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Flavonoids are a group of natural polyphenolic substances that are abundant in vegetables, fruits, grains, and tea. Chiral A-ring-containing flavonoids are an important group of natural flavonoid derivatives applicable in a wide range of biological activities such as, cytotoxic, anti-inflammatory, anti-microbial, antioxidant, and enzyme inhibition. The desirable development of chiral A-ring-containing flavonoids by isolation, semi-synthesis or total synthesis in a short duration proves their great value in medicinal chemistry research. In this review, the research progress of chiral A-ring-containing flavonoids, including isolation and extraction, structural identification, pharmacological activities, and synthetic methods, is comprehensively and systematically summarized. Furthermore, we provide suggestions for future research on the synthesis and biomedical applications of flavonoids.

A new fluorine-containing chalcohalide, Ba4GaS4F3, has been synthesized by conventional high-temperature solid-state reaction. The compound crystallizes in the centrosymmetric space group I41/a with a = b = 16.628 (5) A, c = 17.139 (10) A, Z = 16. Experimental and theoretical results confirm that Ba4GaS4F3 is a direct band gap compound with an experimental band gap of about 3.13 eV, and the band gap is mainly determined by the Ba-5p, F-2p and S-3p orbitals. What's more, different from the many newly discovered chalcohalides in the Ba3AM4Q (A = Ga, In; M = S, Se; Q = Cl, Br, I) family, Ba4GaS4F3 is the first reported compound in the Ba4AM4D3 (A = Ga, In; M = chalcogen; D = halogen) family. The results enrich the structural diversity of metal chalcohalides.

NUMB is an endocytic adaptor protein that contains four isoforms (p65, p66, p71 and p72) due to alternative splicing regulation. Here, we show that NUMB exon12 (E12)-skipping isoforms p65/p66 promote epithelial to mesenchymal transition (EMT) and cancer cell migration in vitro, and facilitate cancer metastasis in mice, whereas E12-included p71/p72 isoforms attenuate these effects. Mechanistically, p65/p66 isoforms significantly increase the sorting of Notch1 through early endosomes (EEs) for enhanced Notch1 activity. In contrast, p71/p72 isoforms act as negative regulators of Notch1 by ubiquitylating the Notch1 intracellular domain (N1ICD) and promoting its degradation. Moreover, we observed that the interaction between N1ICD and SMAD3 is important for their own stabilization, and for NUMB-mediated EMT response and cell migration. Either N1ICD or SMAD3 overexpression could significantly recuse the migration reduction seen in the p65/p66 knockdown, and Notch1 or SMAD3 knockdown rescued the migration advantage seen in the overexpression of p66. Taken all together, our study provides mechanistic insights into the opposite regulation of Notch1-SMAD3 crosstalk by NUMB isoforms and identifies them as critical regulators of EMT and cancer cell migration.

Folic acid, as a significant vitamin, is essential for human bodies, especially for pregnant women. However, folic acid hydrogel for drug delivery has not been reported until now. Herein, folic acid hydrogel was prepared by ion inducing method firstly. Then β-cyclodextrin/camptothecin inclusion complex was loaded into folic acid hydrogel successfully by co-assembly. Camptothecin loading folic acid hydrogel has good rheological mechanical property and thermodynamic stability. Moreover, the possible mechanism of hydrogel formation was proposed by energy dispersive spectrometer and small-angle X-ray scattering. Besides, compared to camptothecin itself, camptothecin release rate from camptothecin loaded hydrogel was prolongated remarkably through dialysis experiment. Finally, the cell inhibitory rate of camptothecin loading folic acid hydrogel was increased observably compared to camptothecin itself. Hence, as a green drug delivery system, our folic acid hydrogel has important potential application in medical engineering material. Herein, a novel β-cyclodextrin/camptothecin inclusion complex loaded folic acid hydrogel was constructed by elaborate design and preparation, which can load camptothecin into folic acid hydrogel effectively. Moreover, compared to camptothecin itself, camptothecin release rate from camptothecin loaded hydrogel was prolongated remarkably through dialysis experiment. Finally, the cell inhibitory rate of camptothecin loading folic acid hydrogel was increased observably compared to camptothecin itself. Hence, as a green drug delivery system, our folic acid hydrogel has important potential application in medical engineering material.

