[Synthetic Studies on Small Molecule Natural Products with Neurotrophic Activity].

Neurotrophic factors have been shown to potentially be beneficial for the treatment of neurodegenerative diseases such as Alzheimer's disease, because endogenous neurotrophic factors (NGF, BDNF) have been recognized to play critical roles in the promotion of neurogenesis, differentiation, and neuroprotection throughout the development of the central nervous system. However, high-molecular-weight proteins are unable to cross the blood-brain barrier and are easily decomposed under physiological conditions. Thus, small molecules that can mimic the functions of neurotrophic factors are promising alternatives for the treatment of neurodegenerative disease. Since 1990, the author has been involved in searching for natural products with typical neurotrophic properties that can cause neurogenesis, enhance neurite outgrowth, and protect against neuronal death by using three cellular systems (PC12, rat cortical neurons, and MEB5 cells). Through these research activities on neurotrophic natural products, the author has tried to induce a paradigm shift from the discipline of natural products chemistry to science disciplines. This review focuses on our independent synthetic studies of the neurotrophic natural products discovered in the plants. The following synthetic elaborations are described: syntheses of dimeric isocuparane-type sesquiterpenes mastigophorenes A and B, macrocyclic bis-bibenzyls plagiochins A-D and cavicularin through a Pd-catalyzed Stille-Kelly reaction; the formal synthesis of merrilactone A and jiadifenin, which are seco-prezizaane-type sesquiterpenes, through intramolecular Pd-catalyzed Mizoroki-Heck and Tsuji-Trost reactions; and finally the first enantioselective synthesis of neovibsanin B, a vibsane-type diterpene, through a Pd-catalyzed cyclic carbopalladation-carbonyl tandem reaction.

[Development of Novel Biologically Active Compounds Based on Synthetic Organic Chemistry].

The aging population has had an impact on society in recent decades. Aging-associated health issues are a particularly challenging aspect to regulate. Therefore, the extension of healthy life expectancy by the application of biologically active compounds is an attractive research topic in the fields of medicinal chemistry, chemical biology, and also organic synthesis. Herein, the first total synthesis of acaulide, acaulone A and 10-keto-acaudiol A is described. These compounds were originally isolated from a culture of Acaulium sp. H-JQSF. Acaulide exhibits anti-osteoporosis activity in a prednisolone-induced osteoporotic zebrafish model; hence, this natural product is expected to be a new lead compound for anti-osteoporosis drugs. The characteristic acaulide skeletons were synthesized via late-stage Michael addition inspired by the proposed biosynthetic pathways. The conformational analysis of the 14-membered macrodiolide revealed the specific conformation that enabled the late-stage stereoselective functionalization.

[Development of New Synthetic Methods for Carbazole Compounds Aimed at Drug Discovery and Exploratory Research on Pharmaceutical Materials].

We are developing the synthesis of biologically interesting carbazole compounds, including natural products by tandem cyclic reactions. In this report, we describe the new synthesis of carbazole-1,4-quinones as follows; 1) the synthesis of carbazole-1,4-quinones using a tandem ring closing metathesis (RCM) -dehydrogenation reaction, 2) a novel one-pot synthesis of carbazole-1,4-quinone by consecutive Pd-catalyzed cyclocarbonylation, desilylation, and oxidation reactions. Two new synthetic strategies were applied to the synthesis of carbazole-1,4-quinone alkaloids and ellipticine quinones, and then the antiproliferative activity against HCT-116 and HL-60 cells of the synthesized compounds were evaluated.

[Development of Green Asymmetric Organocatalytic Synthesis].

