(125)I-Labelled 2-Iodoestrone-3-sulfate: synthesis, characterization and OATP mediated transport studies in hormone dependent and independent breast cancer cells.

INTRODUCTION: Organic Anion Transporting Polypeptides (OATP) are a family of membrane associated transporters that facilitate estrone-3-sulphate (E3S) uptake by hormone dependent, post-menopausal breast cancers. We have established E3S as a potential ligand for targeting hormone dependent breast cancer cells, and in this study sought to prepare and investigate radioiodinated E3S as a tool to study the OATP system. METHODS: 2- and 4-Iodoestrone-3-sulfates were prepared from estrone via aromatic iodination followed by a rapid and high yielding sulfation procedure. The resulting isomers were separated by preparative HPLC and verified by (1)H NMR and analytical HPLC. Transport studies of 2- and 4-[(125)I]-E3S were conducted in hormone dependent (i.e. MCF-7) and hormone independent (i.e. MDA-MB-231) breast cancer cells in the presence or absence of the specific transport inhibitor, bromosulfophthalein (BSP). Cellular localization of OATP1A2, OATP2B1, OATP3A1 and OATP4A1 were determined by immunofluorescence analysis using anti-Na(+)/K(+) ATPase-α (1:100 dilution) and DAPI as plasma membrane and nuclear markers, respectively. RESULTS: Significantly (p<0.01) higher total accumulation of 2-[(125)I]-E3S was observed in hormone dependent MCF-7 as compared to hormone independent MDA-MB-231 breast cancer cells. In contrast 4-[(125)I]-E3S did not show cellular accumulation in either case. The efficiency of 2-[(125)I]-E3S transport (expressed as a ratio of Vmax/Km) was 2.4 times greater in the MCF-7 as compared to the MDA-MB-231 breast cancer cells. OATP1A2, OATP3A1 and OATP4A1 expression was localized in plasma membranes of MCF-7 and MDA-MB-231 cells confirming the functional role of these transporters in radioiodinated E3S cellular uptake. CONCLUSION: An efficient method for the preparation of 2- and 4-[(125)I]-E3S was developed and where the former demonstrated potential as an in vitro probe for the OATP system. The new E3S probe can be used to study the OATP system and as a platform to create radiopharmaceuticals for imaging breast cancer.

Bioinspired synthesis of hirsutellones A, B, and C.

The total synthesis of hirsutellones A (1), B (2), and C (3) has been achieved through a bioinspired late-stage sequence starting from advanced intermediate 6. The sequence proceeded via labile intermediate 17,1'-dehydrohirsutellone B (5) and delivered, in addition to the natural products (1-3), hirsutellone analogue 1',2',17-epi-hirsutellone C (1',2',17-epi-3).

Design, synthesis, and biological evaluation of a biyouyanagin compound library.

Modern drug discovery efforts rely, to a large extent, on lead compounds from two classes of small organic molecules; namely, natural products (i.e., secondary metabolites) and designed compounds (i.e., synthetic molecules). In this article, we demonstrate how these two domains of lead compounds can be merged through total synthesis and molecular design of analogs patterned after the targeted natural products, whose promising biological properties provide the motivation. Specifically, the present study targeted the naturally occurring biyouyanagins A and B and their analogs through modular chemical synthesis and led to the discovery of small organic molecules possessing anti-HIV and anti-arenavirus properties.

Modular synthesis of polyphenolic benzofurans, and application in the total synthesis of malibatol a and shoreaphenol.

A modular strategy for the synthesis of hexacyclic dimeric resveratrol polyphenolic benzofurans is reported. The developed synthetic technology was applied to the total synthesis of malibatol A, shoreaphenol, and other biologically relevant poly-phenols.

Total synthesis and biological evaluation of the resveratrol-derived polyphenol natural products hopeanol and hopeahainol A.