Phytochemicals are natural small-molecule compounds derived from plants that have attracted attention for their anticancer activities. Some phytochemicals have been developed as first-line anticancer drugs, such as paclitaxel and vincristine. In addition, several phytochemicals show good tumor suppression functions in various cancer types. Bladder cancer is a malignant tumor of the urinary system. To date, few specific phytochemicals have been used for bladder cancer therapy, although many have been studied in bladder cancer cells and mouse models. Therefore, it is important to collate and summarize the available information on the role of phytochemicals in the prevention and treatment of bladder cancer. In this review, we summarize the effects of several phytochemicals including flavonoids, steroids, nitrogen compounds, and aromatic substances with anticancer properties and classify the mechanism of action of phytochemicals in bladder cancer. This review will contribute to facilitating the development of new anticancer drugs and strategies for the treatment of bladder cancer using phytochemicals.

A new fluorine-containing chalcohalide, Ba4GaS4F3, has been synthesized by conventional high-temperature solid-state reaction. The compound crystallizes in the centrosymmetric space group I41/a with a = b = 16.628 (5) Å, c = 17.139 (10) Å, Z = 16. Experimental and theoretical results confirm that Ba4GaS4F3 is a direct band gap compound with an experimental band gap of about 3.13 eV, and the band gap is mainly determined by the Ba-5p, F-2p and S-3p orbitals. What's more, different from the many newly discovered chalcohalides in the Ba3AM4Q (A = Ga, In; M = S, Se; Q = Cl, Br, I) family, Ba4GaS4F3 is the first reported compound in the Ba4AM4D3 (A = Ga, In; M = chalcogen; D = halogen) family. The results enrich the structural diversity of metal chalcohalides.

A series of quaternary chalcogenides, Na3ZnMIIIQ4 (MIII = In, Ga; Q = S, Se), were successfully synthesized for the first time through a high temperature solid-state reaction method. All of them exhibit similar structures and crystallize in the I41/acd space group of the tetragonal system. In their structures, typical super-tetrahedron (T2-type) clusters composed of four vertex-sharing (Zn/MIII)S4 tetrahedra are discovered and these T2-clusters further link together to form interesting wavelike chains. Adjacent T2 clusters present a torsion angle of 24.6° with each other when viewed along the c-axis, which has rarely been found among all the reported T2-containing chalcogenides. Moreover, we have systematically investigated the connection modes of NaSn (n = 4–6) in all the known Na-contained quaternary sulfides, and the result shows that the connection modes (corner-, edge-, and face-sharing) of NaS6 ligands in the title sulfides are also rarely (only 3%) found. Besides, the optical properties including diffuse-reflection and Raman spectra are systematically characterized. Theoretical calculations based on the first principles theory were also used to analyze their structure–performance relationships.

The first total synthesis of zalypsis and the practical synthesis of phthalascidin (Pt-650) are achieved through the Pictet-Spengler cyclization coupling strategy. The direct iodination of the primary alcohol in trihydroxyl intermediate 26 followed by SN2 reaction with potassium phthalimide is employed to rapidly introduce the required amino functionality at C-22 on the pentacyclic framework. By the approaches, the two antitumor agents can be obtained from sesamol or N-Cbz- l -tyrosine with ca. 8%-10% overall yield.

The first synthesis of (+)-botryolide-E and its C-7 epimer has been achieved in 8 steps from d -Glucono-δ-lactone, and their antibiotic activities were also investigated preliminarily.

A concise formal synthesis of ecteinascidin 743 is described. Key features involve the coupling of the multisubstituted tetrahydroisoquinoline and phenylalaninol moieties via a regio- and stereoselective Pictet-Spengler cyclization as well as the subsequent chemoselective MOM protection of the phenol group, which opens a rapid access to the desirable pentacycle. The synthesis successfully delivered the advanced intermediate with the characteristic macrolactone from sesamol in 23 steps.

A series of quaternary chalcogenides, Na

A new strategy for the synthesis of l -3,4,5-trioxygenated phenylalanine derivatives from l -tyrosine is developed for the first time. The approach, featuring the transformation of aryl diiodide to bis-phenol via a one-pot procedure including lithiation, boronation, and oxidation, is highly practical. By this robust protocol, N-protected l -3,5-bis(tert-butyldimethylsilyloxy)-4-methoxy-phenylalanine and l -3,4,5-trimethoxy-phenylalanine derivatives were obtained from l -tyrosine in 9 steps with 36–40% overall yields.

