An approach to pancratistatins via ring-closing metathesis: efficient synthesis of novel 1-aryl-1-deoxyconduritols F. cv

Structurally novel cyclitols, 1-aryl-1-deoxyconduritols F, were efficiently prepared from d-xylose, utilizing RCM as a key step. Various aromatic residues were incorporated in the cyclitol skeleton with total stereochemical control, utilizing a diastereoselective aryl cuprate addition to a gamma-alkoxy enoate. The synthetic route establishes a firm foundation for a practical synthesis of the antitumor alkaloid pancratistatin and its aryl analogues. [structure: see text]     

Synthesis of new 9-hydroxy-α- and 7-hydroxy-β-pyran naphthoquinones and cytotoxicity against cancer cell lines

A synthetic method to obtain α- and β-pyran naphthoquinones 10 and 11 with a hydroxyl substituent on the aromatic ring was developed. Two series of α- and β-pyran naphthoquinones were obtained from the 8-hydroxy-lawsone, and their anticancer properties were evaluated against four tumor cell lines. In general, the new compounds displayed good activity, possibly indicating that these compounds have increased pro-oxidant capacity. The 9-hydroxy-α-lapachone and 7-hydroxy-β-lapachone analogues of the natural products α-lapachone and β-lapachone were successfully produced by this methodology.     

Synthetic strategies toward the synthesis of polyphenolic natural products: Pauciflorol F and isopaucifloral F: A review

Pauciflorol F and isopaucifloral F are very important polyphenolic natural products and exhibit a variety of biological activities such as antibiotic, anticancer, anti-HIV, antioxidant, antifungal, and anti-inflammatory activities. These important molecules have gained significant attraction of medicinal chemists and several new strategies have been developed toward the synthesis of pauciflorol F and isopaucifloral F. This review article summarizes the major synthetic approaches adopted for the synthesis of these two indanone-based compounds.     

Conduritol F glucosides and terpenoid glucosides from Cynanchum liukiuense and distribution of conduritol F glucosides in several Asclepiadaceous plants

Conduritol F 3-0- and 4-O-glucosides were obtained from Cynanchum liukiuense, along with conduritol F which was identified in all Asclepiadaceous plants examined, Tylophora tanakae, Asclepias curassavica and A. fruticosa, as well as in Marsdenia tomentosa. The pattern of the glucosidic linkage to conduritol F differed between individual species, 2-O-glucoside from T tanakae and M. tomentosa, 3-O-glucoside from A. curassavica, but none from A. fruticosa. Along with conduritol F glucosides, an 11-glucosyloxy-megastigmane and a monoterpenoid glucoside were isolated from C. liukiuense.     

Cyclotrimerization strategy toward analogues of amaryllidaceae constituents. synthesis of deoxygenated pancratistatin core

[chemical reaction: see text]. A derivative of pancratistatin having no oxygenation in the aromatic ring was synthesized by a new strategy based on the cobalt-catalyzed cyclotrimerization of acetylenes as a prelude to diversity-oriented synthesis of further analogues.     

Diastereoselective one-pot Wittig olefination-Michael addition and olefin cross metathesis strategy for total synthesis of cytotoxic natural product (+)-varitriol and its higher analogues

A stereoselective route for the total synthesis of anticancer marine natural product (+)-varitriol (1) is detailed herein. The impressive biological activity and interesting structural features of natural (+)-varitriol fuelled us to undertake the synthesis of some higher analogues (1a-j) of this molecule. The key features of the synthetic strategy include one-pot Wittig olefination followed by a highly diastereoselective oxa-Michael addition to assemble stereochemically pure tetrasubstituted THF moiety of the natural varitriol and olefin cross metathesis to couple the aromatic part with tetrasubstituted THF moiety. The total synthesis of title natural product is efficient with 21.8% overall yield for 9 linear steps from D-ribose and thus facilitates the more scaled-up practical route for the synthesis of 1 and its analogues as well. The synthetic (+)-varitriol (1) and its analogues were screened for their cytotoxicity. The present synthetic approach paves the way for preparation of numerous analogues of the title natural product for drug development.     

