Investigation of Pictet-Spengler type reactions of secologanin with histamine and its benzyl derivative

The reaction of secologanin (1) (mainly in its tetraacetylated form 1a) with histamine (2) and its benzyl derivative (2b) was investigated. With the benzylated amine (2b), the main product was the normal, tetraacetylated benzyl derivative of histeloside having the R configuration at the new center of chirality, C-1 (5b), with a small amount of an unidentified minor component (probably the 1S epimer 5a). In a slightly acidic medium, the reaction with histamine (2) gave two products in an approximately 6:4 ratio. The main compound proved to be the normal, tetraacetylated derivative of the lactam histelosamide with R configuration at C-1 (7b), and the minor product was the tetraacetylisohisteloside with S configuration at the same C-1 center (3a). When the reaction was carried out under acid-free conditions, in addition to the epimeric pair of the normal tetraacetylated lactam (7a, 7b) and the tetraacetylisohisteloside with 1S configuration (3a), tetraacetylneohistelosamide (8b) was also isolated, in which the cyclization took place at one of the cyclic nitrogens of the imidazole ring. Probably, this latter compound is an intermediate also in the formation of the normal isomers, but under slightly acidic conditions it rapidly isomerized into the normal alkaloid. The tendencies experienced previously in the tryptamine and dopamine series were observed also in the histamine series; that is, at C-1, the R configuration is favored over the S one, and lactamization is faster in the former than in the latter case. The structure of the products and their stereoschemistry were established by NMR spectroscopy.     

Regio- and stereoselectivity in the coupling reaction of secologanin with dopamine derivatives

The coupling reaction of tetraacetylsecologanin with dopamine and its N-benzyl derivative was investigated. In both series, stereoisomers at C-1, as well as regioisomer normal and neo compounds, were formed. Moreover, the N-unsubstituted products were partially lactamized, and the N-benzyl derivatives epimerized at C-1. In the products, the R configuration of C-1 over the S and the formation of the normal structure over the neo one predominated. The epimerization of both epimers gave an equilibrium of R and S in a ratio of 7:3 and was interpreted by cleavage of the C-1-N-2 bond. The fact that lactamization was much faster in the R than in the S series was explained on the basis of the supposed transition states. The structure, the configuration of C-1, and in several cases the conformations were established by detailed NMR studies and supported by chemical correlations.     

Regioselective and stereospecific amination of iridoids: conversion of aucubin into aminoside antibiotic analogues

Treatment of aucubin (1) with tert-butyldimethylsilyl chloride under alkaline conditions permitted regioselective silylation of either the primary hydroxyl groups at C-9 and C-6' or both primary hydroxyl groups and the secondary allylic hydroxyl group at C-6. Acetylation with acetic anhydride, followed by selective removal of the silyl groups and Mitsunobu reaction involving phthalimide as nitrogen donor, gave a stereospecific entry to aminoside antibiotic analogues: 10,6'-diamino-10,6'-dideoxyaucubin (16) and (6R)-6,10,6'-triamino-6,10,6'-trideoxyaucubin (17).     

抗肿瘤氟喹诺酮C-3(稠)杂环化合物双NFDE6二唑甲硫醚及其碘甲烷盐衍生物的合成(Ⅰ)

目的 寻找由抗菌氟喹诺酮向抗肿瘤氟喹诺酮转化的有效结构修饰途径。方法 以抗菌氟喹诺酮药物氧氟沙星1为原料,其相应的酰肼2与二硫化碳缩环合得C-3NFDE6二唑硫醇3中间体,然后分别与5-取代苯基-2-氯甲基-1,3,4-NFDE6二唑4a~4g缩合得含氟喹诺酮骨架的双NFDE6二唑甲硫醚5a~5g,接着用碘甲烷进行季铵化反应得相应的季铵盐6a~6g。用MTT方法评价了目标化合物5a~5g和6a~6g体外对肿瘤细胞的生长抑制活性。结果 合成了14个新的目标化合物,体外均显示潜在的抗癌活性（IC₅₀＜25 μmol·L）,其中季铵盐6a~6g的活性高于相应游离碱5a~5g的活性。结论 基于抗菌氟喹诺酮C-3杂环的抗肿瘤氟喹诺酮的设计值得进一步研究。     

Design and synthesis of a combinatorial chemistry library of 7-acyl, 10-acyl,and 7,10-diacyl analogues of paclitaxel (taxol) using solid phase synthesis

