Stereocontrolled synthesis of (S)-9-cis-4-oxo-13,14-dihydroretinoic acid

(S)-9-cis-4-Oxo-13,14-dihydroretinoic acid (S)-1, a new major endogenous vitamin A metabolite that activates retinoic acid receptor signaling both in vitro and in vivo, has been synthesized stereoselectively by Horner–Wadsworth–Emmons condensation and Stille cross-coupling as bond forming reactions.     

Enantio-selective reduction of the flowering related compound KODA and its analogues in Pharbitis nil cv. Violet

Plant oxylipins are an important class of signaling molecules in plants. The cyclic adducts of epinephrine or norepinephrine with the naturally occurring oxylipin (12Z,15Z)-9-hydroxy-10-oxo-octadeca-12,15-dienoic acid (KODA, 1) or its synthetic analogues (2–6) have been reported to possess flower-inducing activity toward Lemna paucicostata. By in vivo and in vitro experiments with seedlings of Pharbitis nil cv. Violet carbonyl groups of the α-ketols (1 and 3) and the ketones (7 and 9) were enantio-selectively reduced to give their corresponding vicinal diols (2 and 4) and alcohols (8 and 10). The stereo-chemistry at the oxymethine carbon was determined based on the long range C–H coupling constants and the modified Mosher's method. Orientation of the adjacent hydroxyl group in (1 and 3) did not affect the enantio-selectivity, whereas the conversion was slightly affected and higher yields were obtained with the R-enantiomers of the α-ketols.     

Straightforward protocol for the efficient synthesis of varied N-acylated (aza)indole 2-/3-alkanoic acids and esters: optimization and scale-up

A library of approximately 40 N¹-acylated (aza)indole alkanoic esters and acids was prepared employing a microwave-assisted approach. The optimized synthetic route allows for parallel synthesis, variation of the indole substitution pattern, and high overall yield. Additionally, the procedure has been scaled up to yield multi-gram amounts of preferred indole compounds, e.g.: 2′-des-methyl indomethacin 2. The reported compounds were designed as biomedical tools for primary and secondary in vitro and in vivo studies at relevant molecular targets.     

Dysotriflorins A–M,triterpenoids from Dysoxylum densiflorum

Thirteen new triterpenoids, dysotriflorins A–M (1–13), were isolated from Dysoxylum densiflorum barks, and their structures were elucidated on the basis of NMR spectroscopic data and X-ray crystallography. Dysotriflorins A, B, and K–M (1, 2, and 11–13) were concluded to be unique 13,17-secodammarane triterpenoids, and dysotriflorins C–J (3–10) to be dammarane triterpenoids. Dysotriflorins showed in vitro cytotoxic activity against several cancer cell lines.     

Concise synthesis and structure-activity relationship of furospinosulin-1, a hypoxia-selective growth inhibitor from marine sponge

Structure-activity relationship of furospinosulin-1 (1), a hypoxia-selective growth inhibitor isolated from marine sponge, was investigated. Concise synthetic method of 1 was developed, and some structurally modified analogues were prepared. Biological evaluation of them revealed that the whole chemical structure was important for the hypoxia-selective growth inhibitory activity of 1. Among prepared, the desmethyl analogue 30 showed excellent hypoxia-selective inhibitory activity similar to that of 1 and also exhibited in vivo anti-tumor activity with oral administration.     

Total synthesis and structure–activity relationships of caspofungin-like macrocyclic antifungal lipopeptides

The echinocandins represent a well-known class of macrocyclic antifungal lipopeptides that can be used for treatment of invasive fungal infections. Due to their complex chemical structures and synthetic difficulties, the structure–activity relationships (SARs) of them are still limited. A total synthetic approach was developed to synthesize structurally diverse caspofungin-like antifungal cyclic lipopeptides, allowing for systemically investigating their SARs. Most of the designed cyclic lipopeptides showed potent antifungal activities with broad spectrum. In particular, several compounds (e.g., 30a, 30e–h, 31a–d, 32c, and 33a,b) were more active in vitro against Candida albicans or Aspergillus fumigatus than caspofungin. The findings in this work indicated that the ‘left’ tripeptide segment of cyclic lipopeptide scaffold might be suitable for a hydrophilic structural motif, whereas the ‘right’ lipotripeptide segment was preferred as a hydrophobic core. The alkoxy-naphthoyl was found to be optimal side chain and alkyl length could affect the SARs of alkoxy-aroyl side chains.     