Synthesis of Four Diastereomers of Sclerophytin F and Structural Reassignment of Several Sclerophytin Natural Products

Synthesis of the triol that has been proposed to be the marine natural product sclerophytin F has been completed along with the syntheses of three diastereomers. Comparison of the NMR spectroscopic data for all four compounds to the data reported for the natural product reveals that sclerophytin F is not the 3S diastereomer of sclerophytin A as proposed by Friedrich and Paquette. Re‐analysis of the NMR spectroscopic data for known sclerophytin natural products and synthetic analogues leads to the conclusion that sclerophytins E and F are the same compound. This finding has allowed structural reassignment of several other cladiellin natural products.     

Convergent approaches for the synthesis of the antitumoral peptide, Kahalalide F. Study of orthogonal protecting groups

Kahalalide compounds are peptides that are isolated from a Hawaiian herbivorous marine species of mollusc, Elysia rufescens, and its diet, the green alga Bryopsis sp. Kahalalide F and its synthetic analogues are the most promising compounds of the Kahalalide family because they show antitumoral activity. Linear solid-phase syntheses of Kahalalide F have been reported. Here we describe several new improved synthetic routes based on convergent approaches with distinct orthogonal protection schemes for the preparation of Kahaladide analogues. These strategies allow a better control and characterization of the intermediates because more reactions are performed in solution.     

A marked synergistic effect in antitumor activity of salan titanium(IV) complexes bearing two differently substituted aromatic rings

Salan titanium(IV) complexes of differently substituted aromatic rings, where one ring is para-nitrated and another is ortho,para-halogenated, demonstrate exceptionally high anticancer activity, with IC(50) values of <1 μM, exceeding that of cisplatin by ~30-fold. Whereas an additive effect in hydrolytic stability was detected for these highly stable complexes, an unexpected synergistic effect in anticancer activity makes these hybrid complexes substantially more active than both their symmetrical analogues alone and their equimolar mixture.     

Synthesis,biological evaluation and molecular docking study of dihydropyrimidine derivatives as potential anticancer agents

A series of dihydropyrimidine analogues were prepared via one-pot Biginelli three-component condensation reaction and characterized by NMR, FT-IR, MS spectra, and element analysis. Subsequently, they were screened for in vitro anticancer effect. These analogues revealed good cytotoxic activity against three human cancer cell lines including MCF-7, HepG-2, and A549. Among these analogues, compounds 4d and 4h were the most potent against three cell lines. Cell viability assays indicated 4a and 4c had lower cytotoxicity. In vitro cytotoxicity study on all synthesized compounds demonstrated that introduction of electron withdrawing substituents on C4 position of phenyl ring of dihydropyrimidine contributed to the antiproliferative potency. Moreover, in silico molecular docking results stipulated a sign of good correlation between experimental activity and calculated binding affinity. It proved 4d and 4h as the strongest compounds. Binding modes of analogues proposed the involvement of hydrophobic interactions and hydrogen bonds with Eg5 active site. Structure activity relationship studies indicated that incorporating electron withdrawing substituents on C4 position of phenyl ring of dihydropyrimidine are important for this biological activity.     

Parvaxanthines D–F and Asponguanosines C and D,Racemic Natural Hybrids from the Insect Cyclopelta parva

Five new compounds including three pairs of enantiomeric xanthine analogues, parvaxanthines D–F (1–3), two new guanosine derivatives, asponguanosines C and D (6 and 7), along with two known adenine derivatives were isolated from the insect Cyclopelta parva. Racemic 1–3 were further separated by chiral HPLC. Their absolute configurations were assigned by spectroscopic and computational methods. It is interesting that all of these isolates are natural product hybrids. Antiviral, immunosuppressive, antitumor and anti-inflammatory properties of all the isolates were evaluated.     

Synthesis,Antitumor and Antibacterial Studies of New Shortened Analogues of (KLAKLAK)2-NH2 and Their Conjugates Containing Unnatural Amino Acids

