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An efficient and practical method for the synthesis of (9R,14R,17R)-FE399, a novel antitumor bicyclic depsipeptide, was developed. A 2-methyl-6-nitrobenzoic anhydride (MNBA)-mediated dehydration condensation reaction was effectively employed for the formation of the 16-membered macrocyclic depsipeptide moiety of FE399. FE399 was found to exist as an inseparable equilibrium mixture of conformational isomers; the mixture was quantitatively transformed into the corresponding S-benzyl product and isolated as a single isomer. Thus, we could confirm that the molecular structure of FE399 obtained by this method is identical to that of the natural product.

The first total synthesis of violaceoid A, a cytotoxic agent, and the asymmetric total synthesis of (-)- and (+)-violaceoid B are reported. The precursor was accessed by desymmetrization of a substituted quinol moiety, and the racemic secondary alcohol was kinetically resolved using a chiral nucleophilic catalyst. The asymmetric synthesis of (-)- and (+)-violaceoid B elucidated the absolute configuration of the naturally occurring violaceoid B. Synthetic violaceoid A inhibited the growth of human breast cancer cell lines MCF-7 and Hs 578T at concentrations of less than 100 μM, while ( S)- and ( R)-violaceoid B were inactive.

In this paper, we report the first total synthesis of (+)-coprophilin, an anticoccidial agent, by constructing the chiral linear precursor via a Mukaiyama–Evans aldol reaction and a stereoselective intramolecular Diels–Alder reaction. The proposed method can be used to provide large amounts of (+)-coprophilin, which exhibits a 3,4,5,6,7-pentasubstituted Δ1,2-octalin core structure.

An efficient acylative kinetic resolution of racemic aromatic β-hydroxy esters with cyclohexanecarboxylic anhydride was achieved using newly designed (R)-N-methylbenzoguanidine ((R)-NMBG) derivatives. A series of (R)-NMBG derivatives was synthesized by modifying the original (R)-NMBG catalyst with the introduction of branched N-substituents containing a stereogenic center, and their catalytic performance was evaluated. (R,R)-N-(1-(β-1-Naphthyl)ethyl)benzoguanidine [(R,R)-NβNpEtBG] was found to function as an efficient acyl transfer catalyst for the reaction of a broad variety of substrates, regardless of the substituent type and substitution pattern.

Ridaifen-G (RID-G), a tamoxifen analog that we previously synthesized, has potent growth inhibitory activity against various cancer cell lines. Tamoxifen is an anticancer drug known to act on an estrogen receptor (ER) and other proteins. However, our previous studies interestingly suggested that the mechanism of action of RID-G was different from that of tamoxifen. In order to investigate the molecular mode of action of RID-G, we developed a novel chemical genetic approach that combined a phage display screen with a statistical analysis of drug potency and gene expression profiles in thirty-nine cancer cell lines. Application of this method to RID-G revealed that three proteins, calmodulin (CaM), heterogeneous nuclear ribonucleoproteins A2/B1 (hnRNP A2/B1), and zinc finger protein 638 (ZNF638) were the candidates of direct targets of RID-G. Moreover, cell lines susceptible to RID-G show similar expression profiles of RID-G target genes. These results suggest that RID-G involves CaM, hnRNP A2/B1, and ZNF638 in its growth inhibitory activity.

An asymmetric total synthesis of the proposed structure of (16Z,20E)-eushearilide, a novel 24-membered macrolide, was achieved via an enantioselective aldol reaction and 2-methyl-6-nitrobenzoic anhydride-mediated macrolactonization. The obtained synthetic compounds were not identical to the natural product. The newly proposed most likely structure of eushearilide, (±)-(16E,20E)-eushearilide, was determined on the basis of detailed NMR analysis, and (3R,16E,20E,23R)-(−)-eushearilide was successfully synthesized. A comparison of the optical rotation of (3R,16E,20E,23R)-(−)-eushearilide with that of the natural product confirmed that the true structure of naturally occurring eushearilide is the (3S,16E,20E,23S)-(+)-form.

Ridaifen-F (RID-F) potently inhibits proteolytic activities of the 20S proteasome but poorly inhibits those of the 26S proteasome. Here, we report preparation of several conjugates in which various peptides are connected to RID-F. Conjugates with peptides consisting of seven amino acid residues significantly inhibited the 26S proteasome. Particularly, RID-F conjugated to an octaarginine peptide (R8, a so-called cell-penetrating peptide) inhibited intracellular proteasome activities and induced cell death in drug-resistant KMS-11 myeloma cells. RID-F conjugated to hydrophobic peptides also inhibited the 26S proteasome but failed to induce cell death, suggesting poor penetration into cells. We infer that the R8 peptide has dual functions: (1) rapid penetration of conjugates into the cell increases intracellular drug concentrations sufficient for exhibition of its effect, and (2) recognition of the conjugates by the 26S proteasome stimulates drug entry into the catalytic chamber. In the presence of ATPγS, RID-F conjugates containing R8 inhibited the 26S proteasome more potently than in the presence of ATP, suggesting efficient entry of drugs into the catalytic chamber in a similar fashion to the substrate. Taken together with docking simulations of RID-F conjugate interactions with proteasome active sites, the second function of R8 peptide is plausible. Thus, the conjugation of nonpeptidic proteasome inhibitors to a cell-penetrating peptide could represent a viable strategy for overcoming the drug-resistance of tumor cells.

The originally proposed structure of astakolactin was revised, and an asymmetric total synthesis of the newly proposed structure was achieved. The key transformations in the synthesis were a Johnson–Claisen rearrangement, an asymmetric Mukaiyama aldol reaction, and a Mitsunobu-type cyclodehydration. The spectroscopic data and specific rotation of the compound obtained matched well with those reported for naturally occurring astakolactin.

We report an effective dynamic kinetic resolution (DKR) system of racemic 2-(1H-pyrrol-1-yl)alkanoic acids, which consists of a rapid racemization step via an activating substrate and an enantio-di...