Discodermolide is a potentially important antitumor agent that stabilizes microtubules and blocks cells at the G2/M phase of the cell cycle in a manner similar to that of Taxol. Discodermolide also has unique properties that distinguish it from Taxol. In the present study, photoaffinity-labeled discodermolide analogues are used to investigate their binding site in tubulin. Three photoaffinity-labeled discodermolide analogues were synthesized, all of which promoted microtubule polymerization in the absence of GTP. The analogue, C19-[4-(4-(3)H-benzoyl-phenyl)-carbamate]-discodermolide (C19-[3H]BPC-discodermolide), was selected for photolabeling studies because it had the highest extent of photoincorporation, approximately 1%, of the three radiolabeled discodermolide analogues explored. Although compared to discodermolide, C19-BPC-discodermolide revealed no hypernucleation effect in the in vitro microtubule polymerization assay, it was more cytotoxic than discodermolide, and, like discodermolide, demonstrated synergism with Taxol. These results suggest that the hypernucleation effect of discodermolide is not involved in its cytotoxic activity. Similar to discodermolide, C19-BPC-discodermolide can effectively displace [3H]Taxol from microtubules, but Taxol cannot effectively displace C19-[3H]BPC-discodermolide binding. Discodermolide can effectively displace C19-[3H]BPC-discodermolide binding. Formic acid hydrolysis, immunoprecipitation experiments, and subtilisin digestion indicate that C19-BPC-discodermolide labels amino acid residues 305-433 in beta-tubulin. Further digestion with Asp-N and Arg-C enzymes suggested that C19-BPC-discodermolide binds to amino acid residues, 355-359, in beta-tubulin, which is in close proximity to the Taxol binding site. Molecular modeling guided by the above evidence led to a putative binding model for C19-BPC-discodermolide in tubulin.

A plausible origin of biomolecular homochirality is advanced, where alpha-methyl amino acids found on meteorites transfer their chirality in the synthesis of normal amino acids. This asymmetry can be amplified to nearly homochiral levels, thus providing the necessary prerequisite for life to start on this planet and elsewhere in the universe.

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A convergent synthesis of (-)-2-epi-Peloruside A has been achieved. Highlights include implementation of multicomponent Type I Anion Relay Chemistry (ARC) to unite 2-TBS-1,3-dithiane with two epoxides to construct the eastern hemisphere, a late-stage dithiane union to secure the complete, fully functionalized carbon backbone, and Yamaguchi macrolactonization, which led to (-)-2-epi-peloruside A via an unexpected epimerization at C(2).*E-mail: smithab@sas.upenn.edu. Supporting Information Available Spectroscopic and analytical data for compounds 6-28 and selected experimental and computational procedures. This material is available free of charge via the internet at http://pubs.acs.org. In 2000 Northcote and co-workers reported the isolation and relative stereochemistry of (+)-peloruside A (1), 1 an architecturally complex marine metabolite produced by the sponge Mycale (Carmia). Although a microtubule-stabilizing agent with potency similar to Taxol, 2 recent studies reveal that (+)-peloruside A competes competitively for the laulimalide binding site, at a newly discovered microtubule site. 3 NIH Public AccessOur interest in (+)-peloruside A (1) emanated from the synthetic challenge, in conjunction with the opportunity to showcase the synthetic utility of dithiane linchpin tactics, in particular the use of the three-component union of trialkylsilyl dithianes with diverse electrophiles, a synthetic tactic we now recognize as Type I Anion Relay Chemistry (ARC). 4Structurally (+)-peloruside A (1) is comprised of 10-stereogenic centers, a Z-trisubstituted olefin, and a six-membered hemi-ketal ring, inscribed in a 16-membered macrolactone. Not surprisingly, the structural complexity, interesting biological activity, and scarcity, has led to considerable interest from both the chemical 5 and biological communities. 6In 2003, De Brabander and co-workers 7 achieved an elegant total synthesis of unnatural (−)-peloruside A, thus permitting assignment of the absolute configuration. Shortly thereafter (2005), the Taylor group 8 reported the first total synthesis of natural (+)-peloruside A, followed in 2008 by a second total synthesis from the Ghosh laboratory. 9 We report here completion of the total synthesis of (−)-2-epi-peluroside A (28, Scheme 5), the result of a surprising, late stage epimerization (vide infra) that procluded access to (+)-peloruside A (1).Shortly after the report by Northcote and co-workers, 1 we initiated a synthetic venture directed toward the total synthesis of (+)-peloruside A (1). 10 Our endgame strategy called for formation of the inscribed tetrahydropyran ring after macrocyclization (Scheme 1). Central to this scenario was a flexible route that would permit either acid or alcohol activation to achieve macrolactonization. Taken together, (+)-peloruside A (1) was envisioned to arise from macrolide 2 upon removal of the dithiane and isopropylidene protecting groups. To construct the macrolactone precursor, we would employ union of a dithiane 3 with aldehyde 4, followed by appropriate funct...

Chiral polyamines can be utilized for a variety of potential applications, ranging from asymmetric catalysis to nonviral gene delivery systems for DNA and RNA. They can also be utilized to solubilize carbon nanotubes. Thus, methods for the straightforward synthesis of chiral polyamines are needed. We present herein two synthetic strategies for accessing chiral polyamines. The potential of these chiral amines to catalyze two organic reactions with a high degree of chiral induction was also explored. Text: Chiral polyamines have been utilized for a variety of applications. First, polyamines are polycationic at neutral pH; as such, they interact strongly with both DNA and RNA.1 They can therefore be utilized as effective nonviral gene delivery agents.2 Second, chiral polyamines are efficient catalysts for various organic transformations.3 Polyamines have also been used to solubilize carbon nanotubes.4 Finally, chiral polyamines are excellent ligands for many transition metals.5 Due to their numerous applications, high-yielding synthetic strategies for their preparation are in great demand. We present herein two synthetic strategies for accessing chiral polyamines, and the potential of these chiral amines to catalyze two organic reactions.

PAMAM dendrimers have been constructed with a pyridoxamine core, and chiral capping amino groups. Transamination to form phenylalanine and alanine from their related ketoacids produced enantioselectivities induced by the formally remote chiral caps, supporting computer models that indicate folding of the dendrimer chains back into the core region.

The design, synthesis, and evaluation of a series of catechol-based non-peptide peptidomimetics of the peptide hormone somatostatin have been achieved. These ligands comprise the simplest known non-peptide mimetics of the i + 1 and i + 2 positions of the somatostatin beta-turn. Incorporation of an additional side chain to include the i position of the beta-turn induces a selective 9-fold affinity enhancement at the sst2 receptor.

The design, synthesis and structural analysis of two macrocyclic D,L-alternating hexapyrrolinones has been achieved. These cyclic peptide mimics adopt a flat, hexagonal conformation, stabilized by intramolecular hydrogen bonding between adjacent pyrrolinone rings. Extensive NMR studies and X-ray analysis reveal respectively that the macrocyclic hexapyrrolinones aggregate in solution, and in the solid state form staggered stacked nanotube-like assemblies.