Evaluation of a panel of furochromenones as the activator and inhibitor of tyrosinase.

Tyrosinase is a copper-containing enzyme involved in the biosynthesis of melanin pigment. While the excess production of melanin causes hyperpigmentation of human skin, hypopigmentation results in medical conditions like vitiligo. Tyrosinase inhibitors could be used as efficient skin whitening agents and tyrosinase agonists could be used for enhanced melanin synthesis and skin protection from UV exposure. Among a wide range of tyrosinase-regulating compounds, natural and synthetic derivatives of furochromenones, such as 8-methoxypsoralen (8-MOP), are known to both activate and inhibit tyrosinase. We recently reported a synthetic approach to generate a variety of dihydrofuro[3,2-c]chromenones and furo[3,2-c]chromenones in a metal-free condition. In the present study, we investigated these compounds for their potential as antagonists or agonists of tyrosinase. Using fungal tyrosinase-based in vitro biochemical assay, we obtained one compound (3k) which could inhibit tyrosinase activity, and the other compound (4f) that stimulated tyrosinase activity. The kinetic studies revealed that compound 3k caused 'mixed' type tyrosinase inhibition and 4f stimulated the catalytic efficiency. Studying the mechanisms of these compounds may provide a basis for the development of new effective tyrosinase inhibitors or activators.

Biomimetic total syntheses of renifolin F and antiarone K.

The first biomimetic and concise racemic total syntheses of renifolin F and antiarone K, accomplished in 8 and 7 linear steps, respectively, are presented in this article. Our synthetic approach commences with substituted aldehydes to produce prenylated aldol products followed by ene-type intramolecular cyclization affording a five-member core ring. This key step mediated by InCl3·4H2O is a novel procedure first utilized in prenylated systems which directly culminates mainly into tertiary alcohols.

Intramolecular CH-Hydrogen Bonding During the Dissociation of the Oxaphosphetane Intermediate Facilitates Z/E-Selectivity in Wittig Olefination.

Herein, DFT studies corroborating experimental results revealed that the shortest intramolecular hydrogen bonding distance of cis/trans-oxaphosphetane (OPA) oxygen with the CH-hydrogen of a triphenylphosphine phenyl ring provides good evidence for the attained olefin Z/E-selectivity in Wittig olefination of the studied examples. 2-Nitrobenzaldehyde, 3-nitrobenzaldehyde, 2-nitro-3-bromobenzaldehyde, 2-nitro-5-bromobenzaldehyde and 2-nitro-5-arylbenzaldehydes provided Z-nitrostilbenes with (2-chloro-4-hydroxy-3-methoxy-5-(methoxycarbonyl)benzyl) triphenylphosphonium chloride as the major products. However, 4-nitrobenzaldehyde and 2-nitro-6-bromobenzaldehydes furnished E-nitrostilbenes as the major products in high yields. Furthermore, the DFT computed intramolecular CH1/CH2-hydrogen bond distances with Cl/NO2 of selected stilbene derivatives were in good agreement with intramolecular hydrogen bond distances measured from single-crystal X-ray diffraction measurements.

Solvent controlled synthesis of 2,3-diarylepoxy indenones and α-hydroxy diarylindanones and their evaluation as inhibitors of DNA alkylation repair.

Herein, we report a novel and unexpected metal-free oxygenation of 2,3-diphenyl-1-indenones, under an oxygen atmosphere (air), to either 2,3-epoxy-2,3-diphenyl-1-indenone or 2-hydroxy-2,3-diphenyl-1-indanone, depending on the conditions. Several bioactive epoxy indenones and one-pot α-hydroxy indanones (α-acyloin) were synthesized from 2,3-diaryl dihydroindanone and 2,3-diarylindenone, respectively. A plausible reaction mechanism is also proposed, where oxygenation would take place at the α-position and further proton abstraction from the ß-position leads to epoxy indenone derivatives. A one-pot cis-hydroxy indanone protocol is also achieved directly from biaryl indenone via reduction, epimerization, and oxygenation. The synthesized compounds were evaluated for inhibitory activity against the DNA repair protein AlkB. Among the screened (17 tested) compounds, one epoxide derivative was found to be a specific inhibitor of AlkB enzyme function.

