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Large, macrocyclic peptides can achieve surprisingly high membrane permeability, although the properties that govern permeability in this chemical space are only beginning to come into focus. We generated two libraries of cyclic decapeptides with stable, cross-β conformations, and found that peptoid substitutions within the β-turns of the macrocycle preserved the rigidity of the parent scaffold, whereas peptoid substitutions in the opposing β-strands led to “chameleonic” species that were rigid in nonpolar media but highly flexible in water. Both rigid and chameleonic compounds showed high permeability over a wide lipophilicity range, with peak permeabilities differing significantly depending on scaffold rigidity. Our findings indicate that modulating lipophilicity can be used to engineer favorable ADME properties into both rigid and flexible macrocyclic peptides, and that scaffold rigidity can be used to tune optimal lipophilicity.

Cyclic peptides are of great interest as therapeutic compounds due to their potential for specificity and intracellular activity, but specific compounds can be difficult to identify from large libraries without resorting to molecular encoding techniques. Large libraries of cyclic peptides are often DNA-encoded or linearized before sequencing, but both of those deconvolution strategies constrain the chemistry, assays, and quantification methods which can be used. We developed an automated sequencing program, CycLS, to identify cyclic peptides contained within large synthetic libraries. CycLS facilitates quick and easy identification of all library-members via tandem mass spectrometry data without requiring any specific chemical moieties or modifications within the library. Validation of CycLS against a library of 400 cyclic hexapeptide peptoid hybrids (peptomers) of unique mass yielded a result of 95% accuracy when compared against a simulated library size of 234,256 compounds. CycLS was also evaluated by resynthesizing pure compounds from a separate 1800-member library of cyclic hexapeptides and hexapeptomers with high mass redundancy. Of 22 peptides resynthesized, 17 recapitulated the retention times and fragmentation patterns assigned to them from the whole-library bulk assay results. Implementing a database-matching approach, CycLS is fast and provides a robust method for sequencing cyclic peptides that is particularly applicable to the deconvolution of synthetic libraries.

Macrocyclic peptides are considered large enough to inhibit “undruggable” targets, but the design of passively cell-permeable molecules in this space remains a challenge due to the poorly understood role of molecular size on passive membrane permeability. Using split-pool combinatorial synthesis, we constructed a library of cyclic, per-N-methlyated peptides spanning a wide range of calculated lipohilicities (0 < AlogP < 8) and molecular weights (~800 Da < MW < ~1200 Da). Analysis by the parallel artificial membrane permeability assay revealed a steep drop-off in apparent passive permeability with increasing size in stark disagreement with current permeation models. This observation, corroborated by a set of natural products, helps define criteria for achieving permeability in larger molecular size regimes and suggests an operational cutoff, beyond which passive permeability is constrained by a sharply increasing penalty on membrane permeation.

Synthetic and natural cyclic peptides provide a testing ground for studying membrane permeability in nontraditional drug scaffolds. Cyclic peptomers, which incorporate peptide and N-alkylglycine (peptoid) residues, combine the stereochemical and geometric complexity of peptides with the functional group diversity accessible to peptoids. We synthesized cyclic peptomer libraries by split-pool techniques, separately permuting side chain and backbone geometry, and analyzed their membrane permeabilities using the parallel artificial membrane permeability assay. Nearly half of the side chain permutations had permeability coefficients (Papp) > 1 × 10–6 cm/s. Some backbone geometries enhanced permeability due to their ability to form more stable intramolecular hydrogen bond networks compared with other scaffolds. These observations suggest that hexameric cyclic peptomers can have good passive permeability even in the context of extensive side chain and backbone variation, and that high permeability can generally ...

Selective peroxisome proliferator-activated receptor gamma (PPARγ) modulators are expected to be a novel class of drugs improving plasma glucose levels without PPARγ-related adverse effects. As a continuation of our studies for (-)-Cercosporamide derivatives as selective PPARγ modulators, we synthesized substituted naphthalene type compounds and identified the most potent compound 15 (EC(50) = 0.94 nM, E(max) = 38%). Compound 15 selectively activated PPARγ transcription and did not activate PPARα and PPARδ. The potassium salt of compound 15 showed a high solubility and a good oral bioavailability (58%). Oral administration of the potassium salt remarkably improved the plasma glucose levels of female Zucker diabetic fatty rats at 1 mg/kg. Moreover, it did not cause a plasma volume increase or a cardiac enlargement in Wistar-Imamichi rats, even at 100 mg/kg.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a potential drug target for treating type 2 diabetes. The selective PPARγ modulators (SPPARMs), which partially activate the PPARγ transcriptional activity, are considered to improve the plasma glucose level with attenuated PPARγ related adverse effects. However, the relationships between desired pharmacological profiles and ligand specific PPARγ transcriptional profiles have been unclear. And there is also little knowledge of how to control ligand specific PPARγ transcriptional profiles. Herein, we present synthesis of novel derivatives containing substituent at naphthalene C3 position of compound 1. The novel derivatives showed various maximal efficacies as PPARγ partial agonist.