A series of 10-acyl and 7,10-diacyl paclitaxel analogues (7a-7e and 9a-9u) have been synthesized using a solid phase combinatorial chemistry approach, and a second series of 7-acyl-10-deacetylpaclitaxel analogues have been prepared by conventional chemistry. In the first series, 10-deacetylpaclitaxel (4) was linked through its 2'-hydroxyl group using 1% polystyrene-divinyl benzene resin functionalized with butyldiethylsilane linker (PS-DES) and then acylated at the C-10 hydroxyl group with various anhydrides and dialkyl dicarbonates in the presence of CeCl(3). The resin-bound C-10 acylated paclitaxel derivatives (6a-6e) were then treated with various carboxylic acids in the presence of 1,3-diisopropylcarbodiimide in toluene to provide polymer-supported 7,10-diacylpaclitaxels (8a-8u). These 7-acyl- and 7,10-diacylpaclitaxels (6a-6e and 8a-8u) were cleaved from the resin to give the 24 paclitaxel analogues 7a-7e and 9a-9u. Nine 7-acyl-10-deacetylpaclitaxel analogues were also prepared by conventional chemistry. Methodology to determine the tubulin-assembly activity of compounds prepared in small quantities by a combinatorial approach has been developed, and four analogues with improved tubulin-assembly activity as compared with paclitaxel were found, together with two analogues with improved cytotoxicity.     

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??OBJECTIVE To explore an efficient strategy for converting the antibacterial activity of fluoroquinolones to antitumor activity. METHODS An amide group as an isostere modified by rhodanine unsaturated ketone moiety corresponding to the C-3 carboxylic acid group resulted in 12 new title C-3 (5-arylidene-2-thioxo-1, 3-thiozolidin-2,4-dione-3-yl) amides (6a-6l) from ofloxacin 1. Their structures were characterized by elemental analysis and spectral data, and the in vitro antitumor activity of the title compounds against three tested cell lines was evaluated by MTT assay. RESULTS Twelve new title compounds were synthesized from ofloxacin and exhibited significantly higher potency than the parent compound ofloxacin. CONCLUSION Using a rhodanine unsaturated ketone hybrided amide group as the C-3 bioisostere is favorable to improve antitumor activity.     

3-芳苄叉基噻唑酮-氟喹啉-4-酮氧氟沙星衍生物的合成及抗肿瘤活性

目的 进一步发现氟喹诺酮的有效结构修饰策略以提高其抗肿瘤活性。方法 基于药效团拼合药物设计原理,用噻唑酮作为氧氟沙星C-3羧基的等排体、芳苄叉基为其修饰基,构建了新的3-芳苄叉噻唑酮-氟喹啉-4-酮的氧氟沙星衍生物(6a~6l),其结构经用元素分析和光谱数据确证。MTT方法评价了体外对SMMC-7721、Capan-1和HL60这3种癌细胞株的抗增值活性。结果 12个新结构的氟喹诺酮-3-噻唑不饱和酮目标化合物被合成,其活性显著强于母体氧氟沙星1,其中卤苯基化合物强于其他取代基的活性,尤其是氯苯基化合物(6k)对Capan-1细胞的活性与对照抗肿瘤药多柔比星相当。结论 芳苄叉基噻唑酮替代氟喹诺酮C-3羧基有利于提高其抗肿瘤活性。     

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??OBJECTIVE To design and synthesize a series of oleanolic acid analogs posessing anti-tumor activity based on survivin target. METHODS Using the techniques of computer-aided drug design, the docking of Survivin and known active small molecules was simulated and then the key amino acid residue fragment of the target protein was analyzed. It led to the discovery of active groups capable of binding to the critical sites. Through using the natural product, oleanolic acid, as a lead compound, the active groups were introduced onto its A-ring, and the carboxyl group at the C-28 position was modified using amidation. SGC-7901 and A549 cells were used to screen the antitumor activity in vitro through the standard MTT method. RESULTS Ten new oleanolic acid derivatives were designed and synthesized,and their structures were confirmed by MS and NMR. The compounds ??₅ and ??₅ exhibited more potent cytotoxicity than the positive control drugs. CONCLUSION The novel oleanolic acid analogues have better antitumor activity than the parent compound, which are worthy of further study.     