Polycyclic hydroxyquinones—VIII: Preparation of acetylhydroxynaphthazarins by photo-fries rearrangement. A convenient synthesis of spinochrome A

Several synthetic routes to mono- and dihydroxynaphthazarins bearing an acetyl side-chain have been explored. Methoxynaphthazarin1 has always been the starting material. Acylation is brought aboutvia a photo-Fries rearrangement of various adequately substituted acetoxynaphthalenes prepared in several steps from1. Further steps including oxidative demethylation, hydrolysis and ether cleavage reactions, led to the desired mono- and dihydroxysubstituted acetylnaphthazarins. A new synthesis of Spinochrome A24, a natural occurring pigment representative of this kind of naphthazarin derivatives, is described.     

Microbial transformations of buagarofuran,an anti-anxietic agent

19 structurally diverse metabolites (2–20) were isolated from the transformation of buagarofuran (1), an anxiety agent, by three filamentous fungal strains, Cunninghamella echinulata AS 3.3402, Cunninghamella elegans AS 3.3400, and Absidia coerulea AS 3.3538. Their structures and identified on the basis of extensive spectroscopic data (HRMS, NMR, IR, and CD) and chemical methods. All of the metabolites were oxidized products of 1, and metabolite 20 was also one of mammalian metabolites. Metabolites 8, 10–12, and 20 significantly inhibited [³H]-NE re-uptake, and 8 and 9 strongly inhibited [³H]-5-HT re-uptake in the rat brain synaptosomes at 10 μM in vitro. The structural diversity of the microbial transformed metabolites of buagarofuran in the present report would give a favorable opportunity to probe its mammalian metabolism and better shed light on its pharmacokinetics and pharmacodynamics in vivo.     

Synthesis of 12-aza analogs of epothilones and (E)-9,10-dehydroepothilones

N-Boc-12-aza-epothilone analog (azathilone) 1 is a potent inhibitor of human cancer cell growth and represents a structurally new class of natural product-derived microtubule-stabilizing agents. Compound 1 has been prepared employing a convergent strategy that is based on the consecutive assembly of building blocks 3, 4, and 19 into diene 20 and subsequent RCM-mediated macrocycle formation. The aldol reaction between aldehyde 3 and ketone 4 delivered the required 6R,7S diastereoisomer 5 with good selectivity and provided a reliable entry into the stereoselective synthesis of carboxylic acid 12. RCM with diene 20 was highly E-selective, thus giving efficient access to (E)-9,10-dehydro-1 (2). The latter is a key analog in SAR studies with 1.     

Stereoselective synthesis of sugar-based β-lactam derivatives: docking studies and its biological evaluation

Highly diastereoselective synthesis of cis-β-lactams via [2+2] cycloaddition reactions of sugar-imine derivative possessing free hydroxyl groups at C-2 and C-3 positions and ketenes is described. exo-Approach of sugar-imine with ketene leads to the stereoselective formation of cis product and it is facilitated by hydrogen bonding interaction of C2–OH with carbonyl group of ketene. Docking studies show that these derivatives are having greater affinity towards PBP and it has been validated by in vivo studies. Among the different sugar-based azetidine-2-ones, compounds 6a and 6d were superior in activity to the commercial antibiotic tetracycline.     

CmlI is an N-oxygenase in the biosynthesis of chloramphenicol

The N-oxygenation of an amine group is one of the steps in the biosynthesis of the antibiotic chloramphenicol. The non-heme di-iron enzyme CmlI was identified as the enzyme catalyzing this reaction through bioinformatics studies and reconstitution of enzymatic activity. In vitro reconstitution was achieved using phenazine methosulfate and NADH as electron mediators, while in vivo activity was demonstrated in Escherichia coli using two substrates. Kinetic analysis showed a biphasic behavior of the enzyme. Oxidized hydroxylamine and nitroso compounds in the reaction were detected both in vitro and in vivo based on LC–MS. The active site metal was confirmed to be iron based on a ferrozine assay. These findings provide new insights into the biosynthesis of chloramphenicol and could lead to further development of CmlI as a useful biocatalyst.     

