Organic & Biomolecular Chemistry (v.12, #28)
Front cover (5041-5041).
Inside front cover (5042-5042).
Contents list (5043-5051).
Design, synthesis, conformational analysis and application of indolizidin-2-one dipeptide mimics by Arkady Khashper; William D. Lubell (5052-5070).
Growth in the field of peptide mimicry over the past few decades has resulted in the synthesis of many new compounds and the investigation of novel pharmacological agents. Azabicyclo[X.Y.0]alkanone amino acids are among the attractive classes of constrained mimics, because they can create rigid peptide structures for probing the conformation and roles of natural motifs in recognition events important for biological activity. Herein, we review the last ten years of the synthesis, conformational analysis and activity of analogs of the azabicyclo[4.3.0]alkan-2-one amino acid subclass, so-called indolizidin-2-one amino acids, with particular attention on their employment as inputs for biological applications.
Organocatalytic enantioselective allylic alkylation of MBH carbonates with β-keto esters by M. Kamlar; S. Hybelbauerová; I. Císařová; J. Veselý (5071-5076).
The highly stereoselective allylic alkylation of Morita–Baylis–Hillman carbonates with β-ketoesters catalysed by β-ICD is described. The corresponding products containing two adjacent quaternary and tertiary carbon centers were obtained in good yields with high diastereoselectivity (up to 10 : 1 dr) and enantioselectivity (up to 95% ee).
A new synthetic approach to 6-unsubstituted phenanthridine and phenanthridine-like compounds under mild and metal-free conditions by Jumreang Tummatorn; Suppachai Krajangsri; Krissada Norseeda; Charnsak Thongsornkleeb; Somsak Ruchirawat (5077-5081).
A new and mild synthetic approach for the synthesis of 6-unsubstituted phenanthridine and phenanthridine-like compounds under metal-free conditions at room temperature has been developed. The strategy involved a tandem azide rearrangement/intramolecular annulation and oxidation reactions of biarylmethyl azide precursors to obtain the desired products in up to 99% yields with high regioselectivity.
Iron-catalysed, general and operationally simple formal hydrogenation using Fe(OTf)3 and NaBH4 by Alistair J. MacNair; Ming-Ming Tran; Jennifer E. Nelson; G. Usherwood Sloan; Alan Ironmonger; Stephen P. Thomas (5082-5088).
An operationally simple and environmentally benign formal hydrogenation protocol has been developed using highly abundant iron(iii) salts and an inexpensive, bench stable, stoichiometric reductant, NaBH4, in ethanol, under ambient conditions. This reaction has been applied to the reduction of terminal alkenes (22 examples, up to 95% yield) and nitro-groups (26 examples, up to 95% yield). Deuterium labelling studies indicate that this reaction proceeds via an ionic rather than radical mechanism.
Synthesis of nucleobase-caged peptide nucleic acids having improved photochemical properties by Takayoshi Watanabe; Tomoko Hoshida; Jun Sakyo; Mariko Kishi; Satoshi Tanabe; Junichi Matsuura; Shingo Akiyama; Makiko Nakata; Yasuaki Tanabe; Akinobu Z. Suzuki; Soichiro Watanabe; Toshiaki Furuta (5089-5093).
A nucleobase-caged peptide nucleic acid (PNA) having a (6-bromo-7-methoxycoumarin)-4-ylmethoxycarbonyl (Bmcmoc) caging group was newly synthesized. The Bmcmoc-caged PNAs were photolyzed to produce parent PNAs with a high photochemical efficiency. Introduction of a single Bmcmoc group was sufficient to suppress polymerase chain reaction (PCR) clamping activity and triplex invasion complex formation. Photo-mediated restoration of the PCR clamping activity was also demonstrated.
Enantioselective one-pot synthesis of dihydroquinolones via BINOL-derived Lewis acid catalysis by Peter C. Knipe; Martin D. Smith (5094-5097).
