Synthesis of indenofurans, benzofurans and spiro-lactones via Hauser-Kraus annulation involving 1,6-addition of phthalide to quinone methides. Basu Pallabita,Satam Nishikant,Namboothiri Irishi N N Organic & biomolecular chemistry An unprecedented reactivity of 3-sulfonylphthalide with 2-hydroxyaryl-p-quinone methides (HQMs) is reported here. A cascade of reactions starting with 1,6-addition and Dieckmann cyclization produced a diverse array of indenofurans and benzofurans in high yields, depending on the amount of base used, presumably via a common 8-membered ketolactone intermediate. The indenofurans could be transformed to benzofurans in the presence of excess base via a key spiro-lactone intermediate, which could be characterized via in situ oxidation to a stable spirolactone linked quinone methide, providing crucial evidence for the mechanism of the reaction. The three diverse oxygen heterocycles synthesized by our methodology constitute the core structure of several bioactive compounds including natural products. 10.1039/d0ob01115k
    Pristimerin induces apoptosis and tumor inhibition of oral squamous cell carcinoma through activating ROS-dependent ER stress/Noxa pathway. Zhao Qun,Cheng Xinran,Yu Wei,Bi Yun,Guo Jian,Ma Qingzhao,Gong Yingxia,He Li,Yu Xianjun Phytomedicine : international journal of phytotherapy and phytopharmacology BACKGROUND:Pristimerin (Pri), a natural quinone methide triterpenoid isolated from Celastraceae and Hippocrateaceae, exhibits potent antitumor activity against various cancers. However, the mechanism of apoptosis induction by Pri in oral squamous cell carcinoma (OSCC) and its anti-OSCC effect in vivo has not been widely studied. PURPOSE:This study aimed to investigate the anti-OSCC activities of Pri in vitro and in vivo and addressed the potential mechanisms of Pri-induced apoptosis. METHODS:The effects of Pri on OSCC cells were analyzed by cell viability, colony formation and flow cytometry assays. Western blotting and qRT-PCR assays were chosen to detect the expression of proteins and genes. The anti-OSCC efficacy of Pri in vivo was evaluated by CAL-27 xenografts. RESULTS:We showed that Pri inhibited the proliferation of human OSCC cell lines. Additionally, Pri induced apoptosis by upregulating Noxa expression. Furthermore, Pri treatment triggered excessive endoplasmic reticulum (ER) stress activation and subsequently induced c-Jun N-terminal kinase (JNK) signaling. ROS scavengers and ER stress inhibitors significantly attenuated Pri-induced OSCC cell apoptosis. Finally, Pri suppressed tumor growth in CAL-27 xenografts, accompanied ER stress activation and cell apoptosis. CONCLUSION:These results reveal that Pri suppressed tumor growth and triggered cell apoptosis through ER stress activation in OSCC cells and xenografts, suggesting that Pri may serve as a therapeutic agent for OSCC. 10.1016/j.phymed.2021.153723
    A thiol-inducible and quick-response DNA cross-linking agent. Xu Yuanzhen,Wei Hongbo,Chen Jianjun,Gao Kun Bioorganic & medicinal chemistry letters Three new 2,4-dinitrobenzenesulfonyl derivatives 1-3 were successfully prepared for the first time using a simple process. They were efficiently triggered by thiols (glutathione and l-cysteine) to release the corresponding phenol derivatives (4-6) within 5 min. The quick response of 1-3 toward thiols was determined by H NMR and HPLC. Moreover, our results indicated that 1 could induce DNA cross-linking in the presence of glutathione, probably due to the quinone methide formation of phenol intermediate 4 followed by departure of 2,4-dinitrobenzenesulfonyl group. 10.1016/j.bmcl.2018.11.040
    Total synthesis and biological evaluation of an antifungal tricyclic o-hydroxy-p-quinone methide diterpenoid. Huang Jinhua,Foyle Dylan,Lin Xiaorong,Yang Jiong The Journal of organic chemistry A convergent route has been developed to synthesize an antifungal tricyclic o-hydroxy-p-quinone methide diterpenoid and analogues. A Li/naphthalene-mediated reductive alkylation was employed for coupling β-cyclocitral and the corresponding benzyl chloride, while a BBr3-mediated one-pot bis-demethylation and intramolecular Friedel-Crafts alkylation was used to assemble the tricyclic molecular skeleton. The structure-activity relationship of the diterpenoid was assessed on the basis of antiproliferation assays of the natural product and analogues against strains of pathogenic yeasts and filamentous fungi. 10.1021/jo4013964