Organocatalysts, which are less toxic than metal catalysis, as well as inexpensive, environmentally benign, and stable against moisture and oxygen compared to metal-based catalysts, have received considerable attention for being efficient and clean catalysts. With respect to green chemistry, the development of organocatalysis is a significant research subject for a sustainable society. This article reviews studies on the development of novel organocatalysts and the reactions achieved from using them. Focusing on the push-pull ethylene moiety, in which two electron-withdrawing groups (EWGs) were introduced, we proposed that the vinylogous amide proton (N-H) will lead to the design of organocatalysts. We have developed the diaminomethylenemalononitrile (DMM) organocatalysts, which are push-pull ethylenes having two cyano groups as EWGs, and proved that they are effective for highly stereoselective hydrophosphonylation with aldehydes. The catalytic ability of the DMM organocatalyst was demonstrated in the development of the first asymmetric hydrophosphonylation of ketones using organocatalysts. The DMM organocatalyst can be applied to the selective 1,4-addition asymmetric hydrophosphonylation of enones. In addition, we designed and synthesized novel organocatalysts bearing squaramide-sulfonamide motif as multiple hydrogen bond donors. Squaramide-sulfonamide organocatalysts efficiently catalyzed the asymmetric direct vinylogous aldol reactions of furan-2(5H)-one with aldehydes. Successively, we achieved the synthesis of γ,γ-disubstituted-δ-hydroxy-γ-butenolide via asymmetric direct vinylogous aldol reaction of furanone derivatives using the squaramide-sulfonamide organocatalysts.

[Oxidative Deprotection of p-Methoxybenzyl Ethers by a Nitroxyl Radical Catalyst].

The oxidation of p-methoxybenzyl (PMB) ethers was achieved using a nitroxyl radical catalyst 1, which contains electron-withdrawing ester groups adjacent to the nitroxyl group. The oxidative deprotection of the PMB moieties on the hydroxy groups was observed upon treatment of 1 with one equivalent of the co-oxidant phenyl iodonium bis(trifluoroacetate) (PIFA). This system showed an excellent chemoselectivity profile for the deprotection of PMB ethers from a broad range of functional groups including diverse oxidation-sensitive moieties. The corresponding carbonyl compounds were obtained by treating the PMB-protected alcohols with 1 and an excess amount of PIFA.

Size- and Shape-Selective Catalysis with a Functionalized Self-Assembled Cage Host.

A self-assembled Fe4L6 cage with internally oriented carboxylic acid functions was shown to catalyze a variety of dissociative nucleophilic substitution reactions that proceed via oxocarbenium ion or carbocation intermediates. The catalytic behavior of the cage was compared to that of other small acid catalysts, which illustrated large differences in reactivity of the cage-catalyzed reactions, dependent on the structure of the substrate. For example, only a 5% cage confers a 1000-fold rate acceleration of the thioetherification of vinyldiphenylmethanol when compared to the rate with free carboxylic acid surrogates but only a 52-fold acceleration in the formation of small thioacetals. Multiple factors control the variable reactivity in the host, including substrate inhibition, binding affinity, and accessibility of reactive groups once bound. Simple effective concentration increases or the overall charge of the cage does not explain the variations in reactivity shown by highly similar reactants in the host: small differences in structure can have large effects on reactivity. Reaction of large spherical guests is highly dependent on substitution, whereas flat guests are almost unaffected by size and shape differences. The cage is a promiscuous catalyst but has strong selectivity for particular substrate shapes, reminiscent of enzymatic activity.

A Facile Procedure for One-Pot Stable Conjugation of Two Proglucagon Cysteine-Containing Peptide Analogs.

Optimization of peptides for therapeutic purposes often includes chemical conjugation or modification with substituents that serve to broaden pharmacology or improve pharmacokinetics. We report a convenient and rapid procedure for one-pot, site-specific conjugation of two cysteine-containing peptides that utilizes a bivalent linker comprising maleimide and iodoacetyl functional groups. Following maleimide-mediated peptide conjugation the linker was converted from an unstable thiosuccinimide to a stable thioether bond suitable for biological study by mild aqueous hydrolysis. The procedure is exemplified by peptide-peptide, peptide-small molecule, and peptide-fatty acid conjugations. The method provides a facile approach to search for enhanced biological outcomes through additive and sustained peptide pharmacology unencumbered by the prospect of chemical rearrangement in the course of biological study.

Modifications of polysaccharide-based biomaterials under structure-property relationship for biomedical applications.

