Spongistatins: Biological activity and synthetic studies

During the last two decades, marine organisms such as sponges, tunicates, softcoral and starfish proved to be productive sources of structurally complex metabolites presenting unprecedented architectures.[1] These marine natural products often display unexpected biological properties that make them potential candidates for therapeutic applications. Among these fascinating molecules, the polyketide macrolides having a macrolactone as key structural feature represent an important class of biologically active compounds.[2] Many congeners of this family are potent cancer cell growth inhibitors and thus appears to represent promising leads for the development of new anti-cancer agents. Nevertheless, a limitation to their implementation in clinical evaluation is related to their low natural abundance, which is stimulating organic chemists to invent efficient synthetic routes to address this supply issue. In 1993, the research groups of Pettit, Kitagawa/Kobayashi and Fusetani independently reported the isolation, from marine sponges, of a family of related highly oxygenated macrolactones containing highly substituted 6,6-spiroketals and tetrahydropyran rings.[3] These molecules were found to be among the most potent cancer cells growth inhibitors tested to date by the U.S. National Cancer Institute on a panel of 60 human carcinoma cell lines, with GI50 values in the nanomolar and picomolar ranges. Despite these promising properties, further biological investigations were precluded by the extremely low quantities that can be obtained by extraction of marine organisms and the unacceptable ecological impact of larger scale isolation of the producing sponges. This scarce abundance, combined with remarkable structural complexity, prompted many research groups to address the challenge of the synthesis of these macrolides. We give here an overview of the biological properties of spongistatins and related structures and of the different pathways that have been developed for their total syntheses and the synthesis of key-subunits

Frequency Doubling Nanocrystals for Cancer Theranostics

A novel bio-photonics approach based on the nonlinear optical process of second harmonic generation by non-centrosymmetric nanoparticles is presented and demonstrated on malignant human cell lines. The proposed method allows to directly interact with DNA in absence of photosensitizing molecules, to enable independent imaging and therapeutic modalities switching between the two modes of operation by simply tuning the excitation laser wavelength, and to avoid any risk of spontaneous activation by any natural or artificial light source.Comment: 16 pages, 7 figure

Noniterative approach to the total asymmetric synthesis of 15-carbon polyketides and analogs with high stereodiversity

Starting from inexpensive furan and furfuryl alcohol, a noniterative approach to the synthesis of pentadeca-1,3,5,7,9,11,13,15-octols and their derivatives has been developed. The method relies upon the double [4+3]-cycloaddition of 1,1,3-trichloro-2-oxylallyl cation with 2,2'-methylenedifuran and conversion of the adducts into meso and (±)-threo-1,1'-methylenebis (cis- and trans-4,6-dihydroxycyclohept-1-ene) derivatives. The latter undergo oxidative cleavage of their alkene moieties, generating 5-hydroxy-7-oxoaldehydes that are reduced diastereoselectively into either syn or anti-5,7-diols. Asymmetry is realized using either chiral desymmetrization with Sharpless asymmetric dihydroxylation or by kinetic resolution of polyols using lipase-catalyzed acetylations. All of the possible stereomeric pentadeca-1,3,5,7,9,11,13,15-octols and derivatives can be obtained with high stereoselectivity applying simple operations, thus demonstrating the high stereodiversity of this new, noniterative approach to the asymmetric synthesis of long-chain polyketide

Synthetic studies toward the CD spiroketal of spongistatins

Starting from the readily available meso-methylenedi(8-oxa-3-oxobicyclo[3.2.1]hept-6-en-1-yl) (1), meso-1,1'-methylidene [(4R,4'S,6R,6'S)-4,6-dioxycyclohept-1-en-1-yl]tetrasilylethers (7, 8) were obtained and transformed into all-syn 1,3,5,11,13,15-hexahydroxypentadeca-7,9-dione derivatives (9, 10). The conversion of these intermediates into spiroketals was not met with success. An alternative strategy based on the sequential and stereoselective functionalization of 1 afforded a 1-(1,3,5,7-tetrahydroxyoctyl)cyclohept-1-ene-4,6-diol derivative ((+)-15, 94 % ee). Ozonolysis of the cycloheptene moiety of (+)-19 provided equatorial/axial spiroketal (+)-21 ((+)-(2R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-[(2S,4S,6R,8S,10S)-10-{[tert-butyl(dimethyl) silyl]oxy}-4-hydroxy-8-(2-hydroxyethyl)-1,7-dioxaspiro[5.5]undec-2-yl]butan-2-yl 4-methoxybenzoate). Pivaloylation of its primary alcohol moiety and Meerwein's methylation of the remaining secondary alcohol unit furnished (−)-24, a potential precursor of a ketal-isomer of the CD fragment found in spongistatins 1 and 2

