Formulation development, stability and anticancer efficacy of core-shell cyclodextrin nanocapsules for oral chemotherapy with camptothecin

• Hale Ünal,
• Naile Öztürk and
• Erem Bilensoy

Beilstein J. Org. Chem. 2015, 11, 204–212, doi:10.3762/bjoc.11.22

• colon, breast, ovarian, lung cancers in in vitro cell culture studies [17][18]. However its poor aqueous solubility and the pH-dependent stability problem results in the diminishing of clinical efficacy for the drug [19]. CPT is in active lactone form under pH 5 but is rapidly hydrolysed into the

• probably attributed to the lactone–carboxylate equilibrium of CPT. It is known that the active lactone form of CPT rapidly hydrolyses into the inactive carboxylate form at physiological pH. As it was indicated in Supporting Information File 1, all the formulations were diluted with HBSS solution at pH 7.4

• for the permeability studies. At this pH, the active lactone form which is essential for the diffusion of the drug through membranes, was rapidly turned into the inactive carboxylate form which shows a poorer diffusibility than the lactone form [46][47]. Nanocapsules have the ability to maintain the

Cathodic reductive coupling of methyl cinnamate on boron-doped diamond electrodes and synthesis of new neolignan-type products

• Taiki Kojima,
• Rika Obata,
• Tsuyoshi Saito,
• Yasuaki Einaga and
• Shigeru Nishiyama

Beilstein J. Org. Chem. 2015, 11, 200–203, doi:10.3762/bjoc.11.21

• mixture, (±)-2 was submitted to the chemical conversion into the new neolignan-type derivatives E-5 and E-8. Thus, reduction of (±)-2 with LiAlH4 gave the alcohol (±)-4 [15] in quantitative yield, which on oxidation with PCC [16] gave the lactone E-5 in 32% yield. Selective DIBAL reduction of E-5 gave an

Formation of nanoparticles by cooperative inclusion between (S)-camptothecin-modified dextrans and β-cyclodextrin polymers

• Thorbjørn Terndrup Nielsen,
• Catherine Amiel,
• Laurent Duroux,
• Kim Lambertsen Larsen,
• Lars Wagner Städe,
• Reinhard Wimmer and
• Véronique Wintgens

Beilstein J. Org. Chem. 2015, 11, 147–154, doi:10.3762/bjoc.11.14

• potent anticancer activity by inhibition of topoisomerase II. Its major drawback is its extremely low aqueous solubility of 2.5 µg/mL leading to a low bioavailability and it is thus a considerable formulation challenge [4]. Furthermore, at physiological conditions its active lactone form is hydrolysed to

• significantly increase the stability of the CTP lactone, due to the protection from the aqueous environment. Conclusion Novel (S)-camptothecin-dextran polymers were obtained by “click” grafting of azide-modified (S)-camptothecin and alkyne-modified dextrans. Two series based on 10 kDa and 70 kDa dextrans were

Recent advances in the electrochemical construction of heterocycles

• Robert Francke

Beilstein J. Org. Chem. 2014, 10, 2858–2873, doi:10.3762/bjoc.10.303

• , a tethered carboxy group can be used as the nucleophilic component, leading to the formation of lactone rings [39]. A further option is the hydrolysis of alkoxysulfonium species 7 with aqueous NaOH under formation of the corresponding secondary alcohol [40]. The idea of integrating a chemical

Aspergiloid I, an unprecedented spirolactone norditerpenoid from the plant-derived endophytic fungus Aspergillus sp. YXf3

• Zhi Kai Guo,
• Rong Wang,
• Wei Huang,
• Xiao Nian Li,
• Rong Jiang,
• Ren Xiang Tan and
• Hui Ming Ge

Beilstein J. Org. Chem. 2014, 10, 2677–2682, doi:10.3762/bjoc.10.282

• three methyl groups (δC 23.4, 24.5, 29.2), five aliphatic methylenes (δC 18.1, 23.7, 28.4, 28.5, 31.8), one olefinic methylene (δC 113.2), two oxygenated methines (δC 76.9, 64.7), one olefinic methine (δC 142.9), and six non-protonated carbon atoms (one of which was identified as lactone group) (δC 35.1