    Covalent modification of a melanoma-derived antigenic peptide with a natural quinone methide. Preliminary chemical, molecular modelling and immunological evaluation studies. Douat-Casassus Céline,Marchand-Geneste Nathalie,Diez Elisabeth,Aznar Céline,Picard Philippe,Geoffre Serge,Huet Aline,Bourguet-Kondracki Marie-Lise,Gervois Nadine,Jotereau Francine,Quideau Stéphane Molecular bioSystems A LigandFit shape-directed docking methodology was used to identify the best position at which the melanoma-derived MHC class-I HLA-A2-binding antigenic peptide ELAGIGILTV could be modified by attaching a small molecule capable of fitting at the interface of complementary determining regional (CDR) loops of a T-cell receptor (TCR) while triggering T-cell responses. The small molecule selected here for determining the feasibility of this alternative track to chemical alteration of antigenic peptides was the electrophilic quinone methide (+)-puupehenone (), a natural product that belongs to a family of marine metabolites capable of expressing immunomodulatory activities. A preliminary chemical reactivity model study revealed the efficacy of the thiol group of a cysteine (C) side-chain in its nucleophilic addition reaction with in a regio- and diastereoselective manner. The best TCR/HLA-A2 ligand [i.e., ELAGCGILTV-S-puupehenol ()] then identified by the LigandFit docking procedure was synthesized and used to pulse HLA-A2(+) T2 cells for T-cell stimulation. Among the ELAGIGILTV-specific T-cell clones we tested, five of them recognized the conjugate in spite of its low binding affinity for the HLA-A2 molecules. The resulting T-cell stimulation was determined through the intracytoplasmic secretion of IFN-gamma and the percentage of T-cells thus activated. These highly encouraging results indicate that small non-peptidic natural product-derived molecules attached onto the central part of an antigenic peptide can fit at the TCR/HLA-A2 interface with induction of T-cell responses. 10.1039/b518044a
    A new and efficient method for o-quinone methide intermediate generation: application to the biomimetic synthesis of the benzopyran derived natural products (+/-)-lucidene and (+/-)-alboatrin. Rodriguez Raphaël,Moses John E,Adlington Robert M,Baldwin Jack E Organic & biomolecular chemistry Lucidene and alboatrin are complex benzopyran derived natural products. A key step in their biogenesis may involve a hetero Diels-Alder cycloaddition between an o-quinone methide intermediate with a simple, or activated tri-substituted olefin. Experimental evidence is provided to support this hypothesis, with the biomimetic synthesis of both (+/-)-lucidene and (+/-)-alboatrin successfully achieved using a new and efficient method for o-quinone methide generation. 10.1039/b508972g
    Utilizing -Quinone Methide Chemistry: Synthesis of -Ivacaftor. Looker Adam R,Wilde Nathan,Ryan Michael P,Roeper Stefanie,Ye Zhifeng,Lewandowski Bérénice L The Journal of organic chemistry Lead time and cost are important factors for any pharmaceutical API. However, these issues become even more important when the drug substance contains an isotope such as deuterium, which has a natural abundance of only ∼0.016% of all hydrogen. Fewer suppliers and logistical barriers both play a role in driving up the cost. These factors can challenge the supply route used to manufacture -ivacaftor (), requiring investigation into alternative routes. By adapting the work from Pettus et al., a synthetic approach utilizing a transient -quinone methide allowed access to the deuterium-labeled --butylphenol moiety. This was developed and proven on pilot scale to significantly reduce the number of deuterated reagents used, leading to an overall reduction in cost by a factor of 10, while also providing the substantial benefit of applying prior process knowledge from the parent, nonisotopically enriched API ivacaftor (). 10.1021/acs.joc.9b02552