Synthesis of tri- and tetramines containing two 2,3-dihydroxypyrrolidine moieties and their inhibitory activity toward α-mannosidases

Through the reductive amination of N-[(tert-butoxy)carbonyl]-2,5-dideoxy-2,5-imino-3,4-Oisopropylidene-L-ribose with tetramethylenediamine, hexamethylenediamine, 2,7- diaminofluorene, 4,4'-diaminodiphenylmethane and 1,4-(diaminomethyl)benzene, five tetramines containing two (2R,3R,4S)-2-aminomethylpyrrolidine-3,4-diol moieties have been prepared and assayed for their inhibitory activities toward 24 glycosidases. Tetramines containing the tetramethylene or benzene-1,4-dimethylene linkers are more potent αmannosidase inhibitors than simple (2R,3R,4S)-2-aminomethylpyrrolidine-3,4-diols. Triamines such as (2S,3R,4S)-bis(3,4-dihydroxy-pyrrolidin-2-ethyl)amine were also prepared and shown to be better α-mannosidase inhibitors than (2S,3R,4S)-2-(2-aminoethyl)pyrrolidin-3,4-diol.The Swiss National Science Foundation (grants n° 20-63667.00 and 2100-063567.00/1)European COST (COST D13/0001/99) programOffice Fédéral de l'Education et de la Science (Bern)Dirección General de Investigación Científica y Técnica of Spain (grant n° BQU-2001-3779)SOCRATES (EPFL/Sevilla) progra

Synthesis of tri- and tetramines containing two 2,3-dihydroxypyrrolidine moieties and their inhibitory activity toward α-mannosidases

Through the reductive amination of N-[(tert-butoxy)carbonyl]-2,5-dideoxy-2, 5-imino-3,4-O-isopropylidene-L-ribose with tetramethylenediamine, hexamethylenediamine, 2,7-diaminofluorene, 4,4′-diaminodiphenylmethane and 1,4-(diaminomethyl)benzene, five tetramines containing two (2R,3R,4S)-2- aminomethylpyrrolidine-3,4-diol moieties have been prepared and assayed for their inhibitory activities toward 24 glycosidases. Tetramines containing the tetramethylene or benzene-1,4-dimethylene linkers are more potent α-mannosidase inhibitors than simple (2R,3R,4S)-2-aminomethylpyrrolidine- 3,4-diols. Triamines such as (2S,3R,4S)-bis(3,4-dihydroxy-pyrrolidin-2-ethyl) amine were also prepared and shown to be better α-mannosidase inhibitors than (2S,3R,4S)-2-(2-aminoethyl)pyrrolidin-3,4-diol

Risk capital allocation and cooperative pricing of insurance liabilities

The Aumann–Shapley [Values of Non-atomic Games, Princeton University Press, Princeton] value, originating in cooperative game theory, is used for the allocation of risk capital to portfolios of pooled liabilities, as proposed by Denault [Coherent allocation of risk capital, J. Risk 4 (1) (2001) 1]. We obtain an explicit formula for the Aumann–Shapley value, when the risk measure is given by a distortion premium principle [Axiomatic characterisation of insurance prices, Insur. Math. Econ. 21 (2) (1997) 173]. The capital allocated to each instrument or (sub)portfolio is given as its expected value under a change of probability measure. Motivated by Mirman and Tauman [Demand compatible equitable cost sharing prices, Math. Oper. Res. 7 (1) (1982) 40], we discuss the role of Aumann–Shapley prices in an equilibrium context and present a simple numerical example

Synthesis and Biological Evaluation of Modified 2-Deoxystreptamine Dimers

Aminoglycosides are powerful antibiotics, but the emergence of resistant bacterial strains has prompted the search for analogues with better pharmacological profiles. The synthesis of 2-deoxystreptamine (2-DOS) dimers linked by polyamines and analogues based on furylcarbopeptoid skeletons is described. Potent and selective ligands for bacterial 16S rRNA were identified using microarray techniques by determining the affinity of these derivatives toward bacterial and human ribosomal RNA

Optimal Capital Allocation Principles

This article develops a unifying framework for allocating the aggregate capital of a financial firm to its business units. The approach relies on an optimization argument, requiring that the weighted sum of measures for the deviations of the business unit's losses from their respective allocated capitals be minimized. The approach is fair insofar as it requires capital to be close to the risk that necessitates holding it. The approach is additionally very flexible in the sense that different forms of the objective function can reflect alternative definitions of corporate risk tolerance. Owing to this flexibility, the general framework reproduces several capital allocation methods that appear in the literature and allows for alternative interpretations and possible extensions