The reaction of 2-aryl-2,3-epoxy acylates with Lewis acids was examined in detail. Cyclic 2-aryl-2,3-epoxy acylates afforded the rearranged products via the C2-carbocation intermediates obtained by the C2-cleavage of the oxirane rings. On the other hand, acyclic 2-aryl-2,3-epoxy acylates gave the rearranged products via the phenonium ion intermediates obtained by the C3-cleavage of the oxirane rings. The method was also applied to the synthesis of the optically active benzylic quaternary carbon center.

The reactions of 2-aryl-2,3-epoxy acylates with BF3·Et2O were examined in detail. Trans-2-aryl-2,3-epoxy acylates afforded the rearranged products in good yields via the C2-carbocation intermediates. The reaction was used for constructing the optically active benzylic quaternary carbon center.

Regio- and stereoselective rearrangement reactions of various α,β-epoxy acylates including acyclic, monocyclic and bicyclic systems occurred under a suitable combination of acyl groups (benzoyl, p -nitrobenzoyl, camphanoyl) and Lewis acids (BF 3 ·Et 2 O, MABR).

An efficient pinacol rearrangement mediated by trialkyl orthoformate has been developed. The reactions of various types of diols with a catalytic amount of a Lewis acid in the presence of an ortho ester afforded the rearranged product in good yields via a cyclic ortho ester intermediate. This combined system is applicable not only to cyclic and acyclic tri- and tetra-substituted diols but also to the diols having acid-sensitive acetals.

An efficient pinacol rearrangment mediated by trimethyl orthoformate has been developed. The reactions of various types of diols with catalytic amount of a Lewis acid in the presence of an ortho ester afforded the rearranged product in good yields via a cyclic ortho ester intermediate.

Peroxisome proliferator-activated receptor γ (PPARγ; NR1C3) is known as a key regulator of adipocytogenesis and the molecular target of thiazolidinediones (TZDs), also known as antidiabetic agents. Despite the clinical benefits of TZDs, their use is often associated with adverse effects including peripheral edema, congestive heart failure, and weight gain. Here we report the identification and characterization of a non-thiazolidinedione PPARγ partial agonist, Cerco-A, which is a derivative of the natural product, (-)-cercosporamide. Cerco-A was found to be a binder of the PPARγ ligand-binding domain in a ligand competitive binding assay and showed a unique cofactor recruitment profile compared to rosiglitazone. A crystal structure analysis revealed that Cerco-A binds to PPARγ without direct hydrogen bonding to helix12. In PPARγ transcriptional activation assay and an adipocyte differentiation assay, Cerco-A was a potent partial agonist of PPARγ. After a 14-day oral administration, once per day of Cerco-A in Zucker diabetic fatty (ZDF) rats, an apparent decrease of plasma glucose and triglyceride was observed, as with pioglitazone. To evaluate drug safety, Cerco-A was administered for 13 days orally in non-diabetic Zucker fatty (ZF) rats. Each of the hemodilution parameters (hematocrit, red blood cells number, and hemoglobin), which are considered as undesirable effects of TZDs, was improved significantly compared to pioglitazone. While Cerco-A showed body weight gain, as with pioglitazone, Cerco-A had significantly lower effects on heart and white adipose tissues weight gain. The results suggest that Cerco-A offers beneficial effects on glycemic control with attenuated undesirable side effects.

An efficient pinacol rearrangment mediated by trimethyl orthoformate has been developed. The reactions of various types of diols with catalytic amount of a Lewis acid in the presence of an ortho ester afforded the rearranged product in good yields via a cyclic ortho ester intermediate.

An efficient pinacol rearrangement mediated by trialkyl orthoformate has been developed. The reactions of various types of diols with a catalytic amount of a Lewis acid in the presence of an ortho ester afforded the rearranged product in good yields via a cyclic ortho ester intermediate. This combined system is applicable not only to cyclic and acyclic tri- and tetra-substituted diols but also to the diols having acid-sensitive acetals.

Regio- and stereoselective rearrangement reactions of various α,β-epoxy acylates including acyclic, monocyclic and bicyclic systems occurred under a suitable combination of acyl groups (benzoyl, p -nitrobenzoyl, camphanoyl) and Lewis acids (BF 3 ·Et 2 O, MABR).

The reactions of 2-aryl-2,3-epoxy acylates with BF3·Et2O were examined in detail. Trans-2-aryl-2,3-epoxy acylates afforded the rearranged products in good yields via the C2-carbocation intermediates. The reaction was used for constructing the optically active benzylic quaternary carbon center.