Alkyl Enol Ethers: Development in Intermolecular Organic Transformation.

Alkyl enol ethers (AEE) are versatile synthetic intermediates with a unique reactivity pattern. This review article summarizes the synthesis of AEE as well as its reactivity and how enol ether undergoes intermolecular reactions for various bond formation, leading to the construction of several useful organic molecules. The synthetic applications of alkyl enol ethers towards intermolecular bond-forming reactions include metal-catalyzed reactions, cycloaddition and heterocycle formation as well as rwactions in the field of natural products synthesis. The achievement of these impressive transformations prove the countless synthetic potential of AEE. The main objective of this review is to bring attentiveness among synthetic chemists to show how AEE extensively can be used to react with both electrophiles as well as nucleophiles, thereby behaving as an ambiphilic reactant. We trust that the unique reactivity pattern of alkyl enol ethers and the fundamental mechanistic idea can attract chemists in AEE chemistry. Exclusively, intermolecular reactions of AEE with other functionalized moieties have not been reviewed to the best of our knowledge.

Synthesis and antibacterial activities of marine natural product ianthelliformisamines and subereamine synthetic analogues.

Marine sponges of the genusSuberea produce variety of brominated tyrosine alkaloids which display diverse range of biological activities including antiproliferative, antimicrobial and antimalarial activities. In continuation of our search for biologically active marine natural products for antibacterial compounds, we report here the synthesis and evaluation of biological activity of panel of ianthelliformisamines and subereamine analogues using the literature known acid-amine coupling reaction. Several derivatives of Ianthelliformisamine were achieved by the coupling of Boc-protected polyamine chain with brominated aromatic acrylic acid derivatives by varying the bromine substituents on aromatic acid derivatives, amine spacer as well as geometry of the double bond, and then Boc-deprotection using TFA. Similarly, subereamine analogues were also synthesized employing coupling reaction between various brominated phenyl acrylic acids with commercially available chiral amino ester derivatives followed by ester hydrolysis. We screened these synthetic analogues for antibacterial activity against both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) strains. One of the compound 7c showed bactericidal activity against Staphylococcus aureus with an IC50 value of 3.8 µM (MIC = 25 µM).

Symmetrical and un-symmetrical curcumin analogues as selective COX-1 and COX-2 inhibitor.

Curcumin, a popular herbal medicine derived from turmeric, blocks the synthesis of prostaglandins by inhibiting Cyclooxygenase-1 and 2 (COX-1 and COX2). We have recently reported an efficient method of synthesizing curcumin and synthesised analogues. In the present study, we have investigated sixteen novel analogues of curcumin for their ability to inhibit COX-1 and COX-2. We report here that most of the curcumin analogues display selective inhibition of COX-2, whereas a few suppress COX-1 activity. Further, we examined the binding of these inhibitors by molecular docking and observed that the compound with pronounced selectivity for COX-2 displayed better binding to COX-2 compared to curcumin.

Forgotten double-J stent: Experience of a tertiary care center.

INTRODUCTION: We share our experience of managing 15 cases of forgotten double-J (DJ) stent in our tertiary care center. METHODS: This is a retrospective analysis of cases with forgotten DJ stent for a period of 2 years spanning from January 2017 to January 2019. The details included sex, age, literacy, socioeconomic status, stenting indication, duration of indwelling stent, presenting complaints, type of encrustations, various treatments given, intraoperative complications, and their management and eventual outcome. RESULTS: The male-to-female ratio was 2:1, and the mean age was 39.5 years (17-65). The mean indwelling time was 31.7 months. The majority of patients had an education score of 1 out of 7 and belonged to lower socioeconomic class according to the modified Kuppuswamy scale. The most common presentation was irritative voiding symptom. The complicated and heavily encrusted stents were managed by combination of endourological procedures, and procedures were staged whenever deemed necessary. Majority of the stents were removed with simple retrograde cystoscopic removal. There was no mortality in our study. CONCLUSIONS: A forgotten DJ stent affects population having low education score and belonging to the lower end of the socioeconomic class. Endourological procedures are quite successful in managing a forgotten DJ stent, provided the treatment options are selected judiciously and meticulously. We also suggest some protocols to be followed in our study in order to prevent a forgotten DJ stent.

