derivatives as potential anti-Trypanosoma cruzi agents are described. The compounds were evaluated in vitro against the epimastigotes and trypomastigote forms of Trypanosoma cruzi. The replacing of a benzene moiety in the naphthoquinone system by an imidazole enhanced the trypanosomicidal activity against Trypanosoma cruzi. Three of the tested compounds (11a-c) showed potent trypanosomicidal activity and compound 11a, with IC50 of 0.65 µM on the trypomastigote form of T. cruzi, proved to be 15 times more active than nifurtimox. Additionally, molecular docking studies indicate that the quinone derivatives 11a-c could have a multitarget profile interacting preferentially with trypanothione reductase and Old Yellow Enzyme.

Metric-Based Analysis of Convergence in Complex Molecule Synthesis.

Convergent syntheses are characterized by the coupling of two or more synthetic intermediates of similar complexity, often late in a pathway. At its limit, a fully convergent synthesis is achieved when commercial or otherwise readily available intermediates are coupled to form the final target in a single step. Of course, in all but exceptional circumstances this level of convergence is purely hypothetical; in practice, additional steps are typically required to progress from fragment coupling to the target. Additionally, the length of the sequence required to access each target is a primary consideration in synthetic design.In this Account, we provide an overview of alkaloid, polyketide, and diterpene metabolites synthesized in our laboratory and present parameters that may be used to put the degree of convergence of each synthesis on quantitative footing. We begin with our syntheses of the antiproliferative, antimicrobial bacterial metabolite (-)-kinamycin F (1) and related dimeric structure (-)-lomaiviticin aglycon (2). These synthetic routes featured a three-step sequence to construct a complex diazocyclopentadiene found in both targets and an oxidative dimerization to unite the two halves of (-)-lomaiviticin aglycon (2). We then follow with our synthesis of the antineurodegenerative alkaloid (-)-huperzine A (3). Our route to (-)-huperzine A (3) employed a diastereoselective three-component coupling reaction, followed by the intramolecular α-arylation of a ß-ketonitrile intermediate, to form the carbon skeleton of the target. We then present our syntheses of the hasubanan alkaloids (-)-hasubanonine (4), (-)-delavayine (5), (-)-runanine (6), (+)-periglaucine B (7), and (-)-acutumine (8). These alkaloids bear a 7-azatricyclo[4.3.3.01,6]dodecane (propellane) core and a highly oxidized cyclohexenone ring. The propellane structure was assembled by the addition of an aryl acetylide to a complex iminium ion, followed by intramolecular 1,4-addition. We then present our synthesis of the guanidinium alkaloid (+)-batzelladine B (9), which contains two complex polycyclic guanidine residues united by an ester linkage. This target was logically disconnected by an esterification to allow for the independent synthesis of each guanidine residue. A carefully orchestrated cascade reaction provided (+)-batzelladine B (9) in a single step following fragment coupling by esterification. We then discuss our synthesis of the diterpene fungal metabolite (+)-pleuromutilin (10). The synthesis of (+)-pleuromutilin (10) proceeded via a fragment coupling involving two neopentylic reagents and employed a nickel-catalyzed reductive cyclization reaction to close the eight-membered ring, ultimately providing access to (+)-pleuromutilin (10), (+)-12-epi-pleuromutilin (11), and (+)-12-epi-mutilin (12). Finally, we discuss our synthesis of (-)-myrocin G (13), a tricyclic pimarane diterpene that was assembled by a convergent annulation.In the final section of this Account, we present several paramaters to analyze and quantitatively assess the degree of convergence of each synthesis. These parameters include: (1) the number of steps required following the point of convergence, (2) the difference in the number of steps required to prepare each coupling partner, (3) the percentage of carbons (or, more broadly, atoms) present at the point of convergence, and (4) the complexity generated in the fragment coupling step. While not an exhaustive list, these parameters bring the strengths and weaknesses each synthetic strategy to light, emphasizing the key contributors to the degree of convergence of each route while also highlighting the nuances of these analyses.

Palladium-catalysed synthesis of arylnaphthoquinones as antiprotozoal and antimycobacterial agents.