• . Here the hypothetical pimarane compound 2, the hemiketal lactone ring-opening product of aspergiloid E, was proposed as the most probable biosynthetic intermediate. As shown in Scheme 1, we suggest the biosynthesis of 1 starts from the classical diterpene precursor geranylgeranyl diphosphate [14], and

• intermediate 2 undergoes decarboxylation to form 3 through Baeyer–Villiger oxidation to form the 7-membered lactone 4, then hydrolyzation, decarboxylation and lactonization to finally give aspergiloid I (1). Aspergiloid I (1) was evaluated for its cytotoxicity against eleven human cancer cell lines, K562

Synthesis and biological evaluation of novel N-α-haloacylated homoserine lactones as quorum sensing modulators

• Michail Syrpas,
• Ewout Ruysbergh,
• Christian V. Stevens,
• Norbert De Kimpe and
• Sven Mangelinckx

Beilstein J. Org. Chem. 2014, 10, 2539–2549, doi:10.3762/bjoc.10.265

• reports supporting this theory, it has to be noted that this view point has been challenged and is still under debate among scientists [6][7]. Most Gram-negative bacteria use N-acylated homoserine lactones (AHLs) as signal molecules [8]. The general structure of these compounds consist of a lactone ring

• lactone carbonyl group, could increase the affinity of AHLs to their cognate receptors [18]. It was shown that introduction of halogens as electron-withdrawing groups in the N-acyl chain reduced the nucleophilicity of the donor oxygen and led to attenuation of the n→π* interaction (Figure 1). Moreover

• atoms, that could be involved in such interactions seem an interesting strategy to be explored. Surprisingly, most of the studies focus on altering the fatty acid tail or the lactone ring of the AHL molecules [14][19], while modifications at the α-carbon position with respect to the carbonyl function of

Total synthesis of the proposed structure of astakolactin

• Takayuki Tonoi,
• Keisuke Mameda,
• Moe Fujishiro,
• Yutaka Yoshinaga and
• Isamu Shiina

Beilstein J. Org. Chem. 2014, 10, 2421–2427, doi:10.3762/bjoc.10.252

• sesterterpenoid bearing a furan unit and an eight-membered lactone tethered by a non-conjugated triene chain (Figure 1). Although the proposed structure of compound 1 is unusual, given that a number of compounds isolated from sponges of the same species have a steroid-like structure [7][8][9], the structure does

• -sized lactones (8–11 membered rings) are significant structural motifs because they are found in many natural products possessing useful biological activities [14][15][16][17][18][19]. Among them, the 8-membered (and 9-membered) lactone framework is rather unusual in nature [20][21][22][23][24]. We have

• total synthesis of compound 1 by exploitng the MNBA-mediated lactonization for the formation of its 8-membered lactone moiety. Results and Discussion The rationalized synthesis of 1 primarily involved the linear synthesis of the prenyl chain precursor from commercially available (E,E)-farnesol to form

De novo macrolide–glycolipid macrolactone hybrids: Synthesis, structure and antibiotic activity of carbohydrate-fused macrocycles

• Richard T. Desmond,
• Anniefer N. Magpusao,
• Chris Lorenc,
• Jeremy B. Alverson,
• Nigel Priestley and
• Mark W. Peczuh

Beilstein J. Org. Chem. 2014, 10, 2215–2221, doi:10.3762/bjoc.10.229

• ; structure; synthesis; Introduction In contemporary usage, “macrolide” describes any large ring lactone [1]. It was originally coined, however, with reference to a narrower set of compounds: antimicrobial natural products containing a macrolactone ring adorned with deoxygenated carbohydrate residues [2

• lactone 2 [5], on the other hand, represents one example of glycolipid macrolactone natural products. These novel compounds have many potential applications (e.g., food, cosmetics) based on their physical properties; some glycolipid lactones have also been shown to be cytotoxins [6] and 2 also has