A high-yielding and diastereoselective route to biologically significant 2-aryl- and 2-alkyl-3-amido dihydroquinolones has been developed in up to 90 : 10 e.r. by employing a novel Lewis acidic BINOL-derived copper(ii) catalyst.
Regioselective synthesis of 3,4,5-trisubstituted 2-aminofurans by Thi Ngoc Tram Huynh; Pascal Retailleau; Clément Denhez; Kim Phi Phung Nguyen; Dom Guillaume (5098-5101).
Three series of methyl 5-substituted 2-aminofuran-4-keto-3-carboxylates have been prepared following a multicomponent reaction strategy by the addition of an isocyanide to 4-oxo-2-butynoate in the presence of an aldehyde. The cycloaddition regioselectivity is generally high (>95%) but decreases when an electron-rich substituent is located at the butynoate 4-position.
Unusual regio- and stereo-selectivity in Diels–Alder reactions between bulky N-phenylmaleimides and anthracene derivatives by Hao Chen; Erdong Yao; Chi Xu; Xiao Meng; Yuguo Ma (5102-5107).
Unusual regio- and stereo-selectivity in Diels–Alder (D–A) reactions were achieved between bulky N-phenylmaleimides and anthracene derivatives. Using multiple substituents with steric hindrance on both diene and dienophile, a noticeable shift toward 1,4-addition was successfully obtained. The substrate scope in this reaction was broad and the highest yield of anti-1,4-adducts was over 90%. Novel structures of anti-1,4-adducts were confirmed by single crystal X-ray diffraction analysis. This study not only provides the first reported method of synthesizing anti-1,4-adducts and achieving otherwise unattainable regio- and stereo-selectivity, but also elucidates the importance of combining the steric effects of two reactants to shift products toward 1,4-adducts. Moreover, the resulting 1,4-adducts could be further functionalized through their halogen groups via carbon–carbon coupling reactions.
Impact of mono- and disubstitution on the colorimetric dynamic covalent switching chalcone/flavanone scaffold by Brian M. Muller; Jesse Mai; Reid A. Yocum; Marc J. Adler (5108-5114).
The effect of aryl substitution on various aspects of the interconversion of ortho-hydroxychalcones and flavanones has been studied using multiple spectroscopic techniques. Derivatization of the core scaffold predictably alters the midpoint pH of this equilibration process suggesting its viability for application as a functional colorimetric molecular switch.
A colorimetric and ratiometric fluorescent probe for the imaging of endogenous hydrogen sulphide in living cells and sulphide determination in mouse hippocampus by Ling Zhang; Sai Li; Mei Hong; Yuqing Xu; Shuaishuai Wang; Yi Liu; Yong Qian; Jing Zhao (5115-5125).
A naphthalimide-azide based colorimetric and ratiometric fluorescent probe, NAP-1, has been developed for the selective and sensitive detection of hydrogen sulphide. Advantages of the probe NAP-1 include a low detection limit (110 nM), good selectivity, high sensitivity and excellent photostability. A linear relationship between the emission intensity ratios and sulphide concentrations was observed in PBS buffer and bovine serum, respectively. Our probe facilitates ratiometric determination and imaging of endogenous H2S in living cells. Furthermore, this probe was successfully applied to the measurement of endogenous sulphide in human plasma and mouse hippocampus. A significant reduction in sulphide levels and CBS mRNA expression was observed in the hippocampus of mouse models of lipopolysaccharide-induced neuroinflammation-related diseases, suggesting that decreased levels of endogenous H2S might be involved in the pathogenesis of neuroinflammation-related neurodegenerative diseases.
Evaluation of the effect of fluorination on the property of monofluorinated dimyristoylphosphatidylcholines by Marie-Claude Gagnon; Bianka Turgeon; Jean-Daniel Savoie; Jean-François Parent; Michèle Auger; Jean-François Paquin (5126-5135).
