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Herein, we report the development of an 18 F-labeled, activity-based small-molecule probe targeting the cancer-associated serine hydrolase NCEH1. We undertook a focused medicinal chemistry campaign to simultaneously preserve potent and specific NCEH1 labeling in live cells and animals, while permitting facile 18 F radionuclide incorporation required for PET imaging. The resulting molecule, [18 F]JW199, labels active NCEH1 in live cells at nanomolar concentrations and greater than 1000-fold selectivity relative to other serine hydrolases. [18 F]JW199 displays rapid, NCEH1-dependent accumulation in mouse tissues. Finally, we demonstrate that [18 F]JW199 labels aggressive cancer tumor cells in vivo, which uncovered localized NCEH1 activity at the leading edge of triple-negative breast cancer tumors, suggesting roles for NCEH1 in tumor aggressiveness and metastasis.

Inhibitors of histone deacetylases (HDACs) are a promising class of anticancer agents that effect gene regulation. To know the interaction of aliphatic cap groups with HDACs, cyclic tetrapeptide and bicyclic peptide disulfide hybrids were synthesized without aromatic ring in their macrocyclic framework. Benzene ring of l -Phe in chlamydocin was replaced with several aliphatic amino acids and also a fused bicyclic tetrapeptide was synthesized by ring closing metathesis using Grubb’s first generation catalyst. The inhibitory activities of the cyclic peptides against histone deacetylase enzymes were evaluated, which demonstrated most of them are interesting candidates as anticancer agents.

A water-soluble l-lysine dendrimer (6) with links to porphyrins and a fullerene was synthesized, in which the dendrimer surface was modified with carboxylate groups. The aqueous solution of 6 showed the Soret band characteristic of the aggregated porphyrins in the UV−vis spectra; however, this aggregate was dissociated by the addition of 2-hydroxypropyl-β-cyclodextrin (10 wt % in H2O). TEM and AFM showed the formation of submicron-scale particles of 6. TEM showed the spherical particles of 6 with almost uniform size (100−110 nm) in the presence of the cyclodextrin. AFM showed the oval particles of 6 in the absence of the cyclodextrin. DLS measurement indicated that cyclodextrin dissociated the aggregated structure of 6 in H2O. Thus, a large number of porphyrins and fullerenes were successfully accumulated with a narrow size distribution via the particle formation of the amphiphilic dendrimer.

[60]-Fullerene functionalized amino acids with 4–6 methylene spacers from α-carbon to the nitrogen atom of fulleropyrolidine and corresponding multifullerene peptides have been synthesized.

The naturally occurring cyclic tetrapeptide, chlamydocin, originally isolated from fungus Diheterospora chlamydosphoria, consists of α-aminoisobutyric acid, l-phenylalanine, d-proline and an unusual amino acid (S)-2-amino-8-((S)-oxiran-2-yl)-8-oxooctanoic acid (Aoe) and inhibits the histone deacetylases (HDACs), a class of regulatory enzymes. The epoxyketone moiety of Aoe is the key functional group for inhibition. The cyclic tetrapeptide scaffold is supposed to play important role for effective binding to the surface of enzymes. In place of the epoxyketone group, hydroxamic acid and sulfhydryl group have been applied to design inhibitor ligands to zinc atom in catalytic site of HDACs. In the research for more potent HDAC inhibitors, we replaced the epoxyketone moiety of Aoe with different functional groups and synthesized a series of chlamydocin analogs as HDAC inhibitors. Among the functional groups, methoxymethylketone moiety showed as potent inhibition as the hydroxamic acid. On the contrary, we confirmed that borate, trifruoromethylketone, and 2-aminoanilide are almost inactive in HDAC inhibition.

Introduction Enantiomerically pure aliphatic amino acids having easily modifiable functional groups at the end of the side chain on α-carbon atom are highly interesting synthetic targets as the terminal functional groups can be changed to the required groups which provide a series of non-poteinogenic amino acids [1]. As the double bond is a masked functional group and is stable to most acidic and basic reaction conditions, the classical reactivity of alkenes towards addition, oxidation, etc., can be used for the side chain modification. So it is worthy to synthesize α-amino acids containing side chains with a terminal double bond, 2-amino-(n-1)-alkenoic acids (Aens). As a precursor, it can be easily converted to various amino acids having different side chain functionality. In fact several methods are available for the synthesis of specific ω-unsaturated α-amino acids [2,3]. Here we report a convenient method, for the synthesis of Boc-2-amino-(n-1)-alkenoic acids (Boc-Aen-OH, n = 5-9) from commercially available reagents, diethyl Boc-aminomalonate and ω-bromoalkenes. We also explored the possibility of their use in the synthesis of some new zinc ligands for chlamydocin type cyclic tetrapeptide scaffold in order to develop histone deacetylase inhibitors as anti-cancer agents with optimized pharmacokinetic properties.

A series of chlamydocin analogs with various carbonyl functionalities were designed and synthesized as histone deacetylase (HDAC) inhibitors. Chlamydocin is a cyclic tetrapeptide containing an epoxyketone surrogate in the side chain which makes it irreversible inhibitor of HDACs, whereas apicidins are a class of cyclic tetrapeptides that contain an ethylketone moiety as zinc ligand. We replaced the epoxyketone moiety of chlamydocin with several ketones and aldehyde to synthesize potent reversible and selective HDAC inhibitors. The inhibitory activity of the cyclic tetrapeptides against histone deacetylase enzymes were evaluated and the result showed most of them are potent inhibitors. Some of them have remarkable selectivity among the HDACs.