Direct α-Benzylation of Methyl Enol Ethers with Activated Benzyl Alcohols: Its Rearrangement and Access to (±)-Tetrahydronyasol, Propterol A, and 1,3-Diarylpropane.

Herein, we report a one-pot Lewis acid mediated synthesis of bi- and triarylpropanal derivatives and their corresponding isomeric ketones from aromatic enol ethers. This transformation takes place via nucleophilic attack of enol ethers to electron-rich benzyl alcohols. The substrate scope of this indicates that it might proceed via quinomethoxy methide as a key intermediate leading to propanal derivatives, and their Wagner-Meerwein rearrangement afforded isomeric ketones. Further, this methodology was applied for the synthesis of (±)-tetrahydronyasol, propterol A, and 1,3-diarylpropane.

Indenone derivatives as inhibitor of human DNA dealkylation repair enzyme AlkBH3.

The mammalian AlkB homologue-3 (AlkBH3) is a member of the dioxygenase family of enzymes that in humans is involved in DNA dealkylation repair. Because of its role in promoting tumor cell proliferation and metastasis of cancer, extensive efforts are being directed in developing selective inhibitors for AlkBH3. Here we report synthesis, screening and evaluation of panel of arylated indenone derivatives as new class of inhibitors of AlkBH3 DNA repair activity. An efficient synthesis of 2,3-diaryl indenones from 2,3-dibromo indenones was achieved via Suzuki-Miyaura cross-coupling. Using a robust quantitative assay, we have obtained an AlkBH3 inhibitor that display specific binding and competitive mode of inhibition against DNA substrate. Finally, we established that this compound could prevent the proliferation of lung cancer cell line and enhance sensitivity to DNA damaging alkylating agent.

Effect of bridgehead substitution in the Grob fragmentation of norbornyl ketones: a new route to substituted halophenols.

Grob fragmentation of suitably designed bicyclic species often generates novel organic skeletons in a facile manner. Herein, we report a comprehensive account of an effective acid-catalyzed Grob fragmentation of trihalonorbornyl ketones to dihalophenol derivatives in good yields. The transformation entails tri-n-butyltin hydride (TBTH) mediated regioselective reduction of one of the two bridgehead halogens of readily available Diels-Alder adducts resulting from 1,2,3,4-tetrahalo-5,5-dimethoxycyclopentadiene and vinyl acetate derivatives, followed by its conversion to substituted halophenol species via a three-step hydrolysis-oxidation-rearrangement/aromatization strategy. Both alkyl and aryl substituted norbornyl ketones were studied. A detailed mechanistic analysis employing an isotope labeling experiment revealed plausible mechanistic pathways. Among the two bridgehead substituents, when halogen (X = Cl, Br) stays at C-1 and hydrogen (H, or deuterium, D) at C-4, then product formation takes place via exclusive protonation (supplied by an external acid) at ß carbon (i.e. C-1) of a dienol moiety formed in situ during the Grob-fragmentation, followed by the removal of acidic 4-H (or 4-D) and halide ion (X(-)) from the resulting cyclohexenone intermediate prior to nucleophilic attack on the oxocarbenium ion by X(-) and final enolisation of cyclohexadienone species. A sharp deviation was observed with the regioisomeric bicyclic ketone, wherein the 4-X triggers a facile removal of X(-) and forms the end products without necessitating the involvement of the C-1 substituent (i.e. 1-H/D), thereby retaining it in the final halophenols. It clearly demonstrates how the bridgehead substituents in the two regioisomeric trihalo-norbornyl ketones steer the bicyclic systems to follow entirely different reaction pathways thus suggesting their crucial yet distinct roles in the overall reaction. The present transformation thus manifests the relevance of bridgehead substituents in the Grob fragmentation of such norbornyl systems. Our current strategy also allows one to access ortho-deuterated halophenol compounds.

Bridgehead Substitution via Putative Norborn-1-en-3-ones: Application in the Synthesis of Complex Molecules.