The synthesis of three monofluorinated dimyristoylphosphatidylcholines (F-DMPC's), with the fluorine atom located at the extremities of the acyl chain in position 2 of the glycerol (sn-2), is described. The synthetic strategy relies on the coupling of 1-myristoyl-2-hydroxy-sn-glycero-3-phosphocholine (14:0 lyso-PC) and three different fluorinated fatty acids. FTIR results suggest that the presence of the fluorine atom does not significantly perturb the lipid phase transition temperature and conformational order even though a small increase in the phase transition temperature is observed for the 14F derivative. Overall, comparison with previously reported F-DMPC's where the fluorine atom is located in the middle or close from either side supports the fact that monofluorination of the acyl chain in sn-2 brings minimal perturbation to the lipid bilayer. F-DMPC's could therefore potentially be used as NMR probes for the investigation at the molecular level of the interaction between drugs or peptides and lipid membranes and for the study of membrane topology.
Mercuration of thiacalixarenes in the cone and 1,3-alternate conformations by F. Botha; S. Böhm; H. Dvořáková; V. Eigner; P. Lhoták (5136-5143).
The first mercuration in the thiacalixarene series using thiacalixarenes immobilized in the cone or 1,3-alternate conformations gave a mixture of two monomercurated regioisomers (meta and para) in approx. 4 : 1 and 2 : 1 ratios, respectively. The organomercurial intermediates show unusual solid-state behaviour, as evidenced by the formation of η6 complexes, and can be easily transformed into halogen-substituted derivatives, so far inaccessible in thiacalixarene chemistry. This paves the way towards the synthesis of inherently chiral thiacalixarene-based receptors with an unusual substitution pattern.
Methylthiodeoxynivalenol (MTD): insight into the chemistry, structure and toxicity of thia-Michael adducts of trichothecenes by Philipp Fruhmann; Theresa Weigl-Pollack; Hannes Mikula; Gerlinde Wiesenberger; Gerhard Adam; Elisabeth Varga; Franz Berthiller; Rudolf Krska; Christian Hametner; Johannes Fröhlich (5144-5150).
Methylthiodeoxynivalenol (MTD), a novel derivative of the trichothecene mycotoxin deoxynivalenol (DON), was prepared by applying a reliable procedure for the formal Michael addition of methanethiol to the conjugated double bond of DON. Structure elucidation revealed the preferred formation of the hemiketal form of MTD by intramolecular cyclisation between C8 and C15. Computational investigations showed a negative total reaction energy for the hemiketalisation step and its decrease in comparison with theoretical model compounds. Therefore, this structural behaviour seems to be a general characteristic of thia-Michael adducts of type B trichothecenes. MTD was shown to be less inhibitory for a reticulocyte lysate based in vitro translation system than the parent compound DON, which supports the hypothesis that trichothecenes are detoxified through thia-adduct formation during xenobiotic metabolism.
Polyamine modification by acrolein exclusively produces 1,5-diazacyclooctanes: a previously unrecognized mechanism for acrolein-mediated oxidative stress by Ayumi Tsutsui; Rie Imamaki; Shinobu Kitazume; Shinya Hanashima; Yoshiki Yamaguchi; Masato Kaneda; Shinya Oishi; Nobutaka Fujii; Almira Kurbangalieva; Naoyuki Taniguchi; Katsunori Tanaka (5151-5157).
Acrolein, a toxic unsaturated aldehyde generated as a result of oxidative stress, readily reacts with a variety of nucleophilic biomolecules. Polyamines, which produced acrolein in the presence of amine oxidase, were then found to react with acrolein to produce 1,5-diazacyclooctane, a previously unrecognized but significant downstream product of oxidative stress. Although diazacyclooctane formation effectively neutralized acrolein toxicity, the diazacyclooctane hydrogel produced through a sequential diazacyclooctane polymerization reaction was highly cytotoxic. This study suggests that diazacyclooctane formation is involved in the mechanism underlying acrolein-mediated oxidative stress.
Synthesis and photophysical characterisation of new fluorescent triazole adenine analogues by Christopher P. Lawson; Anke Dierckx; Francois-Alexandre Miannay; Eric Wellner; L. Marcus Wilhelmsson; Morten Grøtli (5158-5167).