    Genetically Encoding Photocaged Quinone Methide to Multitarget Protein Residues Covalently in Vivo. Liu Jun,Li Shanshan,Aslam Nayyar A,Zheng Feng,Yang Bing,Cheng Rujin,Wang Nanxi,Rozovsky Sharon,Wang Peng G,Wang Qian,Wang Lei Journal of the American Chemical Society Genetically introducing covalent bonds into proteins in vivo with residue specificity is affording innovative ways for protein research and engineering, yet latent bioreactive unnatural amino acids (Uaas) genetically encoded to date react with one to few natural residues only, limiting the variety of proteins and the scope of applications amenable to this technology. Here we report the genetic encoding of (2 R)-2-amino-3-fluoro-3-(4-((2-nitrobenzyl)oxy) phenyl) propanoic acid (FnbY) in Escherichia coli and mammalian cells. Upon photoactivation, FnbY generated a reactive quinone methide (QM), which selectively reacted with nine natural amino acid residues placed in proximity in proteins directly in live cells. In addition to Cys, Lys, His, and Tyr, photoactivated FnbY also reacted with Trp, Met, Arg, Asn, and Gln, which are inaccessible with existing latent bioreactive Uaas. FnbY thus dramatically expanded the number of residues for covalent targeting in vivo. QM has longer half-life than the intermediates of conventional photo-cross-linking Uaas, and FnbY exhibited cross-linking efficiency higher than p-azido-phenylalanine. The photoactivatable and multitargeting reactivity of FnbY with selectivity toward nucleophilic residues will be valuable for addressing diverse proteins and broadening the scope of applications through exploiting covalent bonding in vivo for chemical biology, biotherapeutics, and protein engineering. 10.1021/jacs.9b01738
    Total Synthesis of Peniphenones A-D via Biomimetic Reactions of a Common o-Quinone Methide Intermediate. Spence Justin T J,George Jonathan H Organic letters The total synthesis of peniphenones A-D has been achieved via Michael reactions between appropriate nucleophiles and a common o-quinone methide intermediate. This strategy, which was based on a biosynthetic hypothesis, minimized the use of protecting groups and thus facilitated concise syntheses of the natural products. The most complex target, the benzannulated spiroketal peniphenone A, was synthesized enantioselectively in nine linear steps from commercially available starting materials. 10.1021/acs.orglett.5b02902
    Oleanane-, ursane-, and quinone methide friedelane-type triterpenoid derivatives: Recent advances in cancer treatment. Salvador Jorge A R,Leal Ana S,Valdeira Ana S,Gonçalves Bruno M F,Alho Daniela P S,Figueiredo Sandra A C,Silvestre Samuel M,Mendes Vanessa I S European journal of medicinal chemistry Natural pentacyclic triterpenoids (PTs) have been often reported to exhibit a wide range of biological activities. Among them, the anticancer and anti-inflammatory activities are the most studied. Over the last two decades, the number of publications reporting the anticancer effects of PTs has risen exponentially, reflecting the increasing interest in these natural products for the development of new antineoplastic drugs. Among of the most investigated PTs regarding their anticancer properties are oleanane-, ursane and friedelane-types, including oleanolic, glycyrrhetinic, ursolic and asiatic acids, and celastrol, among others. The extensive research in this field shows that the anticancer effects of PTs are mediated by several mechanisms, as they modulate a diverse range of molecular targets and signaling pathways, involved in cancer cell proliferation and survival. Considering the anticancer potential of this class of compounds, a number of semisynthetic derivatives has been synthetized aiming to improve their therapeutic activity and pharmacokinetic properties, and decrease their toxicity. Some of these new semisynthetic derivatives have shown improved anticancer activity in various cancer cell lines and animal models compared with the parent compound. Moreover, some of these compounds have been assessed in clinical trials, proving to be safe for human use. This review updates the most recent findings on the semisynthetic derivatives of oleanane-, ursane- and quinone methide friedelane-type PTs with anticancer activity. A brief introduction concerning the PTs and their anticancer activity is given, and the main semisynthetic modifications that have been performed between 2012 and early 2017 are reviewed and discussed. 10.1016/j.ejmech.2017.07.013