(−)-Renieramycin T, an interesting tetrahydroisoquinolinequinone alkaloid with a novel renieramycin–ecteinascidin mixed framework, is synthesized from the known phenol 16 in 22 steps with 6.2% overall yield. In the convergent route, the key cyclocondensation between the isoquinoline moiety 27 and trisubstituted phenylalaninol 14 is achieved with good selectivity to furnish bistetrahydroisoquinoline 29, which permits a rapid construction of the pentacyclic framework having a fully substituted aromatic A ring.

An approach to the synthesis of the multisubstituted ­tetrahydroisoquinoline featuring an asymmetric Ugi reaction of α-amino acid, aromatic aldehyde and an isocyanide has been developed. The promising utility of the strategy is demonstrated by a ­synthesis of an enantiopure functionalized 1,3- trans -tetrahydroisoquinolin-4-ol from natural l -valine. The configuration of the two stereocenters at C-1 and C-4, generated in the Ugi reaction and Pomeranz–Fritsch-type cyclization separately, was controlled very well and determined by NMR studies.

A new catalytic Ugi-type condensation of α-isocyanoacetamide and chiral cyclic imine is developed, where the combination of phenyl phosphilic acid and trifluoroethanol is exploited to promote the Ugi-type condensation with α-isocyanoacetamide for the first time. Under this new catalytic system, the reaction using the cyclic imines as relatively inertial substrates proceed well, and chiral 3-oxazolyl-morpholin/piperazine-2-one derivatives are synthesized with high yield and stereoselectivity. Furthermore, transformation of the condensation product to a novel fused tricyclic structure is attempted initially by treatment with maleic anhydride.

A series of chiral 5,6-dihydro-1,4-oxazin-2-one substrates, as preformed cyclic aldimines and ketoimines, were employed to develop a new asymmetric Ugi three-component reaction for the first time. The Ugi reaction of the imines, isocyanides, and carboxylic acids opens an efficient access to novel morpholin-2-one-3-carboxamide compounds. The chiral imines showed promising stereoinduction for the new chiral center of the Ugi products, and predominant trans-isomers were obtained in the most cases. Addition of some Lewis acids or proton acids could improve the diastereoselectivity further but usually led to a drop in total yield. The Ugi-3CR could be extended to the stereoselective synthesis of ketopiperazine-2-carboxamide derivatives.

A series of 5-substituted morpholin-2-one-3-carbox-amide derivatives were efficiently synthesized by a Ugi three-component reaction involving chiral 5,6-dihydro[1,4]oxazin-2-one substrates, isocyanides and carboxylic acids. The newly formed chiral center in the product was obtained in good diastereoselectivity.

A practical procedure to regioselectively install a methyl group and a phenolic hydroxyl group onto l -tyrosine was developed. By using this approach, protected l -3-hydroxy-4-methoxy-5-methyl-phenylalanine and l -3-hydroxy-4-methoxy-5-methyl-phenylalanol, which are utilized in efficient syntheses of the relevant tetrahydroisoquinoline alkaloids, were prepared conveniently with high yield.

A flexible protocol for the asymmetric synthesis of renieramycin-type alkaloids, such as Renieramycin G (III) and Jorunnamycin A (IV), in which the spontaneous lactamization of (I) after N-deprotection is employed to construct the pentacyclic framework is described.

Three renieramycin-type antitumor alkaloids, (−)-jorunnamycins A (1) and C (2) and (−)-jorumycin (3), have been synthesized by a new convergent approach, which features a highly regio- and stereoselective Pictet–Spengler cyclization to couple the isoquinoline and the trisubstituted phenylalaninol partners. This synthetic strategy opens an economical access to these important antitumor alkaloids with high yields: (−)-jorunnamycin A, as a common precursor to other renieramycin-type alkaloids and their analogues, is obtained with 18.1% overall yield from l-tyrosine.

The title reaction allows a new and highly stereoselective access to oxazole derivatives of type (III) and (XIII).

The optimized conditions allow a highly diastereoselective synthesis of oxazole-substituted heterocyclic systems.

Treatment of chiral cyclic imines like (I) and (VII) with acids and isocyanides allows an efficient and stereoselective access to novel morpholines.

A flexible and practical protocol for the asymmetric synthesis of renieramycin-type antitumor alkaloids is described, in which the stereoselective Pictet-Spengler cyclization of amino ester 16 and aldehyde 15 by regulating temperature and the automatic lactamization after N-deprotection of the cyclization product are exploited to rapidly construct the common pentacyclic framework. (-)-Renieramycin G and (-)-jorunnamycin A, as representative members of the two subgroup renieramycin-type alkaloids, are obtained in 19 steps from l-tyrosine with 15.8% and 14.3% overall yield respectively.