• macrocycle through the C1’ (glycosidic) and C6’ oxygens. The new macrolides bear a resemblance to sophorolipid lactone 2 and to polyketide macrocycles that contain a tetrahydropyran moiety [20][21][22]. We report on the synthesis, X-ray crystal structures and antibiotic activities of the new compounds

Chiral phosphines in nucleophilic organocatalysis

• Yumei Xiao,
• Zhanhu Sun,
• Hongchao Guo and
• Ohyun Kwon

Beilstein J. Org. Chem. 2014, 10, 2089–2121, doi:10.3762/bjoc.10.218

• excellent ee (up to 96%). In subsequent transformations, the β-lactone products underwent various ring opening reactions to provide very useful derivatives, such as 1,3-diketones and enol esters, with good diastereoselectivity. 2.12 Annulations through domino aza-MBH/Michael reactions Because

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• stereocenters would originate from lactone 82, which in turn is the product of a conjugate addition of chiral allyl phosphonamide reagent 28c to butenolide 83 prepared from (R)-citronellol. The correct installation of the stereocenters of 82 was crucial to the success of the synthesis, as they would form a

• three-step procedure and subsequent alkylation with allyl bromide gave alkene 87. Ozonolysis with reductive work-up was followed by spontaneous cyclization to the corresponding γ-lactone, which was then transformed into 83 by means of α-selenenylation, oxidation, and elimination (Scheme 11). With

• ozonolysis, protection of the resulting aldehyde, reduction of the lactone ring to the lactol, and treatment with methylenetriphenylphosphorane delivered 89. Mild acidic hydrolysis of the acetal followed by oxidation then yielded 90 with the γ-lactone unit that constitutes ring A of acetoxycrenulide

Sacrolide A, a new antimicrobial and cytotoxic oxylipin macrolide from the edible cyanobacterium Aphanothece sacrum

• Naoya Oku,
• Miyako Matsumoto,
• Kohsuke Yonejima,
• Keijiroh Tansei and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2014, 10, 1808–1816, doi:10.3762/bjoc.10.190

• /δC 0.97/14.1), which indicated that a lactone linkage is the only possible cyclization topology. The analysis of the COSY spectrum (Figure 2) helped trace six-carbon and ten-carbon spin systems, both of which include an oxymethine (H9: δH 4.50, H13: δH 5.23) and a disubstitued olefin. The geometry of

• H214 (δH 2.61, 2.56) to C12 (δC 196.7), forming an α,β-unsaturated α'-acyloxy ketone functionality, and from H22 (δH 2.50, 2.36), H3 (δH 1.68), and H13 to C1 (δC 173.1), bridging a lactone linkage. The structure assembled to this point used up C18H27O4 of the molecular formula C18H28O4 and a remaining

Human dendritic cell activation induced by a permannosylated dendron containing an antigenic GM₃-lactone mimetic

• Renato Ribeiro-Viana,
• Elena Bonechi,
• Javier Rojo,
• Clara Ballerini,
• Giuseppina Comito,
• Barbara Richichi and
• Cristina Nativi

Beilstein J. Org. Chem. 2014, 10, 1317–1324, doi:10.3762/bjoc.10.133

• expression and MHCII. Furthermore, DCs activated by the glycodendron 5 stimulate T lymphocytes to proliferate in a mixed lymphocytes reaction (MLR). Keywords: cancer immunotherapy; DC-SIGN; DC targeting; glycodendron; GM3-lactone mimetic; multivalent glycosystems; multivalent interactions; Introduction

• of a potential vaccine against melanoma disease [28]. The GM3 metabolite, named GM3-lactone 2 (Figure 1) has also been found in melanoma cells as a minor component [29][30]. Although more immunogenic than GM3-ganglioside 1, GM3-lactone 2 failed as an immunostimulant because under physiological

• conditions the available amount of lactone is below the recognition threshold and therefore scarcely effective as an immunostimulant. Several years ago [31], we reported on the conformational analysis and the synthesis of thioether 3 (Figure 1), a hydrolytically stable mimetic of the GM3-lactone 2

