Design, synthesis, and biological evaluation of diminutive forms of (+)-spongistatin 1: lessons learned.

The design, synthesis, and biological evaluation of two diminutive forms of (+)-spongistatin 1, in conjunction with the development of a potentially general design strategy to simplify highly flexible macrocyclic molecules while maintaining biological activity, have been achieved. Examination of the solution conformations of (+)-spongistatin 1 revealed a common conformational preference along the western perimeter comprising the ABEF rings. Exploiting the hypothesis that the small-molecule recognition/binding domains are likely to comprise the conformationally less mobile portions of a ligand led to the design of analogues, incorporating tethers (blue) in place of the CD and the ABCD components of the (+)-spongistatin 1 macrolide, such that the conformation of the retained (+)-spongistatin 1 skeleton would mimic the assigned solution conformations of the natural product. The observed nanomolar cytotoxicity and microtubule destabilizing activity of the ABEF analogue provide support for both the assigned solution conformation of (+)-spongistatin 1 and the validity of the design strategy.

Spongipyran Synthetic Studies. Evolution of a Scalable Total Synthesis of (+)-Spongistatin 1.

Three syntheses of the architecturally complex, cytotoxic marine macrolide (+)-spongistatin 1 (1) are reported. Highlights of the first-generation synthesis include: use of a dithiane multicomponent linchpin coupling tactic for construction of the AB and CD spiroketals, and their union via a highly selective Evans boron-mediated aldol reaction en route to an ABCD aldehyde; introduction of the C(44)-C(51) side chain via a Lewis acid-mediated ring opening of a glucal epoxide with an allylstannane to assemble the EF subunit; and final fragment union via Wittig coupling of the ABCD and EF subunits to form the C(28)-C(29) olefin, followed by regioselective Yamaguchi macrolactonization and global deprotection. The second- and third- generation syntheses, designed with the goal of accessing one gram of (+)-spongistatin 1 (1), maintain both the first-generation strategy for the ABCD aldehyde and final fragment union, while incorporating two more efficient approaches for construction of the EF Wittig salt. The latter combine the original chelation-controlled dithiane union of the E- and F-ring progenitors with application of a highly efficient cyanohydrin alkylation to append the F-ring side chain, in conjunction with two independent tactics to access the F-ring pyran. The first F-ring synthesis showcases a Petasis-Ferrier union/rearrangement protocol to access tetrahydropyrans, permitting the preparation of 750 mgs of the EF Wittig salt, which in turn was converted to 80 mg of (+)-spongistatin 1, while the second F-ring strategy, incorporates an organocatalytic aldol reaction as the key construct, permitting completion of 1.009 g of totally synthetic (+)-spongistatin 1 (1). A brief analysis of the three syntheses alongside our earlier synthesis of (+)-spongistatin 2 is also presented.

The anti-ischemia agent ranolazine promotes the development of intestinal tumors in APC(Min/+) mice.

Ranolazine was shown to improve exercise parameters in patients with chronic angina. It works by switching myocardial energy metabolism from fatty acids to glucose, thus increasing the efficiency of ATP production under hypoxic conditions. Tumors are hypoxic and may also respond to ranolazine. We found that ranolazine caused a dose-dependent increase in tumor number in APC(Min/+) mice, a model of spontaneous intestinal tumorigenesis. Tumors from drug-treated mice were also more dysplastic and invasive than those from untreated mice. These findings have implications for the use of ranolazine in patients with a history of malignant neoplasms or adenomatous polyps.

Cyclopropane structural units from homoaldol adducts.

[reaction: see text] An efficient two-step homologation of aldehydes to cyclopropylaldehydes has been developed. Activation of homoaldol adducts derived from O-enecarbamates and N-enecarbamates provided high yields of cyclopropylaldehydes with good to excellent levels of trans/cis selectivity. Trapping of the intermediate oxonium ion and iminium ion intermediates has also been demonstrated, leading to direct isolation of cyclopropyl carbinol and cyclopropylamine products.

In vitro and in vivo anticancer activity of (+)-spongistatin 1.

The marine natural product (+)-spongistatin 1 is an extremely potent growth inhibitory agent having activity against a wide variety of cancer cell lines, while exhibiting low cytotoxicity against quiescent human fibroblasts. Consistent with a microtubule-targeting mechanism of action, (+)-spongistatin 1 causes mitotic arrest in DU145 human prostate cancer cells. More importantly, (+)-spongistatin 1 exhibits significant in vivo antitumor activity in the LOX-IMVI human melanoma xenograft model. (+)-Spongistatin 1 is, thus, an important class of microtubule targeting anticancer agent that warrants further investigation.

Design, synthesis, and biological evaluation of EF- and ABEF- analogues of (+)-spongistatin 1.

The design, synthesis, and biological evaluation of two potential (+)-spongistatin 1 analogues have been achieved. The analogues, incorporating tethers (red) in place of the ABCD and the CD components of the (+)-spongistatin 1 macrolide, were designed such that the conformations of the retained skeleton (blue) would mimic the assigned major solution conformation of the natural product The nanomolar cytotoxicity observed for the ABEF analogue provides strong support for the assigned solution conformation.

Gram-scale synthesis of (+)-spongistatin 1: development of an improved, scalable synthesis of the F-ring subunit, fragment union, and final elaboration.

In a quest to develop an effective, scalable synthesis of (+)-spongistatin 1 ( 1), we devised a concise, third-generation scalable synthesis of (+)- 7, the requisite F-ring tetrahydropyran aldehyde, employing a proline-catalyzed cross-aldol reaction. Subsequent elaboration to (+)-EF Wittig salt (+)- 3, followed by union with advanced ABCD aldehyde (-)- 4, macrolactonization and global deprotection permitted access to >1.0 g of totally synthetic (+)-spongistatin 1 ( 1).