Polysaccharides are well accepted biomaterials that have attracted considerable attention. Compared with other materials under research, polysaccharides show unique advantages: they are available in nature and are normally easily acquired, those acquired from nature show favorable immunogenicity, and are biodegradable and bioavailable. The bioactivity and possible applications are based on their chemical structure; however, naturally acquired polysaccharides sometimes have unwanted flaws that limit further applications. For this reason, carefully summarizing the possible modifications of polysaccharides to improve them is crucial. Structural modifications can not only provide polysaccharides with additional functional groups but also change their physicochemical properties. This review based on the structure-property relation summarizes the common chemical modifications of polysaccharides, the related bioactivity changes, possible functionalization methods, and major possible biomedical applications based on modified polysaccharides.

Organophotocatalytic selective deuterodehalogenation of aryl or alkyl chlorides.

Development of practical deuteration reactions is highly valuable for organic synthesis, analytic chemistry and pharmaceutic chemistry. Deuterodehalogenation of organic chlorides tends to be an attractive strategy but remains a challenging task. We here develop a photocatalytic system consisting of an aryl-amine photocatalyst and a disulfide co-catalyst in the presence of sodium formate as an electron and hydrogen donor. Accordingly, many aryl chlorides, alkyl chlorides, and other halides are converted to deuterated products at room temperature in air (>90 examples, up to 99% D-incorporation). The mechanistic studies reveal that the aryl amine serves as reducing photoredox catalyst to initiate cleavage of the C-Cl bond, at the same time as energy transfer catalyst to induce homolysis of the disulfide for consequent deuterium transfer process. This economic and environmentally-friendly method can be used for site-selective D-labeling of a number of bioactive molecules and direct H/D exchange of some drug molecules.

Nucleophilic Aromatic Substitution of Polyfluoroarene to Access Highly Functionalized 10-Phenylphenothiazine Derivatives.

Nucleophilic aromatic substitution (SNAr) reactions can provide metal-free access to synthesize monosubstituted aromatic compounds. We developed efficient SNAr conditions for p-selective substitution of polyfluoroarenes with phenothiazine in the presence of a mild base to afford the corresponding 10-phenylphenothiazine (PTH) derivatives. The resulting polyfluoroarene-bearing PTH derivatives were subjected to a second SNAr reaction to generate highly functionalized PTH derivatives with potential applicability as photocatalysts for the reduction of carbon-halogen bonds.

Recent Advances and Trends in Chemical CPP-Drug Conjugation Techniques.

This review summarizes recent developments in conjugation techniques for the synthesis of cell-penetrating peptide (CPP)-drug conjugates targeting cancer cells. We will focus on small organic molecules as well as metal complexes that were used as cytostatic payloads. Moreover, two principle ways of coupling chemistry will be discussed direct conjugation as well as the use of bifunctional linkers. While direct conjugation of the drug to the CPP is still popular, the use of bifunctional linkers seems to gain increasing attention as it offers more advantages related to the linker chemistry. Thus, three main categories of linkers will be highlighted, forming either disulfide acid-sensitive or stimuli-sensitive bonds. All techniques will be thoroughly discussed by their pros and cons with the aim to help the reader in the choice of the optimal conjugation technique that might be used for the synthesis of a given CPP-drug conjugate.

Ruthenium(II)-Catalyzed Direct C7-Selective Amidation of Indoles with Dioxazolones at Room Temperature.

A protocol for the preparation of 7-amido indoles via regioselective C-H bond functionalization has been first accomplished under Ru(II) catalysis. Indole derivatives and 4-aryl/heteroaryl/benzyl/alkyl dioxzaolines containing various substituents were applicable for this transformation, readily providing the amidated indoles in moderate to good yields. This novel process has many advantages, including good compatibility with diverse functional groups, broad substrate scopes, and mild reaction conditions. Deuteration studies and control experiments have been performed to understand the mechanism of this transformation.

Comparative Chiral Separation of Thalidomide Class of Drugs Using Polysaccharide-Type Stationary Phases with Emphasis on Elution Order and Hysteresis in Polar Organic Mode.

