Recent Achievements in Total Synthesis for Integral Structural Revisions of Marine Natural Products.

A great effort to discover new therapeutic ingredients is often initiated through the discovery of the existence of novel marine natural products. Since substances produced by the marine environment might be structurally more complex and unique than terrestrial natural products, there have been cases of misassignments of their structures despite the availability of modern spectroscopic and computational chemistry techniques. When it comes to refutation to erroneously or tentatively proposed structures empirical preparations through organic chemical synthesis has the greatest contribution along with close and sophiscated inspection of spectroscopic data. Herein, we analyzed the total synthetic studies that have decisively achieved in revelation of errors, ambiguities, or incompleteness of the isolated structures of marine natural products covering the period from 2018 to 2021.

Synthetic Peucedanocoumarin IV Prevents α-Synuclein Neurotoxicity in an Animal Model of Parkinson's Disease.

Pathological protein inclusion formation and propagation are the main causes of neuronal dysfunction in diverse neurodegenerative diseases; therefore, current disease-modifying therapeutic strategies have targeted this disease protein aggregation process. Recently, we reported that peucedanocoumarin III (PCiii) is a promising therapeutic compound with the ability to disaggregate α-synuclein inclusion and protect dopaminergic neurons in Parkinson's disease (PD). Here, we found that trans-4'-acetyl-3'-tigloylkhellactone (racemic peucedanocoumarin IV [PCiv]), a structural isomer of PCiii with a higher synthetic yield presented a strong anti-aggregate activity to a degree comparable to that of PCiii. PCiv retained effective inhibitory function against ß-sheet aggregate-mimic ß23 cytotoxicities and potently prevented α-synucleinopathy in α-synuclein preformed fibril (PFF)-treated mice cortical neurons. In detailed pharmacokinetic profiling of PCiv, oral administration of PCiv in rats exhibited an approximately 97-min half-life and 10% bioavailability. Moreover, tissue distribution analysis revealed favorable profiles of brain penetration with a 6.4 brain-to-plasma concentration ratio. The therapeutic efficacy of PCiv was further evaluated in a sporadic PD mouse model with a combinatorial co-injection of α-synuclein preformed fibril and recombinant adeno-associated virus expressing α-synuclein. Motor dysfunctions induced in this combinatorial α-synucleinopathy PD mouse model was almost completely rescued by PCiv diet administration, and this therapeutic effect is consistent with the marked prevention of dopaminergic neuron loss and suppression of α-synuclein aggregation. Taken together, our translational study suggests that PCiv is advantageous as a therapeutic agent for neurodegenerative diseases, especially with its good synthetic yield, high brain distribution, and anti-aggregate activity. PCiv may be useful in the management of α-synuclein inclusion formation and propagation at different stages of PD.

Recent Advances in the Synthesis of Ibuprofen and Naproxen.

Herein, we review the recent progress in the synthesis of representative nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen and naproxen. Although these drugs were discovered over 50 years ago, novel practical and asymmetric approaches are still being developed for their synthesis. In addition, this endeavor has enabled access to more potent and selective derivatives from the key frameworks of ibuprofen and naproxen. The development of a synthetic route to ibuprofen and naproxen over the last 10 years is summarized, including developing methodologies, finding novel synthetic routes, and applying continuous-flow chemistry.

Synthesis of Tetrabenazine and Its Derivatives, Pursuing Efficiency and Selectivity.

Tetrabenazine is a US Food and Drug Administration (FDA)-approved drug that exhibits a dopamine depleting effect and is used for the treatment of chorea in Huntington's disease. Mechanistically, tetrabenazine binds and inhibits vesicular monoamine transporter type 2, which is responsible for importing neurotransmitters from the cytosol to the vesicles in neuronal cells. This transportation contributes to the release of neurotransmitters inside the cell to the synaptic cleft, resulting in dopaminergic signal transmission. The highly potent inhibitory activity of tetrabenazine has led to its advanced applications and in-depth investigation of prodrug design and metabolite drug discovery. In addition, the synthesis of enantiomerically pure tetrabenazine has been pursued. After a series of research studies, tetrabenazine derivatives such as valbenazine and deutetrabenazine have been approved by the US FDA. In addition, radioisotopically labeled tetrabenazine permits the early diagnosis of Parkinson's disease, which is difficult to treat during the later stages of this disease. These applications were made possible by the synthetic efforts aimed toward the efficient and asymmetric synthesis of tetrabenazine. In this review, various syntheses of tetrabenazine and its derivatives have been summarized.