4-Hydroxy-6-alkyl-2-pyrones as nucleophilic coupling partners in Mitsunobu reactions and oxa-Michael additions

• Michael J. Burns,
• Thomas O. Ronson,
• Richard J. K. Taylor and
• Ian J. S. Fairlamb

Beilstein J. Org. Chem. 2014, 10, 1159–1165, doi:10.3762/bjoc.10.116

• is generally well-developed [7], efficient routes to these types of complex structural units are elusive, and the total synthesis of these and similar natural products remains a challenge [8]. Simple 2-pyrones such as 4-hydroxy-6-methyl-2-pyrone (triacetic acid lactone, 3a, Figure 1) are readily and

Homogeneous and heterogeneous photoredox-catalyzed hydroxymethylation of ketones and keto esters: catalyst screening, chemoselectivity and dilution effects

• Axel G. Griesbeck and
• Melissa Reckenthäler

Beilstein J. Org. Chem. 2014, 10, 1143–1150, doi:10.3762/bjoc.10.114

• products (Scheme 4). Methyl benzoylformate (21) gave a mixture of pinacol and the 1,2-diol without lactone formation. The higher homologs (Table 3, entries 2–4) resulted in the corresponding lactones with ring sizes of 5 and 6, respectively, with the δ-keto ester (Table 3, entry 4) leading to the δ

• -pentyrolactone and not the corresponding seven-membered lactone. The primary product from hydroxymethylation was also isolated from the reaction of the ε-keto ester 25 [40]. Heterogeneous and dye-sensitized photocatalysis The results with the semiconductor particle TiO2 P25 under low catalyst loading conditions

• particle surfaces, CB, VB = conduction and valence band. Homogeneous sensitizer variation for the acetophenone model reaction. Substrate variation under optimized conditions. Photohydroxymethylation of keto esters: 1,2-diol and lactone formation. Heterogeneous sensitizer variation for model reaction in

Synthesis of zearalenone-16-β,D-glucoside and zearalenone-16-sulfate: A tale of protecting resorcylic acid lactones for regiocontrolled conjugation

• Hannes Mikula,
• Julia Weber,
• Dennis Svatunek,
• Philipp Skrinjar,
• Gerhard Adam,
• Rudolf Krska,
• Christian Hametner and
• Johannes Fröhlich

Beilstein J. Org. Chem. 2014, 10, 1129–1134, doi:10.3762/bjoc.10.112

• /bjoc.10.112 Abstract The development of a reliable procedure for the synthesis of the 16-glucoside and 16-sulfate of the resorcylic acid lactone (RAL) type compound zearalenone is presented. Different protective group strategies were considered and applied to enable the preparation of glucosides and

Olefin cross metathesis based de novo synthesis of a partially protected L-amicetose and a fully protected L-cinerulose derivative

• Bernd Schmidt and
• Sylvia Hauke

Beilstein J. Org. Chem. 2014, 10, 1023–1031, doi:10.3762/bjoc.10.102

• L-amicetal 4 [36]. Alternatively, we have used 2 as a substrate for a cross metathesis reaction with methyl acrylate under isomerization-free conditions to furnish enoate 5, which underwent cyclization to the lactone 6 after hydrogenation. Reduction of 6 with DIBAL-H eventually yields a protected L

Visible-light-induced, Ir-catalyzed reactions of N-methyl-N-((trimethylsilyl)methyl)aniline with cyclic α,β-unsaturated carbonyl compounds

• Dominik Lenhart and
• Thorsten Bach

Beilstein J. Org. Chem. 2014, 10, 890–896, doi:10.3762/bjoc.10.86

• lactone and lactam substrates, the latter products were the only products isolated. For the six-membered lactones and lactams and for cyclopentenone the simple addition products prevailed. Keywords: cyclization; electron transfer; iridium; photochemistry; photoredox catalysis; radical reactions