Fluorescent nucleic acid base analogues are powerful probes of DNA structure. Here we describe the synthesis and photo-physical characterisation of a series of 2-(4-amino-5-(1H-1,2,3-triazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) and 2-(4-amino-3-(1H-1,2,3-triazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) analogues via Sonogashira cross-coupling and [3 + 2]-cycloaddition reactions as the key steps in the synthesis. Compounds with a nitrogen atom in position 8 showed an approximately ten-fold increase in quantum yield and decreased Stokes shift compared to analogues with a carbon atom in position 8. Furthermore, the analogues containing nitrogen in the 8-position showed a more red-shifted and structured absorption as opposed to those which have a carbon incorporated in the same position. Compared to the previously characterised C8-triazole modified adenine, the emissive potential was significantly lower (tenfold or more) for this new family of triazoles-adenine compounds. However, three of the compounds have photophysical properties which will make them interesting to monitor inside DNA.
Multicomponent reaction for the first synthesis of 2,2-dialkyl- and 2-alkyl-2-aralkyl-5,6-diaryl-2H-1,3-thiazines as scaffolds for various 3,4-dihydro-2H-1,3-thiazine derivatives by Fabian Brockmeyer; Robin Schoemaker; Marc Schmidtmann; Jürgen Martens (5168-5181).
A two-step sequence for the synthesis of various 3,4-dihydro-2H-1,3-thiazines is presented. In the first step, 2H-1,3-thiazines were prepared by a new multicomponent reaction (MCR). Starting from β-chlorovinyl aldehydes, this MCR offers an efficient and facile access to 2,2-dialkyl- and 2-alkyl-2-aralkyl-5,6-diaryl-2H-1,3-thiazines. The potential of these products in subsequent reactions was verified by the conversion to 3,4-dihydro-2H-1,3-thiazine-containing bisamides, β-lactams, and methoxy amides.
1,2-cis Alkyl glycosides: straightforward glycosylation from unprotected 1-thioglycosyl donors by Bo Meng; Zhenqian Zhu; David C. Baker (5182-5191).
A 1,2-cis-alkyl glycosidation protocol that makes use of unprotected phenyl 1-thioglycosyl donors is reported. Glycosylation of various functionalized alcohols was accomplished in moderate to high yield and selectivity to give the 1,2-cis-glycosides. In order to quickly develop optimum glycosylation conditions, an FIA (flow injection analysis)–ESI-TOF-MS method was developed that enabled rapid and quantitative evaluation of yield on small scale. This methodology, coupled with NMR spectroscopy, allowed for rapid evaluation of the overall reactions.
An efficient synthesis of methyl 2-cyano-3,12-dioxoursol-1,9-dien-28-oate (CDDU-methyl ester): analogues, biological activities, and comparison with oleanolic acid derivatives by Liangfeng Fu; Qi-Xian Lin; Karen T. Liby; Michael B. Sporn; Gordon W. Gribble (5192-5200).
An efficient synthesis of methyl 2-cyano-3,12-dioxoursol-1,9-dien-28-oate (CDDU-methyl ester) from commercially available ursolic acid, which features an oxidative ozonolysis-mediated C-ring enone formation, and provides the first access to ursolic acid-derived cyano enone analogues with C-ring activation. These new ursolic acid analogues show potent biological activities, with potency of approximately five-fold less than the corresponding oleanolic acid derivatives.
Synthesis, characterization and biological evaluation of carboranylmethylbenzo[b]acridones as novel agents for boron neutron capture therapy by A. Filipa F. da Silva; Raquel S. G. R. Seixas; Artur M. S. Silva; Joana Coimbra; Ana C. Fernandes; Joana P. Santos; António Matos; José Rino; Isabel Santos; Fernanda Marques (5201-5211).