Alternative synthesis of cystothiazole A

Palladium-catalyzed methoxycarbonylation of (−)-(2R,3S)-1-tert-butyldimethylsiloxy-3-methyl-2-methoxypenta-4-yne 9 derived from (2R,3S)-epoxy butanoate 5 gave the acetylenic ester 10, which was treated with MeOH in the presence of Bu₃P to afford selectively (Z)-β-methoxy acrylate congener 11 in 86% yield. Treatment of (Z)-11 with 99.8% enrichment of CDCl₃ followed by consecutive desilylation and oxidation afforded the left-half aldehyde (+)-2. The overall yield (10 steps from 5; 23%) of (+)-2 via the present route was improved in comparison to that (10 steps from 5; 10%) of the previously reported route. By applying the modified Julia's coupling method, selectivity (E/Z=14:1) of the (E)-form (cystothiazole A 1) against the (Z)-form was improved in comparison to the Wittig method (E/Z=4:1 to 6.9:1).     

Asymmetric total syntheses of (+)-2,5-dideoxy-2,5-imino-d-glucitol [(+)-DGDP] and (−)-1-deoxymannojirimycin [(−)-DMJ] via an extended chiral 1,3-oxazine

The asymmetric total syntheses of (+)-2,5-dideoxy-2,5-imino-d-glucitol [(+)-DGDP] 1 and (?)-1-deoxymannojirimycin [(?)-DMJ] 2 were achieved using an extended chiral 1,3-oxazine. The key synthetic strategies included extension of the chirality of anti,syn-oxazine 3 using diastereoselective dihydroxylation, and piperidine and pyrrolidine ring formation. Starting from readily available anti,syn-oxazine 3, (+)-DGDP 1 was synthesized in 5 steps with 31.6% overall yield and (?)-DMJ 2 was synthesized in 4 steps with 60.6% overall yield.     

Stereospecific mono- and difluorination of the C7-bridge of norbornenes

Fluorinated norbornenes are very desirable monomers in the semiconductor and high-temperature polyimide industries. We describe herein a synthetic strategy for the stereospecific mono- or difluorination of the C₇-carbon in norbornene systems beginning with 7-ketonadic anhydride 1. In particular, anti-7-fluoro methyl diester 4 and its 7,7-difluoronadic analog 7 can be prepared from 1 in 3 or 4 steps: saponification, reduction (for 4), esterification, fluorination with DAST. In addition, anti-7-fluoro-syn-7-fluoromethylnadic diester 16 is obtained from epoxide 14, and dimethyl 7,7-difluorobicyclo[2.2.2]oct-5-ene-2,3-dicarboxylate (17) from ketone 15. Anchimeric assistance of the norbornene double bond guides the introduction of attacking fluoride anions stereospecifically anti to the olefinic linkage.     

Synthesis of 3-deoxy-3,3-difluoro-d-ribohexose from gem-difluorohomoallyl alcohol

A novel synthetic route to 3-deoxy-3,3-difluoro-d-ribohexose 1 has been developed. Dihydroxidation of gem-difluorohomoallyl alcohol followed by several steps of protection and deprotection gave key intermediate 9. Oxidation of 1,5-diol 9 with 2 equiv. trichloroisocyanuric acid and catalytic TEMPO gave lactone 10. Reduction of 10 with DIBAL-H followed by deprotections afforded the target molecule 1.     

Qingqianliusus A-N, 3,4-seco-dammarane triterpenoids from the leaves of Cyclocarya paliurus and their biological activities

Fourteen previously unreported 3,4-seco-dammarane triterpenoids named Qingqianliusus A-N (1–14), along with four known 3,4-seco-dammarane triterpenoid derivatives (15–18) were isolated from the 95 % ethanol extract of the Cyclocarya paliurus leaves. Compounds 1 and 2 possess a rare 3,11-heptacyclic lactone as natural product, and several pairs of the 3,4-seco-dammarane triterpenoid epimers with R/S configuration at C-24 were investigated and determined in detail for the first time. Compounds 8, 11, and 14 showed good α-glucosidase inhibitory effects with IC₅₀ values of 4.97 ± 0.63, 7.08 ± 0.53, and 3.76 ± 0.77 μM, respectively. Meanwhile, compound 11 was also found potent inhibition rate of 35.83 % against COX-2, as compared with the positive control celecoxib (70.28 %). In addition, compounds 3, 7, 10, and 13 exhibited outstanding cytotoxicities against human gastric cancer cell lines (BGC-823) with IC₅₀ values of 7.69 ± 0.21, 8.47 ± 0.41, 9.04 ± 0.61, and 8.86 ± 0.38 μM, respectively. Compounds 13 and 3 had modest activities on human colon cancer cell lines (HCT-116) with IC₅₀ values of 8.80 ± 0.36 and 9.45 ± 0.93 μM, respectively.     