Diacarperoxides, norterpene cyclic peroxides from the sponge Diacarnus megaspinorhabdosa

Chemical investigation of the hexane extract of the sponge Diacarnus megaspinorhabdosa provided a series of new norterpene derivatives including three norditerpene cyclic peroxides, diacarperoxides A, B, and C (1 to 3), four norsesterterpene cyclic peroxides, diacarperoxides D to G (4 to 7), and the acyclic norsesterterpene diacardiol A (8). In addition, known norterpene peroxide congeners were also isolated, which included a known norsesterterpene cyclic peroxide (9), nuapapuin A methyl ester (10), epimuqubilin B (11), methyl-2-epinuapapuinoate (12), and methyl diacarnoate A (13). The structures of the new compounds were established on the basis of one- and two-dimensional NMR spectroscopic studies ((1)H, (13)C, COSY, HMQC, HMBC, and ROESY) as well as by mass spectrometric analyses. The relative configuration of chiral centers at C-2, C-3, and C-6 was assigned by established empirical rules. All compounds were evaluated for their cytotoxic properties in vitro using several human as well as murine cancer cell lines.     

Investigation of the coupling reaction of tetraacetylsecologanin with oxotryptamine and its derivative

The coupling reaction of tetraacetylsecologanin with 2,3-dihydro-2-oxotryptamine and its N(b)-benzyl derivative was investigated. With the benzylated amine, the reaction was stopped at the tetracyclic ester level, and with the unsubstituted amine it was immediately followed by lactamization. In both cases, the products were formed with high stereoselectivity at C-3, but as an epimeric pair of 7R and 7S in a ratio of 1:3. The bulky benzyl substituent at N-4 directed the stereoselectivity at C-3 in favor of the S configuration. In the nonbenzylated compounds, the reversible coupling reaction is probably nonstereoselective, but in lactamization the 3R epimer is sterically favored and faster and gives the final lactam in this configuration. The formation of the spiro compounds may serve as a model reaction in the interpretation of the stereoselectivity of the coupling reaction of secologanin with tryptamine in the presence of strictosidine synthase.     

Microbial transformation of ent-kaurenoic acid and its 15-hydroxy derivatives by the SG138 mutant of Gibberella fujikuroi.

Feeding experiments with ent-kaurenoic acid (4), 15 alpha-hydroxy-ent-kaurenoic acid (5), 15 beta-hydroxy-ent-kaurenoic acid (6), and mixtures of 4 plus 5 and 4 plus 6 were conducted using the SG138 mutant of Gibberella fujikuroi, to gain information about the phenotype of this unique strain. The biotransformation of 5 gave 7 beta,15 alpha-dihydroxykaurenolide (9) and 7 beta,15 alpha-dihydroxy-ent-kaurenoic acid (13). The incubation of 6 produced 7 beta,15 beta-dihydroxy-ent-kaurenoic acid (7) and 7 beta,15 beta-dihydroxykaurenolide (10). No 15-hydroxylated gibberellins were detected in any of these experiments. The results indicated that a hydroxy group at C-15 does not inhibit 7 beta-hydroxylase activity but in the SG138 strain obstructs the enzymatic ring-B contraction of ent-kaurenoids to gibberellins. Exogenous 4 stimulated both the excretion of ent-kaurene and the fungal metabolism of 5 and 6.     

An efficient conversion of taxinine to taxinine NN-1, an anticancer agent and a modulator of multidrug-resistant tumor cells

Taxinine NN-1 (1), which shows significant activities as a modulator of multidrug-resistant cancer cells and as an anticancer agent in an in vitro assay based on a HCC panel, was synthesized in order to obtain sufficient material for a higher order bioassay from easily available taxinine (2). The synthesis was achieved via intermediate 8, which was derived from 2 by the stepwise protection of a 9,10-dihydroxyl group as acetonide and a 2-hydroxyl group as a MOM protecting group. The temporary elimination of a cinnamoyl group at C-5 of 8 and successive reduction of a C-13 carbonyl group of the resulting 9 gave 10 and the undesired 13-epimer 11. The latter was recycled to 9 by oxidation with MnO(2). Stepwise acetylation and cinnamoylation at C-13 and C-5 of 10 and successive deprotection of the acetonide protecting group at C-9,10 of the resulting 13 gave diol 14. Diacetylation of 14 and deprotection of the MOM protecting group at C-2 of the resulting 15 gave 1. The overall yield of 1 was 45% in 11 steps from 2.     

