The total synthesis of FD–895 was completed through a strategy that featured the use of a tandem esterification ring–closing metathesis (RCM) process to construct the 12–membered macrolide and a modified Stille coupling to append the side chain. These studies combined with detailed analysis of all four possible C16–C17 stereoisomers, was used to confirm the structure of FD–895 and identify an analog with an enhanced sub-nanomolar bioactivity.

Separate areas of differing polarity in the structure of an inorganic cluster compound are favored by the introduction of organic ligands on the periphery of the aggregate. This has been demonstrated by the synthesis of compounds containing the title anion (see picture for an example).

Adenosine is an ubiquitous local modulator that regulates various physiological and pathological functions by stimulating four membrane receptors, namely A(1), A(2A), A(2B), and A(3). Among these G protein-coupled receptors, the A(3) subtype is found mainly in the lung, liver, heart, eyes, and brain in our body. It has been associated with cerebroprotection and cardioprotection, as well as modulation of cellular growth upon its selective activation. On the other hand, its inhibition by selective antagonists has been reported to be potentially useful in the treatment of pathological conditions including glaucoma, inflammatory diseases, and cancer. In this review, we focused on the pharmacology and the therapeutic implications of the human (h)A(3) adenosine receptor (AR), together with an overview on the progress of hA(3) AR agonists, antagonists, allosteric modulators, and radioligands, as well as on the recent advances pertaining to the computational approaches (e.g., quantitative structure-activity relationships, homology modeling, molecular docking, and molecular dynamics simulations) applied to the modeling of hA(3) AR and drug design.

In this report, we describe the discovery of a pair of bioactive spirotetronates, spirohexenolides A (1) and B (2), that arose from the application of mutagenesis, clonal selection techniques, and media optimization to strains of Streptomyces platensis. The structures of spirohexenolides A (1) and B (2) were elucidated through X-ray crystallography and confirmed by 1D and 2D NMR studies. Under all examined culture conditions, spirohexenolide A (1) was the major metabolite with traces of spirohexenolide B (2) arising in cultures containing increased loads of adsorbent resins. Spirohexenolide A (1) inhibited tumor cell growth with GI(50) values spanning from 0.1 to 17 microM across the NCI 60 cell line panel. An increased activity was observed in leukemia (GI(50) value of 254 nM in RPMI-8226 cells), lung cancer (GI(50) value of 191 nM in HOP-92 cells), and colon cancer (GI(50) value of 565 nM in SW-620 cells) tumor cells. Metabolite 1 was fluorescent and could be examined on a confocal fluorescent microscope with conventional laser excitation and filter sets. Time lapse imaging studies indicated that spirohexenolide A (1) was readily taken up by tumor cells, appearing through the cell immediately after dosing and subcellularly localizing in the lysosomes. This activity, combined with a unique selectivity in NCI 60 cancer cell line screening, indicates that 1 warrants further chemotherapeutic evaluation.

No abstract