Herein we present the synthesis and characterization of benzo[b]acridin-12(7H)-ones bearing carboranyl moieties and test their biological effectiveness as boron neutron capture therapy (BNCT) agents in cancer treatment. The cellular uptake of these novel compounds into the U87 human glioblastoma cells was evaluated by boron analysis (ICP-MS) and by fluorescence imaging (confocal microscopy). The compounds enter the U87 cells exhibiting a similar profile, i.e., preferential accumulation in the cytoskeleton and membranes and a low cytotoxic activity (IC50 values higher than 200 μM). The cytotoxic activity and cellular morphological alterations after neutron irradiation in the Portuguese Research Reactor (6.6 × 107 neutrons cm−2 s−1, 1 MW) were evaluated by the MTT assay and by electron microscopy (TEM). Post-neutron irradiation revealed that BNCT has a higher cytotoxic effect on the cells. Accumulation of membranous whorls in the cytoplasm of cells treated with one of the compounds correlates well with the cytotoxic effect induced by radiation. Results provide a strong rationale for considering one of these compounds as a lead candidate for a new generation of BNCT agents.
Design, synthesis and evaluation of new tricyclic endoperoxides as potential antiplasmodial agents by Jérémy Ruiz; Sonia Mallet-Ladeira; Marjorie Maynadier; Henri Vial; Christiane André-Barrès (5212-5221).
Diastereoselective autoxidation allowed preparation of new tricyclic endoperoxides. These compounds and their methylated analogs were evaluated against the in vitro growth of Plasmodium falciparum, the malaria-causing parasite, showing moderate activities. However, hybrid molecules composed of the tricyclic peroxide moiety and 7-chloro-4-aminoquinoline were synthesized and displayed a marked increase in antiplasmodial activity.
Unusual truncation of N-acylated peptoids under acidic conditions by Soomin Kim; Goutam Biswas; Shinae Park; Arim Kim; Hyunjung Park; Eunsook Park; Jeongmi Kim; Yong-Uk Kwon (5222-5226).
The terminal amino groups of peptoids have often been protected with acetyl groups to improve cell permeability and therapeutic potential, and to prevent the poisoning of the catalysts in organometallic reactions. Interestingly, the unusual truncation of the terminal peptoid unit has sometimes been encountered when the acetylated linear peptoids were treated with a TFA cleavage cocktail. In this study, we systematically investigated the electronic effects of acyl groups on the truncation of N-acylated peptoids to rationalize the formation of the deleted peptoids and to establish an appropriate strategy for preventing such undesired truncation.
A survey of enoldiazo nucleophilicity in selective C–C bond forming reactions for the synthesis of natural product-like frameworks by Yuxiao Liu; Yu Liu; Charles S. Shanahan; Xichen Xu; Michael P. Doyle (5227-5234).
A survey of in situ, catalytically generated carbocations for coupling with enoldiazoacetate nucleophiles was performed. These couplings facilitate the rapid assembly of complex organodiazo compounds that provide a template for the synthesis of a variety of carbocyclic and heterocyclic ring systems.
Outstanding effects on antithrombin activity of modified TBA diastereomers containing an optically pure acyclic nucleotide analogue by M. Scuotto; M. Persico; M. Bucci; V. Vellecco; N. Borbone; E. Morelli; G. Oliviero; E. Novellino; G. Piccialli; G. Cirino; M. Varra; C. Fattorusso; L. Mayol (5235-5242).
Herein, we report optically pure modified acyclic nucleosides as ideal probes for aptamer modification. These new monomers offer unique advantages in exploring the role played in thrombin inhibition by a single residue modification at key positions of the TBA structure.
Pd-catalyzed carbonylation for the construction of tertiary and quaternary carbon centers with sp3 carbon partners by Wei Lu; Yang Li; Chao Wang; Dong Xue; Jian-Gang Chen; Jianliang Xiao (5243-5249).
The first examples of a Pd-catalyzed carbonylation of aryl boronic acids with sp3 carbon partners are presented. Various boronic acids were shown to react with 1,3-diesters and 1,3-diketones to afford structurally unique carbonyl compounds. By employing 2-substituted 1,3-diesters, synthetically-challenging quaternary carbon centres were accessed. In total, 42 examples of aryl carbonyl compounds were prepared in moderate to good yields. The catalytic system features the use of a bidentated phosphine ligand and a relatively low CO pressure (5 atm), providing an easy, alternative method for the preparation of triketones.