(1) Background: (KLAKLAK)₂ is a representative of the antimicrobial peptide group which also shows good anticancer properties. (2) Methods: Herein, we report synthesis using SPPS and characterization by HPLC/MS of a series of shortened analogues of (KLAKLAK)₂. They contain single sequence KLAKLAK as C-terminal amides. In addition, substitution of some natural amino acids with unnatural β-Ala and nor-Leu is realized. In addition, these structures are conjugated with second pharmacophore with well proven anticancer properties 1,8-naphthalimide or caffeic acid. Cytotoxicity, antiproliferative effect and antimicrobial activity of newly synthesized structures were studied. (3) Results: The obtained experimental results reveal significant selective index for substances with common chemical structure KLβAKLβAK-NH₂. The antibacterial properties of newly synthesized analogues at two different concentrations 10 μM and 20 μM, were tested against Gram-negative microorganisms Escherichia coli K12 407. Only two of the studied compounds KLAKLAK-NH₂ and the one conjugated with second pharmacophore 1,8-naphthalimide and unnatural amino acid nor-Leu showed moderate activity against tested strains at concentration of 20 μM. (4) Conclusions: The obtained results reveal that the introducing of 1,8-naphthalimideGly- and Caf- increase the cytotoxicity and antiproliferative activity of the peptides but not their selectivity. Only two compounds KLAKLAK-NH₂ and 1,8-naphthalimideGKnLAKnLAK-NH₂ show moderate activity against Escherichia coli K12 at low concentration of 20 μM.     

A survey of marine natural compounds and their derivatives with anti-cancer activity reported in 2010

Although considerable progress in oncology therapeutics has been achieved in the last century, cancer remains one of major death causes in the World and for this reason, the development of novel cancer drugs remains a pressing need. Natural marine compounds represent an interesting source of novel leads with potent chemotherapeutic or chemo-preventive activities. In the last decades, structure-activity-relationship studies have led to the development of naturally-derived or semi-synthetic analogues with improved bioactivity, a simplified synthetic target or less toxicity. We aim here to review a selection of natural compounds with reported anticancer activity isolated of marine sources and their associated analogues published in 2010.     

Total Synthesis of the Natural Chalcone Lophirone E,Synthetic Studies toward Benzofuran and Indole-Based Analogues,and Investigation of Anti-Leishmanial Activity

The potential of natural and synthetic chalcones as therapeutic leads against different pathological conditions has been investigated for several years, and this class of compounds emerged as a privileged chemotype due to its interesting anti-inflammatory, antimicrobial, antiviral, and anticancer properties. The objective of our study was to contribute to the investigation of this class of natural products as anti-leishmanial agents. We aimed at investigating the structure–activity relationships of the natural chalcone lophirone E, characterized by the presence of benzofuran B-ring, and analogues on anti-leishmania activity. Here we describe an effective synthetic strategy for the preparation of the natural chalcone lophirone E and its application to the synthesis of a small set of chalcones bearing different substitution patterns at both the A and heterocyclic B rings. The resulting compounds were investigated for their activity against Leishmania infantum promastigotes disclosing derivatives 1 and 28a,b as those endowed with the most interesting activities (IC₅₀ = 15.3, 27.2, 15.9 μM, respectively). The synthetic approaches here described and the early SAR investigations highlighted the potential of this class of compounds as antiparasitic hits, making this study worthy of further investigation.     

Design,Synthesis, and Anticancer Activity of New Oxadiazolyl‐Linked and Thiazolyl‐Linked Benzimidazole Arylidines,Thioglycoside, and Acyclic Analogs

2‐[(4‐Thiazolylmethyl)thio]‐1H‐benzimidazole 3 was prepared and was allowed to react with ethyl chloroactate then with hydrazine hydrate to afford the hydrazide derivative 5 , which was then reacted with aromatic aldehydes to afford the corresponding arylidine derivatives 6 – 9 . Heterocyclization of the latter hydrazones with acetic anhydride afforded the substituted 1,3,4‐oxadiazoline derivatives 10 – 13 . In addition, new ((thiazolyl)imidazolyl) oxadiazole thioglycoside and acyclic‐C nucleoside analog were prepared via heterocylization of the hydrazide 5 then glycosylation with α‐acetobromoglucose or condensation with D‐xylose, respectively. All the new compounds were structurally characterized. The anticancer activity of some of the newly synthesized compounds was studied against human breast cancer cells (MCF‐7). The results of the anticancer activity showed that compounds 8 , 11 , 12 , 17 , and 18 revealed high activities superior to Doxorubicin; however, the other derivatives showed moderate to low inhibition activities against human breast cancer cells. Docking studies into CDK2 enzyme were investigated, which supported the anticancer activity results.     