Design and Synthesis of Anti-Cancer Chimera Molecules Based on Marine Natural Products.

In this paper, the chemical conjugation of marine natural products with other bioactive molecules for developing an advanced anti-cancer agent is described. Structural complexity and the extraordinary biological features of marine natural products have led to tremendous research in isolation, structural elucidation, synthesis, and pharmacological evaluation. In addition, this basic scientific achievement has made it possible to hybridize two or more biologically important skeletons into a single compound. The hybridization strategy has been used to identify further opportunities to overcome certain limitations, such as structural complexity, scarcity problems, poor solubility, severe toxicity, and weak potency of marine natural products for advanced development in drug discovery. Further, well-designed marine chimera molecules can function as a platform for target discovery or degradation. In this review, the design, synthesis, and biological evaluation of recent marine chimera molecules are presented.

Therapeutic Evaluation of Synthetic Peucedanocoumarin III in an Animal Model of Parkinson's Disease.

The motor and nonmotor symptoms of Parkinson's disease (PD) correlate with the formation and propagation of aberrant α-synuclein aggregation. This protein accumulation is a pathological hallmark of the disease. Our group recently showed that peucedanocoumarin III (PCIII) possesses the ability to disaggregate ß sheet aggregate structures, including α-synuclein fibrils. This finding suggests that PCIII could be a therapeutic lead compound in PD treatment. However, the translational value of PCIII and its safety information have never been explored in relevant animal models of PD. Therefore, we first designed and validated a sequence of chemical reactions for the large scale organic synthesis of pure PCIII in a racemic mixture. The synthetic PCIII racemate facilitated clearance of repeated ß sheet aggregate (ß23), and prevented ß23-induced cell toxicity to a similar extent to that of purified PCIII. Given these properties, the synthetic PCIII's neuroprotective function was assessed in 6-hydroxydopamine (6-OHDA)-induced PD mouse models. The PCIII treatment (1 mg/kg/day) in a 6-OHDA-induced PD mouse model markedly suppressed Lewy-like inclusions and prevented dopaminergic neuron loss. To evaluate the safety profiles of PCIII, high dose PCIII (10 mg/kg/day) was administered intraperitoneally to two-month-old mice. Following 7 days of PCIII treatment, PCIII distributed to various tissues, with substantial penetration into brains. The mice that were treated with high dose PCIII had no structural abnormalities in the major organs or neuroinflammation. In addition, high dose PCIII (10 mg/kg/day) in mice had no adverse impact on motor function. These findings suggest that PCIII has a relatively high therapeutic index. Given the favorable safety features of PCIII and neuroprotective function in the PD mouse model, it may become a promising disease-modifying therapy in PD to regulate pathogenic α-synuclein aggregation.

Investigation of Grignard Reagent as an Advanced Base for Aza-Claisen Rearrangement.

Employing iPrMgCl as an advanced base instead of lithium hexamethyldisilazane (LHMDS) resulted in dramatic improvements in aza-Claisen rearrangement. This advance is considered responsible for the increased bulkiness of the alkoxide moiety (including magnesium cation and ligands), followed by a resultant conformational change of the transition state. To support this hypothesis, various substrates of aza-Claisen rearrangement were prepared and screened. In addition, a molecular dynamic simulation study was performed to investigate and compare the structural stability of reaction intermediates.

Direct and Indirect Targeting of PP2A by Conserved Bacterial Type-III Effector Proteins.