An ESIPT fluorescent probe sensitive to protein α-helix structures by Nan Jiang; Chanli Yang; Xiongwei Dong; Xianglang Sun; Dan Zhang; Changlin Liu (5250-5259).
A large majority of membrane proteins have one or more transmembrane regions consisting of α-helices. Membrane protein levels differ from one type of cell to another, and the expression of membrane proteins also changes from normal to diseased cells. For example, prostate cancer cells have been reported to have downregulated expression of membrane proteins, including zinc transporters, compared with normal prostate cells. These reports inspired us to design a fluorescence probe sensitive to protein α-helical structures to discriminate individual prostate cancer cells from normal ones. A benzazole derivative (1 in this study) was observed to emit strong fluorescence resulting from an excited-state intramolecular proton transfer (ESIPT) in protein α-helical environments. The intensity of ESIPT fluorescence of 1 was observed to be positively correlated with the α-helix content of proteins. The molecular docking simulation suggested that it had low energy for the binding of 1 to proteins when the binding sites were localized within the α-helical regions of protein via H-bonds. Furthermore, 1 was found to be localized in cell membranes through binding to transmembrane α-helical regions of membrane proteins, and was capable of probing differences in the α-helix contents of membrane proteins between normal and cancerous prostate cells through changes in the ESIPT emission intensity. These results indicated that 1 could distinguish individual prostate cancer cells from normal ones, as the changes in the ESIPT fluorescence intensity of 1 could reflect the regulation in expression of the membrane proteins including zinc transporters. This recognition strategy of individual prostate cancer cells might contribute to early diagnosis techniques for prostate cancer.
Pyrene chromophores for the photoreversal of psoralen interstrand crosslinks by Jens M. Stadler; Thorsten Stafforst (5260-5266).
Applying psoralen interstrand crosslinks for the photoactivation of nucleic acids is a new concept. To find chromophores that can efficiently stimulate crosslink repair we screened several pyrenes and appended them to peptide nucleic acids for their site-selective addressing. Even though pyrenes conjugated to uracil revealed desirable spectroscopic properties they were not effective in crosslink reversal. In contrast, bare pyrenes are well suitable for crosslink repair with 350 nm light showing an uncaging efficiency similar to classical photocaging groups.
Modular synthesis of cyclic cis- and trans-1,2-diamine derivatives by Anna K. Weber; Josef Schachtner; Robert Fichtler; Timo M. Leermann; Jörg M. Neudörfl; Axel Jacobi von Wangelin (5267-5277).
Structurally diverse carbocycles with two vicinal nitrogen-substituents were prepared in expedient three-component reactions from simple amines, aldehydes, and nitroalkenes. trans,trans-6-Nitrocyclohex-2-enyl amines were obtained in a one-pot domino reaction involving condensation, tautomerisation, conjugate addition, and nitro-Mannich cyclisation. Upon employment of less nucleophilic carboxamides, a concerted Diels–Alder cycloaddition mechanism operated to give the corresponding cis,trans-nitrocyclohexenyl amides. Both types of substituted carbocycles offer ample opportunities for chemical manipulations at the core and periphery. Ring oxidation with MnO2 affords substituted nitroarenes. Reduction with Zn/HCl provides access to various trans- and cis-diaminocyclohexenes, respectively, in a straight-forward manner. With enantiopure secondary amines, a two-step synthesis of chiral nitrocyclohexadienes was developed (82–94% ee).
Multivalent agents containing 1-substituted 2,3,4-trihydroxyphenyl moieties as novel synthetic polyphenols directed against HIV-1 by Aida Flores; María José Camarasa; María Jesús Pérez-Pérez; Ana San-Félix; Jan Balzarini; Ernesto Quesada (5278-5294).