Design,synthesis and biological evaluation of novel quinazoline derivatives as potential NF-κb inhibitors

A series of novel 4-aminoquinazoline derivatives were designed, synthesized and biological properties on nuclear factor-kappaB (NF-κb) pathway inhibitory and potential in vitro anti-proliferation against breast cancer lines were also evaluated. Among them, LU1501 exhibited potent inhibition with IC₅₀ values in SK-BR-3 (10.16 ± 0.86 µM) and HCC1806 (10.66 ± 1.01 µM) cell lines. In vivo studies in breast cancer tumor model proved the correlation between anticancer activity of LU1501 and proliferation inhibition through the NF-κb signal pathway. The molecular docking studies also portrayed the potential binding mechanism between LU1501 and the key proteins of p65 and IkBα in NF-κb pathway. Accordingly, compound LU1501 could serve as a potent agent against breast cancer for further investigation.     

Linear and convergent approaches to 2-substituted adenosine-5′-N-alkylcarboxamides

Herein we report both linear and convergent pathways for the preparation of 2-alkynyl substituted adenosine-5′-N-ethylcarboxamides via the versatile synthetic intermediate, 2-iodoadenosine-5′-N-ethylcarboxamide (13). The linear approach afforded 13 in an overall yield of 30% from guanosine over eight synthetic steps. The convergent approach was shorter, but proceeded in lower yield (five steps, 20% yield). Both approaches compare favourably with previously reported syntheses of 13, which has been prepared in 15% yield from guanosine over nine steps. 2-Iodoadenosine-5′-N-ethylcarboxamide (13) was subsequently converted to HENECA (2) and PHPNECA (3) to exemplify the utility of this approach for the preparation of potent A_2A adenosine receptor agonists. The linear approach was also amenable to the synthesis of 2-fluoropurine ribosides, which were subsequently elaborated into 2-alkylaminoadenosine-5′-N-ethylcarboxamides. Furthermore, both of these synthetic approaches are readily amenable to the synthesis of adenosine analogues with varied 2-, 6- and 5′-substitution patterns.     

Epoxides related to dioncoquinone B: Synthesis,activity against multiple myeloma cells,and search for the target protein

Epoxide 2b is an analog of the synthetic intermediate 2a en route to the polyketide-derived antitumoral naphthoquinone dioncoquinone B (1), isolated from cell cultures of the tropical liana Triphyophyllum peltatum (Dioncophyllaceae). Compound 2b was found to induce strong apoptosis in multiple myeloma cells at a concentration (EC₅₀?=?3.5?μM), distinctly lower than that of 1 and any related analog, without exerting significant toxicity against normal blood cells. Preliminary studies showed that 2b follows different SAR rules as compared to the naphthoquinones. Among the series of synthesized epoxides, 2b was the most active one and was thus, after biotinylation, subjected to mass spectrometry-based affinity capture experiments aiming at the identification of target proteins. The MS data revealed 2b to address proteins that are associated with stress regulation processes which are critical for multiple myeloma cell survival.     

Kadpolysperins A–N,lanostane triterpene acids possessing rich structure types from Kadsura polysperma

Fourteen new lanostane triterpene acids (1–14), and five known analogues (15–19) were isolated from the stems of Kadsura polysperma. Compound 1, with a rearranged tetracyclic skeleton, is an important biogenic precursor of longipedlactone skeleton. Compounds 2–6 are members of 18(13→12)-abeo-lanostane triterpene acids. The structures of new compounds were elucidated by spectroscopic evidence. Selected compounds were evaluated for their in vitro cytotoxicity against human tumor HL-60, SMMC-7721, A-549, MCF-7, and SW-480 cell lines.