Bacterial AvrE-family Type-III effector proteins (T3Es) contribute significantly to the virulence of plant-pathogenic species of Pseudomonas, Pantoea, Ralstonia, Erwinia, Dickeya and Pectobacterium, with hosts ranging from monocots to dicots. However, the mode of action of AvrE-family T3Es remains enigmatic, due in large part to their toxicity when expressed in plant or yeast cells. To search for targets of WtsE, an AvrE-family T3E from the maize pathogen Pantoea stewartii subsp. stewartii, we employed a yeast-two-hybrid screen with non-lethal fragments of WtsE and a synthetic genetic array with full-length WtsE. Together these screens indicate that WtsE targets maize protein phosphatase 2A (PP2A) heterotrimeric enzyme complexes via direct interaction with B' regulatory subunits. AvrE1, another AvrE-family T3E from Pseudomonas syringae pv. tomato strain DC3000 (Pto DC3000), associates with specific PP2A B' subunit proteins from its susceptible host Arabidopsis that are homologous to the maize B' subunits shown to interact with WtsE. Additionally, AvrE1 was observed to associate with the WtsE-interacting maize proteins, indicating that PP2A B' subunits are likely conserved targets of AvrE-family T3Es. Notably, the ability of AvrE1 to promote bacterial growth and/or suppress callose deposition was compromised in Arabidopsis plants with mutations of PP2A genes. Also, chemical inhibition of PP2A activity blocked the virulence activity of both WtsE and AvrE1 in planta. The function of HopM1, a Pto DC3000 T3E that is functionally redundant to AvrE1, was also impaired in specific PP2A mutant lines, although no direct interaction with B' subunits was observed. These results indicate that sub-component specific PP2A complexes are targeted by bacterial T3Es, including direct targeting by members of the widely conserved AvrE-family.

Recent Synthesis and Discovery of Brefeldin A Analogs.

The recent development of analogs of brefeldin A (BFA), a fungal metabolite, for the improvement of BFA apoptosis-inducing activity is described. BFA has been isolated from various soil or, more recently, marine fungi and has shown versatile beneficial activities. More importantly, the apoptosis-inducing activity of BFA in cancer cells highlights the possibility of further developing this natural product as an anticancer agent. Besides its biological importance, its structural features have also gathered tremendous interest from both medicinal and synthetic chemists. By a medicinal chemistry and total synthesis approach, numerous analogs from BFA have been developed to improve its inferior bioavailability and its antiproliferative ability. In this review, the recent medicinal chemistry efforts in relation to the production of BFA analogs are extensively presented.

Structure-Based Classification and Anti-Cancer Effects of Plant Metabolites.

A variety of malignant cancers affect the global human population. Although a wide variety of approaches to cancer treatment have been studied and used clinically (surgery, radiotherapy, chemotherapy, and immunotherapy), the toxic side effects of cancer therapies have a negative impact on patients and impede progress in conquering cancer. Plant metabolites are emerging as new leads for anti-cancer drug development. This review summarizes these plant metabolites with regard to their structures and the types of cancer against which they show activity, organized by the organ or tissues in which each cancer forms. This information will be helpful for understanding the current state of knowledge of the anti-cancer effects of various plant metabolites against major types of cancer for the further development of novel anti-cancer drugs.

Construction of the Azacyclic Core of Tabernaemontanine-Related Alkaloids via Tandem Reformatsky-Aza-Claisen Rearrangement.

A divergent synthetic methodology for a tabernaemontanine-related alkaloid was developed. The synthetic route features practical improvements in the Pictet-Spengler cyclization for the tetrahydro-ß-carboline intermediate and an unprecedented tandem Reformatsky-aza-Claisen rearrangement to create the core carbon skeleton and stereochemistries of tabernaemontanine-related alkaloids.

Perturbation of maize phenylpropanoid metabolism by an AvrE family type III effector from Pantoea stewartii.

AvrE family type III effector proteins share the ability to suppress host defenses, induce disease-associated cell death, and promote bacterial growth. However, despite widespread contributions to numerous bacterial diseases in agriculturally important plants, the mode of action of these effectors remains largely unknown. WtsE is an AvrE family member required for the ability of Pantoea stewartii ssp. stewartii (Pnss) to proliferate efficiently and cause wilt and leaf blight symptoms in maize (Zea mays) plants. Notably, when WtsE is delivered by a heterologous system into the leaf cells of susceptible maize seedlings, it alone produces water-soaked disease symptoms reminiscent of those produced by Pnss. Thus, WtsE is a pathogenicity and virulence factor in maize, and an Escherichia coli heterologous delivery system can be used to study the activity of WtsE in isolation from other factors produced by Pnss. Transcriptional profiling of maize revealed the effects of WtsE, including induction of genes involved in secondary metabolism and suppression of genes involved in photosynthesis. Targeted metabolite quantification revealed that WtsE perturbs maize metabolism, including the induction of coumaroyl tyramine. The ability of mutant WtsE derivatives to elicit transcriptional and metabolic changes in susceptible maize seedlings correlated with their ability to promote disease. Furthermore, chemical inhibitors that block metabolic flux into the phenylpropanoid pathways targeted by WtsE also disrupted the pathogenicity and virulence activity of WtsE. While numerous metabolites produced downstream of the shikimate pathway are known to promote plant defense, our results indicate that misregulated induction of phenylpropanoid metabolism also can be used to promote pathogen virulence.