The synthesis and the assessment of the anti-HIV activity of a set of molecules inspired by the multivalent structures of some naturally-occurring polyphenols (tannins) are reported. Different multibranched scaffolds have been derived from pentaerythritol as the central core which distribute spatially synthetic polyphenolic subunits based on 1-substituted 2,3,4-trihydroxyphenyl moieties. A tetrapodal compound (13b) bearing four N-(2,3,4-trihydroxyphenyl)amide groups, exhibits remarkable selective activity against HIV-1 with EC50 values in the micromolar scale, in the same range as those reported for the most representative anti-HIV tannins. Preliminary SAR studies emphasize the importance of the 1-substituted 2,3,4-trihydroxyphenyl moiety, the presence of an amide as the linker and the multivalent architecture of these molecules, since the anti-HIV activity increases with the number of polyphenolic moieties. The data support the interest in synthetic polyphenols and represent a promising starting point for further design and development of selective HIV-1 inhibitors.
Marine natural products-inspired phenylmethylene hydantoins with potent in vitro and in vivo antitumor activities via suppression of Brk and FAK signaling by Asmaa A. Sallam; Mohamed M. Mohyeldin; Ahmed I. Foudah; Mohamed R. Akl; Sami Nazzal; Sharon A. Meyer; Yong-Yu Liu; Khalid A. El Sayed (5295-5303).
Breast and prostate cancers are among the most common cancers worldwide with devastating statistics for the metastatic, chemotherapy- and radiotherapy-resistant phenotypes. Novel therapies interfering with new and/or multiple pathways involved in the pathology of cancer are urgently needed. Preliminary results showed that the marine natural product Z-4-hydroxyphenylmethylene hydantoin (PMH, 1) and its 4-ethylthio-analog (SEth, 2) promoted tight junction formation and showed anti-invasive and anti-migratory activities in vitro against metastatic prostate cancer cells and inhibited tumor growth and micrometastases in distant organs in orthotopic and transgenic mice models. This study focuses on the design and synthesis of second-generation PMHs with enhanced antitumor activities. A series of substituted benzaldehydes was selected based on earlier SAR studies and reacted with hydantoin to yield 11 new compounds 3–13. Compounds were evaluated for their antiproliferative, antimigratory and anti-invasive properties in vitro against the human mammary and prostate cancer cell lines MDA-MB-231 and PC-3, respectively. A Western blot analysis of the most active analog 7 showed its ability to suppress the expression of the total levels of c-Met and FAK, with subsequent reduction of their phosphorylated (activated) levels in MDA-MB-231 cells. In addition, 7 also inhibited Brk, paxillin and Rac1 phosphorylation. 7 was formulated using hydroxypropyl β-cyclodextrin (HPCD) to improve its solubility and was further evaluated in a nude mice xenograft model using MDA-MB-231/GFP cells. PMH 7 reduced breast tumor growth and suppressed Ki-67, CD31, p-Brk and p-FAK expression in tumor samples. Thus, 7 is a potential lead for the control of invasive breast malignancies.
Exploring mutasynthesis to increase structural diversity in the synthesis of highly oxygenated polyketide lactones by J. M. Botubol-Ares; M. J. Durán-Peña; A. J. Macías-Sánchez; J. R. Hanson; I. G. Collado; R. Hernández-Galán (5304-5310).
The enantioselective synthesis of (2R,3R,4E,8E)-3-hydroxy-2,4,8-trimethyldeca-4,8-dienolide (5) by ring-closing metathesis is described. This compound is an analogue of 3,4-dihydroxy-2,4,6,8-tetramethyldec-8-enolide (4) which is a rare 11-membered lactone produced by the fungus, Botrytis cinerea. Mutasynthetic studies with compound 5 using two mutants of B. cinerea led to the isolation of four new highly oxygenated 11-membered lactones (11–14) in which compound 5 has been stereoselectively epoxidized and hydroxylated at sites that were not easily accessible by classical synthetic chemistry.
Back cover (5311-5312).