Malaria and tuberculosis are still among the leading causes of death in low-income countries. The 1,4-naphthoquinone (NQ) scaffold can be found in a variety of anti-infective agents. Herein, we report an optimised, high yield process for the preparation of various 2-arylnaphthoquinones by a palladium-catalysed Suzuki reaction. All synthesised compounds were evaluated for their in-vitro antiprotozoal and antimycobacterial activity. Antiprotozoal activity was assessed against Plasmodium falciparum (P.f.) NF54 and Trypanosoma brucei rhodesiense (T.b.r.) STIB900, and antimycobacterial activity against Mycobacterium smegmatis (M.s.) mc2 155. Substitution with pyridine and pyrimidine rings significantly increased antiplasmodial potency of our compounds. The 2-aryl-NQs exhibited trypanocidal activity in the nM range with a very favourable selectivity profile. (Pseudo)halogenated aryl-NQs were found to have a pronounced effect indicating inhibition of mycobacterial efflux pumps. Cytotoxicity of all compounds towards L6 cells was evaluated and the respective selectivity indices (SI) were calculated. In addition, the physicochemical parameters of the synthesised compounds were discussed.

Near-Infrared Hypocrellin Derivatives for Synergistic Photodynamic and Photothermal Therapy.

Hypocrellin B (HB) derived from naturally produced hypocrellins has attracted considerable attention in photodynamic therapy (PDT) because of its excellent photosensitive properties. However, the weak absorption within a "phototherapy window" (600-900 nm) and poor water solubility of HB have limited its clinical application. In this study, two HB derivatives (i. e., HE and HF) were designed and synthesized for the first time by introducing two different substituent groups into the HB structure. The obtained derivatives showed a broad absorption band covering the near-infrared (NIR) region, NIR emission (peaked at 805 nm), and singlet oxygen quantum yields of 0.27/0.31. HE-PEG-NPs were also prepared using 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-mPEG2000) to achieve excellent dispersion in water and further explored their practical applications. HE-PEG-NPs not only retained their 1 O2 -generating ability, but also exhibited a photothermal conversion efficiency of 25.9%. In vitro and in vivo therapeutic results revealed that the synergetic effect of HE-PEG-NPs on PDT and photothermal therapy (PTT) could achieve a good performance. Therefore, HE-PEG-NPs could be regarded as a promising phototheranostic agent.

Synthesis and biological evaluation of novel isothiazoloquinoline quinone analogues.

Natural quinones and their analogues have attracted growing attention because of their novel anticancer activities. A series of novel isothiazoloquinoline quinone analogues were synthesized and evaluated for antitumor activities against four different kind of cancer cells. Among them, isothiazoloquinolinoquinones inhibited cancer cells proliferation effectively with IC50 values in the nanomolar range, and isothiazoloquinolinoquinone 13a induced the cell apoptosis. Further exploration of possible mechanism of action indicates that 13a not only activates ROS production through NQO1-directed redox cycling but also inhibits the phosphorylation of STAT3. These findings indicate that 13a has potential use for the development of new skeleton drug candidate as an efficient substrate of NQO1 and STAT3 inhibitor.

Advances in catalytic and protecting-group-free total synthesis of natural products: a recent update.

Catalytic processes in protecting-group-free syntheses of natural products are fast emerging towards achieving the goal of efficiency and economy in total synthesis. Present day sustainable development in synthesis of natural products does not permit the luxury of using stoichiometric reagents and protecting groups. Catalysis and step-economy can contribute significantly toward economy and efficiency of synthesis. This feature article details the ingenious efforts by many researchers in the last couple of years toward concise total syntheses, based on catalytic steps and protecting-group-free-strategies. These would again serve as guidelines in future development of reagents and catalysts aimed at achieving higher efficiency and chemoselectivity to the point that catalysis and protecting-group-free synthesis will be an accepted common practice.

Antiplasmodial Activity of p-Substituted Benzyl Thiazinoquinone Derivatives and Their Potential against Parasitic Infections.

Malaria is a life-threatening disease and, what is more, the resistance to available antimalarial drugs is a recurring problem. The resistance of Plasmodium falciparum malaria parasites to previous generations of medicines has undermined malaria control efforts and reversed gains in child survival. This paper describes a continuation of our ongoing efforts to investigate the effects against Plasmodium falciparum strains and human microvascular endothelial cells (HMEC-1) of a series of methoxy p-benzyl-substituted thiazinoquinones designed starting from a pointed antimalarial lead candidate. The data obtained from the newly tested compounds expanded the structure-activity relationships (SARs) of the thiazinoquinone scaffold, indicating that antiplasmodial activity is not affected by the inductive effect but rather by the resonance effect of the introduced group at the para position of the benzyl substituent. Indeed, the current survey was based on the evaluation of antiparasitic usefulness as well as the selectivity on mammalian cells of the tested p-benzyl-substituted thiazinoquinones, upgrading the knowledge about the active thiazinoquinone scaffold.