• and delivered product 14 in 41% yield. Addition to cyclic α,β-unsaturated ketones Based on the results obtained with five-membered lactone 9, it was suprising to note that the related five-membered enone, 2-cyclopentenone (15), delivered mainly the direct addition product 17 instead of the tricyclic

• yield (49%) was recorded for the Ts-protected product 19b. The two protons at the ring junction show a similar coupling constant (3J = 8.1 Hz for 19a, 3J = 7.9 Hz for 19b) as the protons in the related lactone 10 suggesting a cis-annulation of the two heterocyclic rings. The instability of Boc

Structure elucidation of female-specific volatiles released by the parasitoid wasp Trichogramma turkestanica (Hymenoptera: Trichogrammatidae)

• Armin Tröger,
• Teris A. van Beek,
• Martinus E. Huigens,
• Isabel M. M. S. Silva,
• Maarten A. Posthumus and
• Wittko Francke

Beilstein J. Org. Chem. 2014, 10, 767–773, doi:10.3762/bjoc.10.72

• -cis-2,4,6-trimethylcyclohexanone. Subsequent Baeyer–Villiger oxidation, followed by reduction of the obtained lactone, yielded syn,syn-2,4-dimethylheptan-1,6-diol 16 (Figure 4). Protection of the primary hydroxy group gave 17 followed by a Mitsunobu sequence involving the secondary hydroxy group

Decandrinin, an unprecedented C₉-spiro-fused 7,8-seco-ent-abietane from the Godavari mangrove Ceriops decandra

• Hui Wang,
• Min-Yi Li,
• Félix Zongwe Katele,
• Tirumani Satyanandamurty,
• Jun Wu and
• Gerhard Bringmann

Beilstein J. Org. Chem. 2014, 10, 276–281, doi:10.3762/bjoc.10.23

• 333.2053, calcd for [M + H]+, 333.2060). From this formula, it was suggested that 1 has seven degrees of unsaturation, of which four could be ascribed to one carbon–carbon double bond, one lactone carbonyl group, and two ketone groups, according to its 1H and 13C NMR data (Table 1); the molecule should

• , 195.9), and a lactone carbonyl group (δC 170.9). The NMR spectroscopic data indicated that 1 was a rearranged abietane. The existence of an isopropyl group was suggested by 1H,1H-COSY correlations between H-15 and protons of two methyl groups [δH 1.11 (d, J = 6.9 Hz, 3H), 1.11 (d, J = 6.9 Hz, 3H)]. From

• carbonyl carbon (δC 170.9) of a δ-lactone suggested its location at C-7, while those from H2-11, H-14, and H3-20 to the quaternary carbon (δC 88.3) placed it at C-9 (Figure 2). The NOE interactions for the two methyl groups at C-4 suggested that one methyl group is located at the same side as H-5, while

Boron-substituted 1,3-dienes and heterodienes as key elements in multicomponent processes

• Ludovic Eberlin,
• Fabien Tripoteau,
• François Carreaux,
• Andrew Whiting and
• Bertrand Carboni

Beilstein J. Org. Chem. 2014, 10, 237–250, doi:10.3762/bjoc.10.19

• three-component process (Scheme 3) [34]. Extension of this work to the intramolecular version is depicted in Scheme 4. The bicyclic lactone 1 was obtained stereoselectively from a diene-yne in a one-pot process with control of the relative stereochemistry of the five stereogenic centers [35]. Concerning

Recent applications of the divinylcyclopropane–cycloheptadiene rearrangement in organic synthesis

• Sebastian Krüger and
• Tanja Gaich

Beilstein J. Org. Chem. 2014, 10, 163–193, doi:10.3762/bjoc.10.14

• Iguchi and co-workers [44] applied the DVCPR to the total synthesis of the marine prostanoid clavubicyclone [45]. Known aldehyde 33 (see Scheme 7) [46] was subjected to Wittig conditions to furnish an intermediate lactone, which was then opened reductively followed by selective oxidation of the allylic

• this compound was subjected to oxidative conditions both alcohols were oxidized to the corresponding aldehyde/ketone. Base-induced epoxide opening led to the formation of a double bond (C4/C5) and concomitant lactol-formation. The lactol was oxidized to the corresponding lactone under the same reaction