弥拜霉素类似物的合成、表征和杀虫活性研究

以弥拜霉素类似物依维菌素为原料,根据类同合成法和亚结构连接法原理,对依维菌素进行脱糖,再与相应的酰氯进行酯化、肟化反应制得两个系列弥拜霉素类似物化合物4Ia～5IId,所有目标化合物都通过核磁共振氢谱、高分辨质谱的确认,并分别对朱砂叶螨(Tetranychus cinnabarinus)、南方粘虫(Mythimna sepatara)和蚕豆蚜(Aphis fabae)进行室内杀虫活性测定,结果表明所有衍生物均表现出不同程度的杀虫活性,其中化合物4IIa和4IIb对粘虫和蚜虫表现出很高的杀虫活性.     

Herbicidal Activity of Phosphonic,Phosphinic and Phosphinous Acid Analogues of Aromatic Amino Acids

Abstract

Over 40 phosphonic, phosphinic and phosphinous acid analogues of phenylglycine and phenylalanine were synthesized and screened for their herbicidal activity on Lepidium sativum (crest) and Cucumis sativus (cucumber). The most active appeared to be 2-amino-1-hydroxy-3-phenylpropylphosphonic acid which was equipotent with popular herbicide glyphosate. Also aminobenzylphosphonic acids, analogues of phenylglycine, exhibited notable herbicidal activity and thus represent a group of the most active herbicides found among simple aminophosphonic acids. Other compounds showed moderate herbicidal activity. Preliminary results indicate that analogues of aromatic amino acids display their activity as effectors of biosynthesis of aromatic amino acids.     

Synthesis, characterization, and antioxidant activity of some ebselen analogues

Simple synthetic routes for several analogues of the anti-inflammatory organoselenium drug, ebselen, are described. The compounds are characterized by (1)H, (13)C, and (77)Se NMR spectroscopy and mass spectral techniques and, in some cases, by single-crystal X-ray diffraction studies. The glutathione peroxidase (GPx)-like antioxidant activity has been studied by using H(2)O(2), tBuOOH, and Cum-OOH as substrates, and thiophenol (PhSH, 4-Me-C(6)H(4)SH) and glutathione (GSH) as cosubstrates. Density functional theory (DFT) calculations have been performed on these systems to understand the effects of various substituents on the (77)Se NMR chemical shifts; these results have been compared with the experimental data. The experimental and theoretical results suggest that the presence of a phenyl substituent on the nitrogen atom is important for the antioxidant activity of ebselen. While ebselen and its analogues are poor catalysts in aromatic thiol assays, these compounds exhibit high GPx activity when GSH is used as the cosubstrate. The poor catalytic activity of ebselen analogues in the presence of aromatic thiols such as PhSH and 4-Me-C(6)H(4)SH can be ascribed to the undesired thiol exchange reaction that takes place at the selenium center due to SeO nonbonding interactions. To understand the effects of different peroxides on the catalytic activities, we have determined the initial rates at various concentrations of GSH and peroxides. These data suggest that the nature of peroxide has little effect on the catalytic efficiencies, although the initial reaction rates observed with hydrogen peroxide were found to be higher than that with tBuOOH and Cum-OOH. In contrast to the effect of peroxides, the nature of thiols appears to have a dramatic effect on the catalytic activity of ebselen and its related derivatives.     

Design,Synthesis, and In Vitro Evaluation of Novel Indolyl DiHydropyrazole Derivatives as Potential Anticancer Agents

Indoles derived from both natural sources or artificial synthetic methods have been known to interact with aryl hydrocarbon receptors (AhR), and exhibit anticancer activity. In light of these attractive properties, a series of hybrid molecules with structural features of indoles, i.e., those bearing a pyrazoline nucleus, were evaluated for their enhanced anticancer activity. The designed molecules were subjected to molecular docking in order to screen for potential AhR interacting compounds, and the identified indolyl dihydropyrazole derivatives were synthesized. The synthesized compounds were characterized, and their cytotoxicity was evaluated against four human cancer cell lines using the MTT assay. Based on the Glide g-score, H-bonding interactions and bonding energy of 20 candidate molecules were selected for further analysis from the 64 initially designed molecules. These candidate molecules have shown promising anti-proliferative activity against the cell lines tested. Among these candidate molecules, the compounds with hydroxy phenyl substitution on the pyrazoline ring have shown potent activity across all the tested cell lines. The designed scaffold was proven effective for screening potential candidate molecules with anticancer properties, and may be further optimized structurally for yielding the ideal anti-tumorigenic compound for the treatment of various cancers.