A remarkable effect of (C(6)F(5)O)(3)Al for promoting the rearrangement of epoxy acylates via stable cation intermediates was found, and new methods for constructing chiral benzylic, vinylic, and acetylenic quaternary carbon centers were developed. During the study, the importance of the ionic nature of the O-metal bond in the intermediates of such epoxides was addressed. This method was applied to the asymmetric total synthesis of (S)-(+)-sporochnol A.

In an investigation of (-)-Cercosporamide derivatives with a plasma glucose-lowering effect, we found that N-benzylcarboxamide derivative 4 was a partial agonist of PPARgamma. A SAR study of the substituents on carboxamide nitrogen afforded the N-(1-naphthyl)methylcarboxamide derivative 23 as the most potent selective PPARgamma modulator. An X-ray crystallography study revealed that compound 23 bounded to the PPARgamma ligand binding domain in a unique way without any interaction with helix12. Compound 23 displayed a potent plasma glucose-lowering effect in db/db mice without the undesirable increase in body fluid and heart weight that is typically observed when PPARgamma full agonists are administrated.

In our exploratory campaign for an antihyperglycemic agent with a novel mechanism of action, (-)-Cercosporamide 1, which is known as an antifungal agent, showed a potent plasma glucose lowering effect in hyperglycemic KK/Ta mice. The trouble was that it was accompanied by a decrease in food intake and a loss of body weight. We synthesized some (-)-Cercosporamide derivatives and succeeded to separate these actions. N,O-ketal type derivatives, especially compound 10, had the most potent plasma glucose lowering effect without affecting the food consumption or body weight.

In our exploratory campaign for an antihyperglycemic agent with a novel mechanism of action, (-)-Cercosporamide 1, which is known as an antifungal agent, showed a potent plasma glucose lowering effect in hyperglycemic KK/Ta mice. The trouble was that it was accompanied by a decrease in food intake and a loss of body weight. We synthesized some (-)-Cercosporamide derivatives and succeeded to separate these actions. N,O-ketal type derivatives, especially compound 10, had the most potent plasma glucose lowering effect without affecting the food consumption or body weight.

A remarkable effect of (C(6)F(5)O)(3)Al for promoting the rearrangement of epoxy acylates via stable cation intermediates was found, and new methods for constructing chiral benzylic, vinylic, and acetylenic quaternary carbon centers were developed. During the study, the importance of the ionic nature of the O-metal bond in the intermediates of such epoxides was addressed. This method was applied to the asymmetric total synthesis of (S)-(+)-sporochnol A.

The reaction of 2-aryl-2,3-epoxy acylates with Lewis acids was examined in detail. Cyclic 2-aryl-2,3-epoxy acylates afforded the rearranged products via the C2-carbocation intermediates obtained by the C2-cleavage of the oxirane rings. On the other hand, acyclic 2-aryl-2,3-epoxy acylates gave the rearranged products via the phenonium ion intermediates obtained by the C3-cleavage of the oxirane rings. The method was also applied to the synthesis of the optically active benzylic quaternary carbon center.

A testing apparatus for inspecting the beams formed by a multisource module (MSM) was built for the feasibility study of a beam splitting array (BSA), a multielectron beam system the authors are developing. In this BSA, the MSM plays the following three key roles: splitting the beam from a single cathode into 32×32 beams, converging the 32×32 beams, and blanking them individually. Accordingly, the inspection of all beams formed by the MSM is essential for the feasibility study of the system. The testing apparatus was therefore designed for measuring all the beams formed by the MSM without demagnifying them. To maintain the accuracy during the inspection of all 32×32 beams, the measurement process was automated. This testing apparatus was used to measure the diameters and misalignments of all beams formed by a prototype MSM. As a result, the mean values of the transverse and the longitudinal diameters were found to be 0.88 and 0.92μm, respectively. A single stigmator can cancel the difference between these...

Photo-stabilization and solubilization of an aldose reductase inhibitor, (E) -3-carboxymethyl-5- [(2E) -methyl-3-phenylpropenylidene] rhodanine (ONO-2235), by human serum albumin (HSA) were investigated in aqueous solution. ONO-2235 dissolved in pH 7.4 phosphate buffer was photostabilized by a factor of about 150 in the presence of a 5-fold excess of HSA per mole of the drug. The solubilities of ONO-2235 in the buffer and distilled water were increased about 17-fold and 57-fold, respectively, by the presence of 6 ×10-4 M or more HSA. The binding parameters for the interaction between ONO-2235 and HSA were determined from equilibrium dialysis data. These results indicate the usefulness of HSA as a drug additive.