Synthesis of five- and six-membered cyclic organic peroxides: Key transformations into peroxide ring-retaining products

• Alexander O. Terent'ev,
• Dmitry A. Borisov,
• Vera A. Vil’ and
• Valery M. Dembitsky

Beilstein J. Org. Chem. 2014, 10, 34–114, doi:10.3762/bjoc.10.6

Plakilactones G and H from a marine sponge. Stereochemical determination of highly flexible systems by quantitative NMR-derived interproton distances combined with quantum mechanical calculations of ¹³C chemical shifts

• Simone Di Micco,
• Angela Zampella,
• Maria Valeria D’Auria,
• Carmen Festa,
• Simona De Marino,
• Raffaele Riccio,
• Craig P. Butts and
• Giuseppe Bifulco

Beilstein J. Org. Chem. 2013, 9, 2940–2949, doi:10.3762/bjoc.9.331

• , 1 and 2 share with other members of this family a large portion of their chemical scaffold including the γ-lactone moiety and the ethyl-branched side chain. Even if the absolute configuration at C-4 and C-6 has been previously determined for plakilactone A (4) and notably for the corresponding 7,8

• oxygenated carbons and one acyl group. The acyl carbon signal at 175.9 ppm (C-1), along with the oxygenated carbon resonance at δC 91.9 (C-4) suggested the presence of a lactone. The olefinic methine carbon at δC 153.5 (C-3) with the quaternary carbon at δC 136.6 (C-2) completed the five-membered α,β

• -unsaturated lactone ring. The linkage of an ethyl side chain at C-2, suggested by the long range allylic coupling between protons H-3 and H2-11, was supported by the diagnostic HMBC correlations H-3/C-11 and H3-12/C-2 (Figure 2). A second isolated ethyl system was linked at C-4 on the basis of the HMBC

Studies toward bivalent κ opioids derived from salvinorin A: heteromethylation of the furan ring reduces affinity

• Thomas A. Munro,
• Wei Xu,
• Douglas M. Ho,
• Lee-Yuan Liu-Chen and
• Bruce M. Cohen

Beilstein J. Org. Chem. 2013, 9, 2916–2924, doi:10.3762/bjoc.9.328

• bivalent derivatives. Installation of a leaving group on hydroxymethyl compound 4, for instance, would permit coupling with diverse N-dealkylated opiate scaffolds. Alternative attachment points would also be worth exploring, such as the C-17 lactone, which tolerates reduction and alkylation [1]. As noted

• binding pose of 1 may be similar. If so, converting the lactone to a cyclic amine may provide the desired H-bond to Asp1383.32 without the need for additional functional groups. Our results provide no evidence of negative allosteric modulation of κ-OR by low-affinity derivatives of 1, and the mutagenesis

SF002-96-1, a new drimane sesquiterpene lactone from an Aspergillus species, inhibits survivin expression

• Silke Felix,
• Louis P. Sandjo,
• Till Opatz and
• Gerhard Erkel

Beilstein J. Org. Chem. 2013, 9, 2866–2876, doi:10.3762/bjoc.9.323

• production of inhibitors of survivin promoter activity, a new drimane sesquiterpene lactone, SF002-96-1, was isolated from fermentations of an Aspergillus species. The compound inhibited survivin promoter activity in transiently transfected Colo 320 cells in a dose dependent manner with IC50 values of 3.42

• attractive target for new anticancer therapeutics [13]. In a search for new inhibitors of survivin expression from natural sources, we found that cultures of Aspergillus sp. strain IBWF002-96 produced a new drimane sesquiterpene lactone, SF002-96-1, with inhibitory activity on survivin promoter activity in

• chain (δ 173.5). The relative configuration was deduced from NOESY data. Thus, protons of a methyl group at δ 1.04 showed NOE correlations with those of one of the geminal methyl groups (δ 1.15) and one of the oxymethylene protons (δ 4.48) of the lactone ring (Figure 3). Besides, the protons of the