The total synthesis and biological evaluation of the resveratrol-derived natural products hopeanol (2) and hopeahainol A (3) in their racemic and antipodal forms are described. The Friedel-Crafts-based synthetic strategy employed was developed from model studies that established the feasibility of constructing the C(7b) quaternary center through an intramolecular Friedel-Crafts reaction and a Grob-type fragmentation to introduce an obligatory olefinic bond in the growing molecule. The final stages of the synthesis involved an epoxide substrate and an intramolecular Friedel-Crafts reaction, followed by oxidation to afford, upon global deprotection, hopeahainol A (3). The latter was converted under basic conditions to hopeanol (2), whereas the reverse transformation, previously suggested as a step in the biosynthesis of hopeahainol A (3), was not observed under a variety of conditions. Biological evaluation of the synthesized compounds confirmed the reported acetylcholinesterase inhibitory activity of hopeahainol A (3) but not the reported cytotoxic potencies of hopeanol (2).

Total synthesis of hopeahainol A and hopeanol.

Similar, but different: Possessing almost the same but not identical structures, the recently discovered natural products hopeahainol A (1) and hopeanol (2) exhibit important but differing biological properties (see structures). Their first total synthesis has now been achieved through a series of novel cascade reactions and skeletal rearrangements.

Total synthesis, revised structure, and biological evaluation of biyouyanagin A and analogues thereof.

Isolated from Hypericum species H. chinese L. var. salicifolium, biyouyanagin A was assigned structure 1a or 1b on the basis of NMR spectroscopic analysis. This novel natural product exhibited significant anti-HIV properties and inhibition of lipopolysaccharide-induced cytokine production. Described herein are the total syntheses of biyouyanagin A and several analogues (3-11), structural revision of biyouyanagin A to 2b, and the biological properties of all synthesized compounds. The total synthesis proceeded through cascade sequences that efficiently produced enantiomerically pure key building blocks 15b (ent-zingiberene) and 18 (hyperolactone C) and featured a novel [2 + 2] photoinduced cycloaddition reaction which occurred with complete regio- and stereoselectivity. Biological investigations with the synthesized biyouyangagins A (2-11) and hyperolactones C (12-16) revealed that the activity of biyouyanagin A most likely resides in its hyperolactone C structural domain.

Asymmetric allylboration of cyclic imines and applications to alkaloid synthesis.

Treatment of cyclic imines with 3,3'-disubstituted binaphthol modified allylboronates provides the expected allylated products in good yields and with high stereoselectivities (91-99% ee). The products may be readily transformed into various alkaloids.

Asymmetric synthesis of propargylamides via 3,3'-disubstituted binaphthol-modified alkynylboronates.

[reaction: see text] Alkynylboronates derived from 3,3'-disubstituted-2,2'-binaphthols react with various N-acylimines to give the expected chiral propargylamides with up to 99% ee. This new methodology was applied to the first enantioselective synthesis of the antitubulin agent (-)-N-acetylcolchinol.

Ligand-catalyzed asymmetric alkynylboration of enones: a new paradigm for asymmetric synthesis using organoboranes.

Asymmetric conjugate alkynylation of enones may be effected using a B-1-alkynyldiisopropylboronate and catalytic amounts of binaphthol ligands. The high enantioselectivities observed are comparable to those obtained using stoichiometric amounts of binaphthol-modified boronate reagents, suggesting that this is a ligand-accelerated process. This is the first demonstration that catalytic amounts of chiral diols can be used with boronates to effect high levels of stereochemical control.

Asymmetric allylboration of aldehydes and ketones using 3,3'-disubstitutedbinaphthol-modified boronates.

Allylboronates derived from 3,3'-disubstituted 2,2'-binaphthols react with aldehydes and ketones to give the expected allylated products with up to >99:1 er. Highest selectivities were observed for aromatic ketones. The bis(trifluoromethyl) derivative is particularly outstanding in terms of reactivity, selectivity, and robustness. [reaction: see text]