The base-mediated formation of a bridgehead double bond in a bicyclo[2.2.1]heptane system (anit-Bredt molecules) is described. The synthesis of exocyclic norbornyl enones by Wittig reaction of α-diketones is reported. These enones and their Michael adducts are used as substrates for the generation of transient bridgehead enones and their trapping with MeOH and H2 O. Bridgehead alcohols are easily synthesized from norbornyl enones and are exploited for the diversity oriented synthesis of frameworks of natural and unnatural products.

BF3-Et2O mediated skeletal rearrangements of norbornyl appended cyclopentanediols.

An unusual cascade rearrangement has been noticed as a competitive reaction during the treatment of norbornyl appended cyclopentanediols with a Lewis acid (LA): a BF3-Et2O mediated pinacol-pinacolone rearrangement. Deketalization and pinacolone rearrangement occur at two different sites in the molecule and are responsible for the observed cascade rearrangement product. However, deketalization appears to be triggering the cascade steps. The kinetically more stable pinacolone product with an exo-Me group was observed in the case of the bromo analogue, whereas, the thermodynamically more stable pinacolone product with an endo-Me group was observed in the case of the chloro analogue. Epimerization via tautomerization of one diastereomer to the other diastereomer under Lewis acid reflux conditions is possible. On the contrary, the diol equivalent epoxides provide only the diastereomeric mixture of pinacolone products under similar LA reaction conditions. The lower yields observed in the case of the epoxides are due to unwanted side reactions taking place between the two competitive reactive centers, namely, ketal and epoxide. Further, a sequence of elimination, nucleophilic substitution and Ritter type hydrolysis reactions of the epoxides resulted in unexpected elimination products. This transformation not only facilitates a regioselective epoxide opening, but also provides a new route for the preparation of allylic amides of the norbornyl appended cyclopentane ring system.

A domino reaction of tetrahalo-7,7-dimethoxybicyclo[2.2.1]heptenyl alcohols leading to indenones and a de novo synthesis of ninhydrin derivatives.

An efficient acid induced rearrangement of a tetrahalo-7,7-dimethoxybicyclo[2.2.1]heptenyl system leading to substituted indenones is reported. This domino reaction involves dehydration, olefin isomerization, ketal hydrolysis, [3,3]-sigmatropic rearrangement and dehydrohalogenation. The resultant vicinal dihalo olefin moiety in the efficiently generated indenone derivatives was utilized to transform into ninhydrin derivatives by employing Ru(III)-catalyzed oxidation.

Superoxide chemistry revisited: synthesis of tetrachloro-substituted methylenenortricyclenes.

An unexpected reactivity of the superoxide ion leading to the synthesis of tetrachloroaryl/vinyl-substituted nortricyclenes through its dual mode of action has been reported. KO2 was found to be superior and the only reagent to perform this kind of reaction over other conventional bases. Addition of the antioxidant BHT (2,6-di-tert-butyl-4-methylphenol) improved the yields of methylenenortricyclenes. A complete deuterium incorporation was observed in the superoxide-mediated reaction in DMSO-d 6. Friedel-Crafts acylation reactions of 3-methylenenorticyclenes yielded 2-propanone-substituted pentachloronorbornenes.

Syntheses of a library of molecules on the marine natural product ianthelliformisamines platform and their biological evaluation.

Ianthelliformisamines A-C are a novel class of bromotyrosine-derived antibacterial agents isolated recently from the marine sponge Suberea ianthelliformis. We have synthesized ianthelliformisamines A-C straightforwardly by the condensation of (E)-3-(3,5-dibromo-4-methoxyphenyl)acrylic acid and the corresponding Boc-protected polyamine followed by Boc-deprotection with TFA. Further, using this reaction protocol, a library of their analogues (39 analogues) has been synthesized by employing 3-phenylacrylic acid derivatives and Boc-protected polyamine chains through various combinations of these two fragments differing in phenyl ring substitution, double bond geometry or chain length of the central spacer of the polyamine chain (shown in red color). All the synthesized compounds (ianthelliformisamines A-C and their analogues) were screened for antibacterial activity against both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) strains. All synthetic analogues of ianthelliformisamine A showed bacterial growth inhibition against both strains (Escherichia coli and Staphylococcus aureus), having MIC values in the range of 117.8-0.10 µM, while none of the synthetic analogues of ianthelliformisamine C as well as the parent compound showed any detectable antibacterial activity. Interestingly, some of the synthetic analogues of ianthelliformisamines A and B exerted a bactericidal effect against both E. coli and S. aureus strains, decreasing viable bacterial count by 99% at concentrations as low as 2 × MIC.