    Pterocarpan synthase (PTS) structures suggest a common quinone methide-stabilizing function in dirigent proteins and proteins with dirigent-like domains. Meng Qingyan,Moinuddin Syed G A,Kim Sung-Jin,Bedgar Diana L,Costa Michael A,Thomas Dennis G,Young Robert P,Smith Clyde A,Cort John R,Davin Laurence B,Lewis Norman G The Journal of biological chemistry The biochemical activities of dirigent proteins (DPs) give rise to distinct complex classes of plant phenolics. DPs apparently began to emerge during the aquatic-to-land transition, with phylogenetic analyses revealing the presence of numerous DP subfamilies in the plant kingdom. The vast majority (>95%) of DPs in these large multigene families still await discovery of their biochemical functions. Here, we elucidated the 3D structures of two pterocarpan-forming proteins with dirigent-like domains. Both proteins stereospecifically convert distinct diastereomeric chiral isoflavonoid precursors to the chiral pterocarpans, (-)- and (+)-medicarpin, respectively. Their 3D structures enabled comparisons with stereoselective lignan- and aromatic terpenoid-forming DP orthologs. Each protein provides entry into diverse plant natural products classes, and our experiments suggest a common biochemical mechanism in binding and stabilizing distinct plant phenol-derived mono- and bis-quinone methide intermediates during different C-C and C-O bond-forming processes. These observations provide key insights into both their appearance and functional diversification of DPs during land plant evolution/adaptation. The proposed biochemical mechanisms based on our findings provide important clues to how additional physiological roles for DPs and proteins harboring dirigent-like domains can now be rationally and systematically identified. 10.1074/jbc.RA120.012444
    Quinone Methide Bioactivation Pathway: Contribution to Toxicity and/or Cytoprotection? Bolton Judy L Current organic chemistry The formation of quinone methides (QMs) from either direct 2-electron oxidation of 2- or 4-alkylphenols, isomerization of -quinones, or elimination of a good leaving group could explain the cytotoxic/cytoprotective effects of several drugs, natural products, as well as endogenous compounds. For example, the antiretroviral drug nevirapine and the antidiabetic agent troglitazone both induce idiosyncratic hepatotoxicity through mechanisms involving quinone methide formation. The anesthetic phencyclidine induces psychological side effects potentially through quinone methide mediated covalent modification of crucial macromolecules in the brain. Selective estrogen receptor modulators (SERMs) such as tamoxifen, toremifene, and raloxifene are metabolized to quinone methides which could potentially contribute to endometrial carcinogenic properties and/or induce detoxification enzymes and enhance the chemopreventive effects of these SERMs. Endogenous estrogens and/or estrogens present in estrogen replacement formulations are also metabolized to catechols and further oxidized to -quinones which can isomerize to quinone methides. Both estrogen quinoids could cause DNA damage which could enhance hormone dependent cancer risk. Natural products such as the food and flavor agent eugenol can be directly oxidized to a quinone methide which may explain the toxic effects of this natural compound. Oral toxicities associated with chewing areca quid could be the result of exposure to hydroxychavicol through initial oxidation to an -quinone which isomerizes to a -quinone methide. Similar -quinone to -quinone methide isomerization reactions have been reported for the ubiquitous flavonoid quercetin which needs to be taken into consideration when evaluating risk-benefit assessments of these natural products. The resulting reaction of these quinone methides with proteins, DNA, and/or resulting modulation of gene expression may explain the toxic and/or beneficial effects of the parent compounds. 10.2174/138527281801140121123046
    Increasing Structural Diversity of Natural Products by Michael Addition with -Quinone Methide as the Acceptor. Liao Ge,Fan Jie,Ludwig-Radtke Lena,Backhaus Katja,Li Shu-Ming The Journal of organic chemistry The active form of clavatol, -quinone methide, can be generated from hydroxyclavatol in an aqueous system and used as a highly reactive intermediate for coupling with diverse natural products under very mild conditions. These include flavonoids, hydroxynaphthalenes, coumarins, xanthones, anthraquinones, phloroglucinols, phenolic acids, indole derivatives, tyrosine analogues, and quinolines. The clavatol moiety was mainly attached via C-C bonds to the - or -positions of phenolic hydroxyl/amino groups and the C2-position of the indole ring. 10.1021/acs.joc.9b02971