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

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

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

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

Pancreatic islet cells isolation and transplantation into the bone marrow

Bone marrow is currently being considered as an alternative site for pancreatic islet transplantation. The goal of the present review is to report preclinical and clinical studies taking advantage of this new implantation site. Preclinical studies in mice demonstrated that syngeneic islets could survive in bone marrow indefinitely with a higher success in providing euglycemia compared to islets transplanted into the traditionally used implantation site, namely, the liver. In concordant and discordant xenogeneic models, the immune response was more stringent when islets were transplanted to the bone marrow as compared to the traditional implantation site in rodents, the kidney capsule. As demonstrated by histology, cellular and humoral rejection was prevented by islets protected by micro-encapsulation in calcium-alginate beads, and a similar degree of fibrotic reaction was induced at both site, although functional studies in diabetic animals are still needed. In clinical settings, a pilot study of four patients who received islet auto-transplantation into the bone marrow after a total pancreatectomy had been showed to be safe and feasible. Three out of four patients had a functioning graft, as measured by serum C-peptide, at an average follow-up of 545 ± 369 days. In conclusion, islet transplantation into the bone marrow may be a viable alternative to the liver as an implantation site, particularly with the perspective of transplanting encapsulated xenogeneic islets. Meanwhile, the efficacy of immunosuppressive drugs would still require to be evaluated in allogeneic and xenogeneic preclinical models of islet transplantation into the bone marrow

Synthesis of different glutathione–sulfur mustard adducts of verified and potential biomarkers

Sulfur Mustard (SM) is a blistering agent used as a chemical weapon. Glutathione (GSH) is involved in the β-lyase degradation pathway of SM and recently, bioadducts between SM and GSH were observed in vitro. While these bioadducts have never been isolated from in vivo tests or real poisoning with SM, they could be of interest as potential future biomarkers for the retrospective validation of exposure. We herein report the synthesis of different observed and new potential GSH–SM bioadducts as reference materials for analytical investigation. Two distinct approaches were investigated: a building-block pathway and the direct reaction with GSH. The availability of these references will aid future studies and may lead to the discovery of new GSH–SM biomarkers

Total Synthesis and Biological Evaluation of Jerantinine E

The first total synthesis of the alkaloid natural product jerantinine E is based on a selective cyclization of an aminocyclopropane. Preliminary investigations show that it inhibits the polymerization of tubulin, displaying significant cytotoxicity and antimigratory activity against both breast and lung cancer cell lines

Synthesis strategies to extend the variety of alginate-based hybrid hydrogels for cell microencapsulation

The production of hydrogel microspheres (MS) for cell immobilization, maintaining the favorable properties of alginate gels but presenting enhanced performance in terms of in vivo durability and physical properties, is desirable to extend the therapeutic potential of cell transplantation. A novel type of hydrogel MS was produced by straightforward functionalization of sodium alginate (Na-alg) with heterotelechelic poly(ethylene glycol) (PEG) derivatives equipped with either end thiol or 1,2-dithiolane moieties. Activation of the hydroxyl moieties of the alginate backbone in the form of imidazolide intermediate allowed for fast conjugation to PEG oligomers through a covalent carbamate linkage. Evaluation of the modified alginates for the preparation of MS combining fast ionic gelation ability of the alginate carboxylate groups and slow covalentcross-linking provided by the PEG-end functionalities highlighted the influence of the chemical composition of the PEG-grafting units on the physical characteristics of the MS. The mechanical properties of the MS (resistance and shape recovery) and durability of PEG-grafted alginates in physiological environment can be adjusted by varying the nature of the end functionalities and the length of the PEG chains. In vitro cell microencapsulation studies and preliminary in vivo assessment suggested the potential of these hydrogels for cell transplantation applications

Multipotent mesenchymal stromal cells enhance insulin secretion from human islets via N-Cadherin interaction and prolong function of transplanted encapsulated islets in mice

Background: Multipotent mesenchymal stromal cells (MSC) enhance viability and function of islets of Langerhans. We aimed to examine the interactions between human MSC and human islets of Langerhans that influence the function of islets. Methods: Human MSC and human islets (or pseudoislets, obtained after digestion and reaggregation of islet cells) were cocultured with or without cellular contact and glucose-stimulated insulin secretion assays were performed to assess cell function. The expression of several adhesion molecules, notably ICAM-1 and N-cadherin on islets and MSC, was investigated by qPCR. The role of N-cadherin was analyzed by adding an anti-N-cadherin antibody in islets cultured with or without MSC for 24 h followed by insulin measurements in static incubation assays. Islets and MSC were coencapsulated in new hydrogel microspheres composed of calcium alginate and covalently crosslinked polyethylene glycol. Encapsulated cells were transplanted intraperitoneally in streptozotocin-induced diabetic mice and glycemia was monitored. Islet function was evaluated by the intraperitoneal glucose tolerance test. Results: In vitro, free islets and pseudoislets cocultured in contact with MSC showed a significantly increased insulin secretion when compared to islets or pseudoislets cultured alone or cocultured without cell-to-cell contact with MSC (p < 0.05). The expression of ICAM-1 and N-cadherin was present on islets and MSC. Blocking N-cadherin prevented the enhanced insulin secretion by islets cultured in contact with MSC whereas it did not affect insulin secretion by islets cultured alone. Upon transplantation in diabetic mice, islets microencapsulated together with MSC showed significantly prolonged normoglycemia when compared with islets alone (median 69 and 39 days,respectively, p < 0.01). The intraperitoneal glucose tolerance test revealed an improved glycemic response in mice treated with islets microencapsulated together with MSC compared to mice transplanted with islets alone (p < 0.001). Conclusions: MSC improve survival and function of islets of Lan gerhans by cell-to-cell contact mediated by the adhesion molecule N-cadherin