Phytotoxic withanolides from Jaborosa rotacea

Twelve new withanolides were isolated from the aerial part of Jaborosa rotacea: five had a spiranoid delta-lactone (1-5); one contained a 26,12-delta-lactone and a C-12-C-23 bond (6); five corresponded to trechonolide-type withanolides with configuration at C-23 opposite of those previously isolated (7, 8, 10-12); two of these have an additional oxido-bridge between C-21 and C-24; finally a withanolide with a hemiketal ring formed between a 21-hydroxyl and a 12-ketone (13) and the closely related jaborosalactone R were also isolated. New compounds were fully characterized by a combination of spectroscopic methods (1D and 2D NMR and MS). The structures of the spiranoid withanolide and of the epimer of trechonolide A were confirmed by X-ray diffraction studies. Compounds 4, 5, 6, and 8 showed selective phytotoxicity toward monocotyledoneous and dicotyledoneous species.     

Inhibitors of bacterial multidrug efflux pumps from the resin glycosides of Ipomoea murucoides

A reinvestigation of the CHCl 3-soluble extract from flowers of the Mexican medicinal arborescent morning glory, Ipomoea murucoides, through preparative-scale recycling HPLC, yielded six new pentasaccharides, murucoidins VI-XI (1- 6), as well as the known pescaprein III (7), stoloniferin I (8), and murucoidins I-V (9- 13). Their structures were characterized through the interpretation of their NMR spectroscopic and FABMS data. Compounds 1-6 were found to be macrolactones of three known glycosidic acids identified as simonic acids A and B, and operculinic acid A, with different fatty acids esterifying the same positions, C-2 on the second rhamnose unit and C-4 on the third rhamnose moiety. The lactonization site of the aglycone was placed at C-2 or C-3 of the second saccharide unit. The esterifying residues were composed of two short-chain fatty acids, 2-methylpropanoic and (2S)-methylbutyric acids, and two long-chain fatty acids, n-dodecanoic (lauric) acid and the new (8R)-(-)-8-hydroxydodecanoic acid. For the latter residue, its absolute configuration was determined by analysis of its Mosher ester derivatives. All members of the murucoidin series exerted a potentiation effect of norfloxacin against the NorA overexpressing Staphylococcus aureus strain SA-1199B by increasing the activity 4-fold (8 microg/mL from 32 microg/mL) at concentrations of 5-25 microg/mL. Stoloniferin I (8) enhanced norfloxacin activity 8-fold when incorporated at a concentration of 5 microg/mL. Therefore, this type of amphipathic oligosaccharide could be developed further to provide more potent inhibitors of this multidrug efflux pump.     

Preparation, stereochemical study and evaluation of the antileukemic activity of glucoside derivatives of (-)-steganol

The optically active lignan (-)-steganol was prepared from natural (-)-steganacin by selective deacetylation and was transformed, via a three-step sequence, into the corresponding 4', 6'-O-ethylidene- and thenylidene-beta-D-glucopyranosides, 3b and 3c, respectively, which are the analogues, in the steganol series, of the podophyllotoxin derived, and clinically useful, anticancer drugs, VP16-213 and VM26. Formation of the dimeric compound distegyl ether as a minor by-product was established. Complete elucidation of all the asymmetric centres was performed with the help of high resolution 1H-nmr studies at 400 MHz, COSY experiment at 500 MHz and X-ray analysis. Contrary to the podophyllotoxin series, the glycosylation of (-)-steganol occurred with retention of configuration, and all the synthesized compounds, including distegyl ether, exhibited the starting natural R configuration at C-5.     

Oxidation,reduction, and methylation of carnosic acid by Nocardia

Preparative-scale incubations with Nocardia sp. NRRL 5646 were conducted to produce new derivatives of the abietane diterpene chemoprotectant and antioxidant carnosic acid (1). Reductive biotransformation of the C-20 carboxylic acid functional group followed by biological methylation at the C-11 phenol afforded 4. Oxidative cyclization of 1 to carnosol 5 followed by dihydroxylation at the isopropyl moiety afforded 6. Metabolites 4 and 6 are new carnosic acid derivatives whose structures were confirmed by mass spectrometry and NMR spectroscopic analysis. The radical quenching properties of 4-6 using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) free-radical-scavenging assay showed activities similar to that of mixed tocopherols and carnosic acid.     