Recent Advances in Substrate-Controlled Asymmetric Induction Derived from Chiral Pool α-Amino Acids for Natural Product Synthesis.

Chiral pool α-amino acids have been used as powerful tools for the total synthesis of structurally diverse natural products. Some common naturally occurring α-amino acids are readily available in both enantiomerically pure forms. The applications of the chiral pool in asymmetric synthesis can be categorized prudently as chiral sources, devices, and inducers. This review specifically examines recent advances in substrate-controlled asymmetric reactions induced by the chirality of α-amino acid templates in natural product synthesis research and related areas.

Development of advanced macrosphelides: potent anticancer agents.

Synthetic approaches to macrosphelide derivatives, based on medicinal chemistry, are summarized. This review contains conventional medicinal chemistry approaches, combinatorial chemistry, fluorous tagging techniques and affinity chromatography preparation. In addition, advances in their apoptosis-inducing activities are also included.

Design and synthesis of a macrosphelide A-biotin chimera.

The rational design and synthesis of a biochemical probe of natural (+)-macrosphelide A, a potent cell-cell adhesion inhibitor, was completed to aid in the identification of its biological target. The key features of the synthesis include: (1) an efficient synthesis of the macrosphelide core structure using Yamaguchi-Hirao alkynylation, (2) a cross metathesis to connect a linker unit to the allyl-macrosphelide and (3) coupling of the linker-bound macrosphelide A with a chemical biotin tag.

Synthetic advances in macrosphelides: natural anticancer agents.

Total synthesis of macrosphelides is summarized. Synthetic approaches contain the preparation of key fragments and the final ring-closure reaction for unique 16- or 15-membered macrolactone skeletons.

Development of an advanced synthetic route to macrosphelides and its application to the discovery of a more potent macrosphelide derivative.

The discovery of a more cytotoxic macrosphelide derivative, including its total synthesis and bioassay are described. Application of the Koide protocol to a readily available propagylic alcohol allowed the rapid and practical synthesis of a macrosphelide A skeleton. This strategy enabled the successful improvement of the cytotoxic activity of the macrosphelide derivative.

Ring expansion of vinylaziridines through the strain-release pericyclic reaction: recent developments and applications.

Recent syntheses of azetidines, pyrrolidines, piperidines and azepines through cycloaddition or sigmatropic rearrangements of vinylaziridines are described. Applications to natural product synthesis and mechanistic investigations are also summarized.

Caspase Cleavage of Receptor Tyrosine Kinases in the Dependence Receptor Family.

Dependence receptors are a group of receptor proteins with shared characteristics of transducing two different signals within cells. They can transduce a positive signal of survival and differentiation in the presence of ligands. On the other hand, dependence receptors can transduce an apoptosis signal in the absence of ligands. The function of these receptors depends on the availability of their ligands. Several receptor tyrosine kinases (RTKs) have been reported as dependence receptors. When cells undergo apoptosis by dependence receptors, the intracellular domain of some RTKs is cleaved by the caspases. Among the RTKs that belong to dependence receptors, we focused on eight RTKs (RET, HER2, MET, ALK, TrkC, EphA4, EphB3, and c-KIT) that are cleaved by caspases. In this review, we describe the features of the receptors, their cleavage sites, and the fate of the cleaved products, as well as recent implications on them being used as potential therapeutics for cancer treatment.

Synthesis of tetrasubstituted alkenes via metathesis.

Fully substituted olefin generation via metathesis is presented. Catalyst development, optimization of reaction conditions and substrate screening are included. In addition, asymmetric alkene metathesis, the cross metathesis reaction for this transformation and its application in natural products will be discussed.