The enantioseparation of four phthalimide derivatives (thalidomide, pomalidomide, lenalidomide and apremilast) was investigated on five different polysaccharide-type stationary phases (Chiralpak AD, Chiralpak AS, Lux Amylose-2, Chiralcel OD and Chiralcel OJ-H) using neat methanol (MeOH), ethanol (EtOH), 1-propanol (PROP), 2-propanol (IPA) and acetonitrile (ACN) as polar organic mobile phases and also in combination. Along with the separation capacity of the applied systems, our study also focuses on the elution sequences, the effect of mobile phase mixtures and the hysteresis of retention and selectivity. Although on several cases extremely high resolutions (Rs > 10) were observed for certain compounds, among the tested conditions only Chiralcel OJ-H column with MeOH was successful for baseline-separation of all investigated drugs. Chiral selector- and mobile-phase-dependent reversals of elution order were observed. Reversal of elution order and hysteresis of retention and enantioselectivity were further investigated using different eluent mixtures on Chiralpak AD, Chiralcel OD and Lux Amylose-2 column. In an IPA/MeOH mixture, enantiomer elution-order reversal was observed depending on the eluent composition. Furthermore, in eluent mixtures, enantioselectivity depends on the direction from which the composition of the eluent is approached, regardless of the eluent pair used on amylose-based columns. Using a mixture of polar alcohols not only the selectivities but the enantiomer elution order can also be fine-tuned on Chiralpak AD column, which opens up the possibility of a new type of chiral screening strategy.

Spatial modeling and dynamics of organic matter biodegradation in the absence or presence of bacterivorous grazing.

Biodegradation is a pivotal natural process for elemental recycling and preservation of an ecosystem. Mechanistic modeling of biodegradation has to keep track of chemical elements via stoichiometric theory, under which we propose and analyze a spatial movement model in the absence or presence of bacterivorous grazing. Sensitivity analysis shows that the organic matter degradation rate is most sensitive to the grazer's death rate when the grazer is present and most sensitive to the bacterial death rate when the grazer is absent. Therefore, these two death rates are chosen as the primary parameters in the conditions of most mathematical theorems. The existence, stability and persistence of solutions are proven by applying linear stability analysis, local and global bifurcation theory, and the abstract persistence theory. Through numerical simulations, we obtain the transient and asymptotic dynamics and explore the effects of all parameters on the organic matter decomposition. Grazers either facilitate biodegradation or has no impact on biodegradation, which resolves the "decomposition-facilitation paradox" in the spatial context.

The Activation of Procarcinogens by CYP1A1/1B1 and Related Chemo-Preventive Agents: A Review.

CYP1A1 and CYP1B1 are extrahepatic P450 family members involved in the metabolism of procarcinogens, such as PAHs, heterocyclic amines and halogen-containing organic compounds. CYP1A1/1B1 also participate in the metabolism of endogenous 17-ß-estradiol, producing estradiol hydroquinones, which are the intermediates of carcinogenic semiquinones and quinones. CYP1A1 and CYP1B1 proteins share approximately half amino acid sequence identity but differ in crystal structures. As a result, CYP1A1 and CYP1B1 have different substrate specificity to chemical procarcinogens. This review will introduce the general molecular biology knowledge of CYP1A1/1B1 and the metabolic processes of procarcinogens regulated by these two enzymes. Over the last four decades, a variety of natural products and synthetic compounds which interact with CYP1A1/1B1 have been identified as effective chemo-preventive agents against chemical carcinogenesis. These compounds are mainly classified as indirect or direct CYP1A1/1B1 inhibitors based on their distinct mechanisms. Indirect CYP1A1/1B1 inhibitors generally impede the transcription and translation of CYP1A1/1B1 genes or interfere with the translocation of aryl hydrocarbon receptor (AHR) from the cytosolic domain to the nucleus. On the other hand, direct inhibitors inhibit the catalytic activities of CYP1A1/1B1. Based on the structural features, the indirect inhibitors can be categorized into the following groups: flavonoids, alkaloids and synthetic aromatics, whereas the direct inhibitors can be categorized into flavonoids, coumarins, stilbenes, sulfur containing isothiocyanates and synthetic aromatics. This review will summarize the in vitro and in vivo activities of these chemo-preventive agents, their working mechanisms, and related SARs. This will provide a better understanding of the molecular mechanism of CYP1 mediated carcinogenesis and will also give great implications for the discovery of novel chemo-preventive agents in the near future.