An unusual fragmentation of oxetane-embedded tetracyclic ketal systems.

An unusual route for the synthesis of functionalized cyclobutane derivatives starting from functionalized norbornane derivatives is reported. Base-induced fragmentation of an oxetanol-type moiety embedded in a tetracyclic norbornyl ketal leads to a cyclobutane-fused derivative as the major or exclusive product. The fragmentation reaction for bridgehead-bromine-substituted derivatives was much faster than for the corresponding chlorine-substituted substrates. The functionalized cyclobutane product was formed exclusively in high yield in the former case, while the latter furnished a minor uncyclized side product in varying yields.

Synthesis of reported and revised structures of amathamide D and synthesis of convolutamine F, H and lutamide A, C.

Total synthesis of the published structure of amathamide D is described. Methyl 2,3,4-tribromo-5-hydroxybenzoate was selected as starting compound because it is readily accessible via acid-mediated Grob fragmentation-aromatization reaction of 1,4,5,6-tetrabromo-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-one. The aforementioned ester was transformed into the reported structure of amathamide D through methylation of a hydroxyl group and conversion of the ester moiety to a ß-aminoethyl side chain. The NMR data of the synthetic compound did not conform to the reported natural product structure possessing contiguously positioned ß-aminoethyl side chain, a set of three adjacent bromines, and a methyl ether linkage on the phenyl ring. This prompted us to redefine the natural product structure by synthesizing a product whose spectral data exactly matched with the reported data of amathamide D. The convolutamine H, with completely substituted phenyl ring adorned with an extra methyl ether functional group, has also been synthesized by application of Grob fragmentation-aromatization strategy to 3-(benzyloxy)-1,4,5,6-tetrabromo-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-one. This approach furnished directly methyl 2,3,4-tribromo-5,6-dimethoxybenzoate, which was converted straightforwardly into convolutamine H. Further, synthesis of convolutamine F and lutamide A and C is also described.

Grob fragmentation of norbornyl α-diketones: a route to α-ketoenols and aromatic compounds.

An efficient acid-catalyzed Grob fragmentation of symmetrical and asymmetrically substituted norbornyl α-diketones to the corresponding six-membered α-ketoenols is reported. The regio- and stereochemical outcome of the Grob fragmentation of C2 mono- and disubstituted α-diketones was investigated. A single regioisomer resulting from a favorable half-chair intermediate was normally observed. A departure from the normal course was noticed for C2 disubstituted α-diketones possessing an exo-methyl and an endo-methoxycarbonyl derivative, giving the opposite regioisomers due to initial formation of the hemiketal. The bromo analogues of the C2 disubstituted α-diketones furnished an unusual byproduct, which appears to have been formed through highly reactive fused four-membered bicyclo[2.2.0]hexane intermediates. A plausible mechanistic proposal involving the gem-dihalo intermediate, which in one case was actually isolated as its BF(2)-complex, is outlined. The fragmentation protocol was applied to various norbornyl substrates including bis-α-diketone derivatives. The methodology was successfully utilized for the synthesis of substituted aromatic compounds.

Synthesis of oxa-bridged derivatives from Diels-Alder bis-adducts of butadiene and 1,2,3,4-tetrahalo-5,5-dimethoxycyclopentadiene.

Bis-adducts of 1,2,3,4-tetrahalo-5,5-dimethoxycyclopentadiene and 1,3-butadiene, generated in situ from 3-sulfolene, have been synthesized in excellent yield. Ruthenium catalyzed oxidation of the bis-adducts followed by a one-pot transformation of the resulting alpha-diketone furnished oxa-bridged compounds. Unambiguous stereochemical assignments of both diastereomeric series are reported.