Biotransformation of phenolic 1-benzyl-N-methyltetrahydroisoquinolines in plant cell cultures followed by LC/NMR, LC/MS, and LC/CD

(+/-)-1-Benzyl- N-methyltetrahydroisoquinolines 7-10 and 11-14 with one and two hydroxy groups on the aromatic rings, respectively, were fed individually to cultured cells of Corydalis and Macleaya species, respectively. The structures of the metabolites were determined by using combinatorial techniques, including LC/NMR, LC/MS-MS, and LC/CD. The enantiomeric excesses of the metabolites were derived from LC/CD and LC/MS-MS analyses. In cell cultures of Corydalis and Macleaya species, laudanine (7), with a hydroxy group at C-3', can form the berberine bridge at C-2' and C-6' to produce S- and R-enantiomers of 2,3,9,10- and 2,3,10,11-oxygenated protoberberines (20 and 21), respectively, whereas reticuline (11) and protosinomenine (12), incoporating a hydroxy group at C-3', form the berberine bridge at C-2' to furnish the S-enantiomer of 2,3,9,10-oxygenated protoberberines (23 and 21), respectively.     

New insecticidal rocaglamide derivatives and related compounds from Aglaia oligophylla

Organic-soluble extracts of the twigs of Aglaia oligophylla collected in Vietnam yielded four insecticidal cyclopentatetrahydrobenzofurans of the rocaglamide type including one new natural product (compound 4). Moreover, two cyclopentatetrahydrobenzopyran derivatives, belonging to the aglain and aglaforbesin types, respectively, were also isolated. The aglaforbesin derivative 6 proved likewise to be a new natural product. All isolated rocaglamide, aglain, and aglaforbesin derivatives have a characteristic methylenedioxy substituent linked to C-6 and C-7 or to C-7 and C-8, respectively. Structure elucidation of the new natural products and the determination of the absolute configuration of compound 1 by calculation of its CD spectrum with molecular dynamics simulation are described. All isolated rocaglamide derivatives exhibited strong insecticidal activity toward neonate larvae of the polyphageous pest insect Spodoptera littoralis when incorporated into an artificial diet, with LC(50) values varying between 2.15 and 6.52 ppm.     

Configurational assignment of cyclic peroxy metabolites provides an insight into their biosynthesis: isolation of plakortolides, seco-plakortolides, and plakortones from the Australian marine sponge Plakinastrella clathrata

Sixteen new compounds, comprising nine new plakortolides K-S (1-9), four seco-plakortolides (10-13), and three plakortones (14-16), were isolated from the Australian sponge Plakinastrella clathrata. Structural elucidation, including relative configurational assignment, was based on extensive spectroscopic analysis, while the absolute configurations of 1-4 were deduced from (1)H NMR analyses on MPA esters derived from Zn/AcOH reduction products. Diastereomeric sets of plakortolides, e.g., K and L, or M and N, differed in configuration at C-3/C-4 rather than at C-6, a stereochemical result that compromises a biosynthetic pathway involving Diels-Alder cycloaddition of molecular oxygen to a Δ(3,5)-diunsaturated fatty acid precursor. The biosynthesis may plausibly involve cyclization of a 6-hydroperoxydienoic acid intermediate following stereospecific introduction of the hydroperoxy group into a polyketide-derived precursor. Isolated seco-plakortolides converted under mild conditions into plakortones with full retention of configuration, suggesting C-6 hydroxy attack on an α,β-unsaturated lactone intermediate. The NMR data reported for the compound named plakortolide E are inconsistent with the current literature structure and are those of the corresponding seco-plakortolide (19). The reported conversion of the metabolite into a plakortone ether on storage is consistent with this structural revision.     

Absolute configuration of (-)-gambogic acid, an antitumor agent

(-)-Gambogic acid (1), a biologically active "caged xanthone" from gamboge, the dried resin of Garcinia hanburyi, is of interest as a potential anticancer agent. The planar structure of (-)-gambogic acid has been determined previously by analysis of its detailed NMR data and confirmed by single-crystal X-ray diffraction, with the absolute configuration at C-13 deduced as R through a series of chemical degradations. Using (-)-morellic acid (2), an analogue of (-)-gambogic acid, as a model compound, the 5R, 7S, 10aS, 13R, 27S absolute configuration of (-)-gambogic acid was determined for the first time by comparison of physical and spectroscopic data, especially experimental and calculated electronic circular dichroism.