[Total Synthesis of Dictyodendrins].

In total and formal syntheses of dictyodendrins A, B, C, D, E and F, the key step involved the direct construction of the pyrrolo[2,3-c]carbazole core by the gold-catalyzed annulation of a conjugated diyne with a pyrrole to form three bonds and two aromatic rings. The subsequent introduction of substituents at the C1 (Suzuki-Miyaura coupling), C2 (acylation), N3 (alkylation) and C5 positions (Ullmann coupling) provided divergent access to dictyodendrins. Some dictyodendrin analogues exhibited inhibitory activities toward CDK2/CycA2 and GSK3.

Synthesis of a Bolaamphiphilic Alkenyl Phosphonic Acid by Ru-catalyzed Olefin Cross Metathesis Reaction.

We report the synthesis of bolaamphiphilic alkenyl phosphonic acid (BPC12) through the olefin crossmetathesis reaction of vinylphosphonic acid with 1,11-dodecadiene in the presence of a Ru-carbene catalyst. BPC12 possesses two trans-P-C=C moieties and is thus readily soluble in water up to 3.4 g L-1, as confirmed by 1H nuclear magnetic resonance (NMR) measurements. Surface tension measurements revealed that BPC12 reduced the surface tension of water from 72.0 to 47.0 mN m‒1. The occupied area per molecule at the air/water interface (A) of BPC12 (216 Å2) was ten times larger than that of dodecenyl phosphonic acid PC12 (23 Å2). Moreover, dynamic light scattering measurement of an aqueous BPC12 solution (5 mM) revealed the formation of large aggregates with an average diameter of 81.8±27.0 nm.

A Kinetic Investigation of Metal-Dipeptide Complex with Ninhydrin in the Absence and Presence of CTAB Micelles.

This paper presents the results of a kinetic study performed between ninhydrin and a Ni(II) dipeptide complex under various conditions. The rate of formation of the imine adduct was measured spectrophotometrically both in plain aqueous media and in aqueous micellar media in which CTAB (cetyltrimethylammonium bromide) is used as the surfactant. These studies were carried out at pH 5 and over a temperature a range of 50 to 70°C. Studies were also conducted to elucidate the effect of some organic sodium salts on the rate of this reaction. In these studies, it was found that the formation of imine adduct followed a first-order kinetics with respect to [Ni(II)-Gly-Leu]+ in both aqueous and micellar medium. A fractional-order kinetics was observed with respect to ninhydrin, again in both aqueous and micellar media. Increase in the total concentration of CTAB from 0 to 40×10-3 mol dm-3 resulted in approximately two folds increase in the pseudo-first-order rate constant (kψ). The rate constant (kΨ) in micellar medium first increased with increase in CTAB concentration, reached a maximum value, and finally, with further increase in CTAB concentration, a decreasing effect was observed. Quantitative kinetic analysis of kψ-[CTAB] data was performed on the basis of the pseudo-phase model of the micelles. The rate profile in presence of CTAB suggests a cooperative effect in the enhanced formation of the imine adduct as is commonly found in enzyme catalyzed reactions. Addition of organic sodium salts (such as benzoate, salicylate and tosylate) enhanced the rate at lower concentrations but rates start to decrease at higher concentrations. This suggests that tightly binding organic counter-anions were the most effective. Viscosity of the reaction media seems to affect the kinetic behavior in micellar media.

Asymmetric Synthesis of Tertiary α -Hydroxyketones by Enantioselective Decarboxylative Chlorination and Subsequent Nucleophilic Substitution.

Chiral tertiary α-hydroxyketones were synthesized with high enantiopurity by asymmetric decarboxylative chlorination and subsequent nucleophilic substitution. We recently reported the asymmetric decarboxylative chlorination of ß-ketocarboxylic acids in the presence of a chiral primary amine catalyst to obtain α-chloroketones with high enantiopurity. Here, we found that nucleophilic substitution of the resulting α-chloroketones with tetrabutylammonium hydroxide yielded the corresponding α-hydroxyketones without loss of enantiopurity. The reaction proceeded smoothly even at a tertiary carbon. The proposed method would be useful for the preparation of chiral tertiary alcohols.